Conference Coverage

While the likelihood of a cesarean delivery usually drops as maternal education level increases, the disparities seen in cesarean rates between White and Black or Hispanic women actually increase with more maternal education, according to findings from a new study presented at the Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.

Typically, higher maternal education is associated with a lower likelihood of cesarean delivery, but this protective effect is much smaller for Black women and nonexistent for Hispanic women, leading to bigger gaps between these groups and White women, found Yael Eliner, MD, an ob.gyn. residency applicant at Boston University who conducted this research with her colleagues in the ob.gyn. department at Lenox Hill Hospital, New York, and Hofstra University, Hempstead, N.Y..

Researchers have previously identified racial and ethnic disparities in a wide range of maternal outcomes, including mortality, overall morbidity, preterm birth, low birth weight, fetal growth restriction, hypertensive disorders of pregnancy, diabetes, and cesarean deliveries. But the researchers wanted to know if the usual protective effects seen for cesarean deliveries existed in the racial and ethnic groups with these disparities. Past studies have already found that the protective effect of maternal education is greater for White women than Black women with infant mortality and overall self-rated health.

The researchers conducted a retrospective analysis of all low-risk nulliparous, term, singleton, vertex live births to U.S. residents from 2016 to 2019 by using the natality database of the Centers for Disease Control and Prevention. They looked only at women who were non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic women. They excluded women with pregestational and gestational diabetes, chronic hypertension, and hypertensive disorders of pregnancy.

Maternal education levels were stratified into those without a high school diploma, high school graduates (including those with some college credit), college graduates, and those with advanced degrees. The total population included 2,969,207 mothers with a 23.4% cesarean delivery rate.

Before considering education or other potential confounders, the cesarean delivery rate was 27.4% in Black women and 25.6% in Asian women, compared with 22.4% in White women and 23% in Hispanic women (P < .001).

Among those with less than a high school education, Black (20.9%), Asian (23.1%), and Hispanic (17.9% cesarean delivery prevalence was greater than that among White women (17.2%) (P < .001). The same was true among those with a high school education (with or without some college): 22% of White women in this group had cesarean deliveries compared with 26.3% of Black women, 26.3% of Asian women, and 22.5% of Hispanic women (P < .001).

At higher levels of education, the disparities not only persisted but actually increased.

The prevalence of cesarean deliveries was 23% in White college graduates, compared with 32.5% of Black college graduates, 26.3% of Asian college graduates, and 27.7% of Hispanic college graduates (P < .001). Similarly, in those with an advanced degree, the prevalence of cesarean deliveries in their population set was 23.6% of Whites, 36.3% of Blacks, 26.1% of Asians, and 30.1% of Hispanics (P < .001).

After adjusting for maternal education as well as age, prepregnancy body mass index, weight gain during pregnancy, insurance type, and neonatal birth weight, the researchers still found substantial disparities in cesarean delivery rates. Black women had 1.54 times greater odds of cesarean delivery than White women (P < .001). Similarly, the odds were 1.45 times greater for Asian women and 1.24 times greater for Hispanic women (P < .001).

Controlling for race, ethnicity, and the other confounders, women with less than a high school education or a high school diploma had similar likelihoods of cesarean delivery. The likelihood of a cesarean delivery was slightly reduced for women with a college degree (odds ratio, 0.93) or advanced degree (OR, 0.88). But this protective effect did not dampen racial/ethnic disparities. In fact, even greater disparities were seen at higher levels of education.

“At each level of education, all the racial/ethnic groups had significantly higher odds of a cesarean delivery than White women,” Dr. Eliner said. “Additionally, the racial/ethnic disparity in cesarean delivery rates increased with increasing level of education, and we specifically see a meaningful jump in the odds ratio at the college graduate level.”

She pointed out that the OR for cesarean delivery in Black women was 1.4 times greater than White women in the group with less than a high school education and 1.44 times greater in those with high school diplomas. Then it jumped to 1.69 in the college graduates group and 1.7 in the advanced degree group.

Higher maternal education was associated with a lower likelihood of cesarean delivery in White women and Asian women. White women with advanced degrees were 17% less likely to have a cesarean than White women with less than a high school education, and the respective reduction in risk was 19% for Asian women.

In Black women, however, education has a much smaller protective effect: An advanced degree reduced the odds of a cesarean delivery by only 7% and no significant difference showed up between high school graduates and college graduates, Dr. Eliner reported.

In Hispanic women, no protective effect showed up, and the odds of a cesarean delivery actually increased slightly in high school and college graduates above those with less than a high school education.

Dr. Eliner discussed a couple possible reasons for a less protective effect from maternal education in Black and Hispanic groups, including higher levels of chronic stress found in past research among racial/ethnic minorities with higher levels of education.

“The impact of racism as a chronic stressor and its association with adverse obstetric and prenatal outcomes is an emerging theme in health disparity research and is yet to be fully understood,” Dr. Eliner said in an interview. “Nonetheless, there is some evidence suggesting that racial/ethnic minorities with higher levels of education suffer from higher levels of stress.”

Implicit and explicit interpersonal bias and institutional racism may also play a role in the disparities, she said, and these factors may disproportionately affect the quality of care for more educated women. She also suggested that White women may be more comfortable advocating for their care.

“While less educated women from all racial/ethnic groups may lack the self-advocacy skills to discuss their labor course, educated White women may be more confident than women from educated minority groups,” Dr. Eliner told attendees. “They may therefore be better equipped to discuss the need for a cesarean delivery with their provider.”

Dr. Eliner elaborated on this: “Given the historical and current disparities of the health care system, women in racial/ethnic minorities may potentially be guarded in their interaction with medical professionals, with a reduced trust in the health care system, and may thus not feel empowered to advocate for themselves in this setting,” she said.

Allison Bryant Mantha, MD, MPH, vice chair for quality, equity, and safety in the ob.gyn. department at Massachusetts General Hospital, Boston, suggested that bias and racism may play a role in this self-advocacy as well.

“I’m wondering if it might not be equally plausible that the advocacy might be met differently by who’s delivering the message,” Dr. Bryant Mantha said. “I think from the story of Dr. Susan Moore and patients who advocate for themselves, I think that we know there is probably some differential by who’s delivering the message.”

Finally, even though education is usually highly correlated with income and frequently used as a proxy for it, but the effect of education on income varies by race/ethnicity.

Since education alone is not sufficient to reduce these disparities, potential interventions should focus on increasing awareness of the disparities and the role of implicit bias, improving patients’ trust in the medical system, and training more doctors from underrepresented groups, Dr. Eliner said.

“I was also wondering about the overall patient choice,” said Sarahn M. Wheeler, MD, an assistant professor of ob.gyn. at Duke University Medical Center in Durham, N.C., who comoderated the session with Dr. Bryant Mantha. “Did we have any understanding of differences in patient values systems that might go into some of these differences in findings as well? There are lots of interesting concepts to explore and that this abstract brings up.”

Dr. Eliner, Dr. Wheeler, and Dr. Bryant Mantha had no disclosures.
 

While the likelihood of a cesarean delivery usually drops as maternal education level increases, the disparities seen in cesarean rates between White and Black or Hispanic women actually increase with more maternal education, according to findings from a new study presented at the Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.

Typically, higher maternal education is associated with a lower likelihood of cesarean delivery, but this protective effect is much smaller for Black women and nonexistent for Hispanic women, leading to bigger gaps between these groups and White women, found Yael Eliner, MD, an ob.gyn. residency applicant at Boston University who conducted this research with her colleagues in the ob.gyn. department at Lenox Hill Hospital, New York, and Hofstra University, Hempstead, N.Y..

Researchers have previously identified racial and ethnic disparities in a wide range of maternal outcomes, including mortality, overall morbidity, preterm birth, low birth weight, fetal growth restriction, hypertensive disorders of pregnancy, diabetes, and cesarean deliveries. But the researchers wanted to know if the usual protective effects seen for cesarean deliveries existed in the racial and ethnic groups with these disparities. Past studies have already found that the protective effect of maternal education is greater for White women than Black women with infant mortality and overall self-rated health.

The researchers conducted a retrospective analysis of all low-risk nulliparous, term, singleton, vertex live births to U.S. residents from 2016 to 2019 by using the natality database of the Centers for Disease Control and Prevention. They looked only at women who were non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic women. They excluded women with pregestational and gestational diabetes, chronic hypertension, and hypertensive disorders of pregnancy.

Maternal education levels were stratified into those without a high school diploma, high school graduates (including those with some college credit), college graduates, and those with advanced degrees. The total population included 2,969,207 mothers with a 23.4% cesarean delivery rate.

Before considering education or other potential confounders, the cesarean delivery rate was 27.4% in Black women and 25.6% in Asian women, compared with 22.4% in White women and 23% in Hispanic women (P < .001).

Among those with less than a high school education, Black (20.9%), Asian (23.1%), and Hispanic (17.9% cesarean delivery prevalence was greater than that among White women (17.2%) (P < .001). The same was true among those with a high school education (with or without some college): 22% of White women in this group had cesarean deliveries compared with 26.3% of Black women, 26.3% of Asian women, and 22.5% of Hispanic women (P < .001).

At higher levels of education, the disparities not only persisted but actually increased.

The prevalence of cesarean deliveries was 23% in White college graduates, compared with 32.5% of Black college graduates, 26.3% of Asian college graduates, and 27.7% of Hispanic college graduates (P < .001). Similarly, in those with an advanced degree, the prevalence of cesarean deliveries in their population set was 23.6% of Whites, 36.3% of Blacks, 26.1% of Asians, and 30.1% of Hispanics (P < .001).

After adjusting for maternal education as well as age, prepregnancy body mass index, weight gain during pregnancy, insurance type, and neonatal birth weight, the researchers still found substantial disparities in cesarean delivery rates. Black women had 1.54 times greater odds of cesarean delivery than White women (P < .001). Similarly, the odds were 1.45 times greater for Asian women and 1.24 times greater for Hispanic women (P < .001).

Controlling for race, ethnicity, and the other confounders, women with less than a high school education or a high school diploma had similar likelihoods of cesarean delivery. The likelihood of a cesarean delivery was slightly reduced for women with a college degree (odds ratio, 0.93) or advanced degree (OR, 0.88). But this protective effect did not dampen racial/ethnic disparities. In fact, even greater disparities were seen at higher levels of education.

“At each level of education, all the racial/ethnic groups had significantly higher odds of a cesarean delivery than White women,” Dr. Eliner said. “Additionally, the racial/ethnic disparity in cesarean delivery rates increased with increasing level of education, and we specifically see a meaningful jump in the odds ratio at the college graduate level.”

She pointed out that the OR for cesarean delivery in Black women was 1.4 times greater than White women in the group with less than a high school education and 1.44 times greater in those with high school diplomas. Then it jumped to 1.69 in the college graduates group and 1.7 in the advanced degree group.

Higher maternal education was associated with a lower likelihood of cesarean delivery in White women and Asian women. White women with advanced degrees were 17% less likely to have a cesarean than White women with less than a high school education, and the respective reduction in risk was 19% for Asian women.

In Black women, however, education has a much smaller protective effect: An advanced degree reduced the odds of a cesarean delivery by only 7% and no significant difference showed up between high school graduates and college graduates, Dr. Eliner reported.

In Hispanic women, no protective effect showed up, and the odds of a cesarean delivery actually increased slightly in high school and college graduates above those with less than a high school education.

Dr. Eliner discussed a couple possible reasons for a less protective effect from maternal education in Black and Hispanic groups, including higher levels of chronic stress found in past research among racial/ethnic minorities with higher levels of education.

“The impact of racism as a chronic stressor and its association with adverse obstetric and prenatal outcomes is an emerging theme in health disparity research and is yet to be fully understood,” Dr. Eliner said in an interview. “Nonetheless, there is some evidence suggesting that racial/ethnic minorities with higher levels of education suffer from higher levels of stress.”

Implicit and explicit interpersonal bias and institutional racism may also play a role in the disparities, she said, and these factors may disproportionately affect the quality of care for more educated women. She also suggested that White women may be more comfortable advocating for their care.

“While less educated women from all racial/ethnic groups may lack the self-advocacy skills to discuss their labor course, educated White women may be more confident than women from educated minority groups,” Dr. Eliner told attendees. “They may therefore be better equipped to discuss the need for a cesarean delivery with their provider.”

Dr. Eliner elaborated on this: “Given the historical and current disparities of the health care system, women in racial/ethnic minorities may potentially be guarded in their interaction with medical professionals, with a reduced trust in the health care system, and may thus not feel empowered to advocate for themselves in this setting,” she said.

Allison Bryant Mantha, MD, MPH, vice chair for quality, equity, and safety in the ob.gyn. department at Massachusetts General Hospital, Boston, suggested that bias and racism may play a role in this self-advocacy as well.

“I’m wondering if it might not be equally plausible that the advocacy might be met differently by who’s delivering the message,” Dr. Bryant Mantha said. “I think from the story of Dr. Susan Moore and patients who advocate for themselves, I think that we know there is probably some differential by who’s delivering the message.”

Finally, even though education is usually highly correlated with income and frequently used as a proxy for it, but the effect of education on income varies by race/ethnicity.

Since education alone is not sufficient to reduce these disparities, potential interventions should focus on increasing awareness of the disparities and the role of implicit bias, improving patients’ trust in the medical system, and training more doctors from underrepresented groups, Dr. Eliner said.

“I was also wondering about the overall patient choice,” said Sarahn M. Wheeler, MD, an assistant professor of ob.gyn. at Duke University Medical Center in Durham, N.C., who comoderated the session with Dr. Bryant Mantha. “Did we have any understanding of differences in patient values systems that might go into some of these differences in findings as well? There are lots of interesting concepts to explore and that this abstract brings up.”

Dr. Eliner, Dr. Wheeler, and Dr. Bryant Mantha had no disclosures.
 

While the likelihood of a cesarean delivery usually drops as maternal education level increases, the disparities seen in cesarean rates between White and Black or Hispanic women actually increase with more maternal education, according to findings from a new study presented at the Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.

Typically, higher maternal education is associated with a lower likelihood of cesarean delivery, but this protective effect is much smaller for Black women and nonexistent for Hispanic women, leading to bigger gaps between these groups and White women, found Yael Eliner, MD, an ob.gyn. residency applicant at Boston University who conducted this research with her colleagues in the ob.gyn. department at Lenox Hill Hospital, New York, and Hofstra University, Hempstead, N.Y..

Researchers have previously identified racial and ethnic disparities in a wide range of maternal outcomes, including mortality, overall morbidity, preterm birth, low birth weight, fetal growth restriction, hypertensive disorders of pregnancy, diabetes, and cesarean deliveries. But the researchers wanted to know if the usual protective effects seen for cesarean deliveries existed in the racial and ethnic groups with these disparities. Past studies have already found that the protective effect of maternal education is greater for White women than Black women with infant mortality and overall self-rated health.

The researchers conducted a retrospective analysis of all low-risk nulliparous, term, singleton, vertex live births to U.S. residents from 2016 to 2019 by using the natality database of the Centers for Disease Control and Prevention. They looked only at women who were non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic women. They excluded women with pregestational and gestational diabetes, chronic hypertension, and hypertensive disorders of pregnancy.

Maternal education levels were stratified into those without a high school diploma, high school graduates (including those with some college credit), college graduates, and those with advanced degrees. The total population included 2,969,207 mothers with a 23.4% cesarean delivery rate.

Before considering education or other potential confounders, the cesarean delivery rate was 27.4% in Black women and 25.6% in Asian women, compared with 22.4% in White women and 23% in Hispanic women (P < .001).

Among those with less than a high school education, Black (20.9%), Asian (23.1%), and Hispanic (17.9% cesarean delivery prevalence was greater than that among White women (17.2%) (P < .001). The same was true among those with a high school education (with or without some college): 22% of White women in this group had cesarean deliveries compared with 26.3% of Black women, 26.3% of Asian women, and 22.5% of Hispanic women (P < .001).

At higher levels of education, the disparities not only persisted but actually increased.

The prevalence of cesarean deliveries was 23% in White college graduates, compared with 32.5% of Black college graduates, 26.3% of Asian college graduates, and 27.7% of Hispanic college graduates (P < .001). Similarly, in those with an advanced degree, the prevalence of cesarean deliveries in their population set was 23.6% of Whites, 36.3% of Blacks, 26.1% of Asians, and 30.1% of Hispanics (P < .001).

After adjusting for maternal education as well as age, prepregnancy body mass index, weight gain during pregnancy, insurance type, and neonatal birth weight, the researchers still found substantial disparities in cesarean delivery rates. Black women had 1.54 times greater odds of cesarean delivery than White women (P < .001). Similarly, the odds were 1.45 times greater for Asian women and 1.24 times greater for Hispanic women (P < .001).

Controlling for race, ethnicity, and the other confounders, women with less than a high school education or a high school diploma had similar likelihoods of cesarean delivery. The likelihood of a cesarean delivery was slightly reduced for women with a college degree (odds ratio, 0.93) or advanced degree (OR, 0.88). But this protective effect did not dampen racial/ethnic disparities. In fact, even greater disparities were seen at higher levels of education.

“At each level of education, all the racial/ethnic groups had significantly higher odds of a cesarean delivery than White women,” Dr. Eliner said. “Additionally, the racial/ethnic disparity in cesarean delivery rates increased with increasing level of education, and we specifically see a meaningful jump in the odds ratio at the college graduate level.”

She pointed out that the OR for cesarean delivery in Black women was 1.4 times greater than White women in the group with less than a high school education and 1.44 times greater in those with high school diplomas. Then it jumped to 1.69 in the college graduates group and 1.7 in the advanced degree group.

Higher maternal education was associated with a lower likelihood of cesarean delivery in White women and Asian women. White women with advanced degrees were 17% less likely to have a cesarean than White women with less than a high school education, and the respective reduction in risk was 19% for Asian women.

In Black women, however, education has a much smaller protective effect: An advanced degree reduced the odds of a cesarean delivery by only 7% and no significant difference showed up between high school graduates and college graduates, Dr. Eliner reported.

In Hispanic women, no protective effect showed up, and the odds of a cesarean delivery actually increased slightly in high school and college graduates above those with less than a high school education.

Dr. Eliner discussed a couple possible reasons for a less protective effect from maternal education in Black and Hispanic groups, including higher levels of chronic stress found in past research among racial/ethnic minorities with higher levels of education.

“The impact of racism as a chronic stressor and its association with adverse obstetric and prenatal outcomes is an emerging theme in health disparity research and is yet to be fully understood,” Dr. Eliner said in an interview. “Nonetheless, there is some evidence suggesting that racial/ethnic minorities with higher levels of education suffer from higher levels of stress.”

Implicit and explicit interpersonal bias and institutional racism may also play a role in the disparities, she said, and these factors may disproportionately affect the quality of care for more educated women. She also suggested that White women may be more comfortable advocating for their care.

“While less educated women from all racial/ethnic groups may lack the self-advocacy skills to discuss their labor course, educated White women may be more confident than women from educated minority groups,” Dr. Eliner told attendees. “They may therefore be better equipped to discuss the need for a cesarean delivery with their provider.”

Dr. Eliner elaborated on this: “Given the historical and current disparities of the health care system, women in racial/ethnic minorities may potentially be guarded in their interaction with medical professionals, with a reduced trust in the health care system, and may thus not feel empowered to advocate for themselves in this setting,” she said.

Allison Bryant Mantha, MD, MPH, vice chair for quality, equity, and safety in the ob.gyn. department at Massachusetts General Hospital, Boston, suggested that bias and racism may play a role in this self-advocacy as well.

“I’m wondering if it might not be equally plausible that the advocacy might be met differently by who’s delivering the message,” Dr. Bryant Mantha said. “I think from the story of Dr. Susan Moore and patients who advocate for themselves, I think that we know there is probably some differential by who’s delivering the message.”

Finally, even though education is usually highly correlated with income and frequently used as a proxy for it, but the effect of education on income varies by race/ethnicity.

Since education alone is not sufficient to reduce these disparities, potential interventions should focus on increasing awareness of the disparities and the role of implicit bias, improving patients’ trust in the medical system, and training more doctors from underrepresented groups, Dr. Eliner said.

“I was also wondering about the overall patient choice,” said Sarahn M. Wheeler, MD, an assistant professor of ob.gyn. at Duke University Medical Center in Durham, N.C., who comoderated the session with Dr. Bryant Mantha. “Did we have any understanding of differences in patient values systems that might go into some of these differences in findings as well? There are lots of interesting concepts to explore and that this abstract brings up.”

Dr. Eliner, Dr. Wheeler, and Dr. Bryant Mantha had no disclosures.
 

Research has shown that, compared with their urban counterparts, rural cancer patients have higher cancer-related mortality and other negative treatment outcomes.

Among other explanations, the disparity has been attributed to lower education and income levels, medical and behavioral risk factors, differences in health literacy, and lower confidence in the medical system among rural residents (JCO Oncol Pract. 2020 Jul;16(7):422-30).

The COVID-19 and Oncology Patient Experience Consortium

Ms. Daniels explained that the COVID-19 and Oncology Patient Experience (COPES) Consortium was created to investigate various aspects of the patient experience during the pandemic. Three cancer centers – Moffitt Cancer Center, Huntsman Cancer Institute, and the Sylvester Comprehensive Cancer Center – participate in COPES.

At Huntsman, investigators studied social and health behaviors of cancer patients to assess whether there was a difference between those from rural and urban areas. The researchers looked at the impact of the pandemic on psychosocial outcomes, preventive measures patients implemented, and their perceptions of the risk of SARS-CoV-2 infection.

The team’s hypothesis was that rural patients might be more vulnerable than urban patients to the effects of social isolation, emotional distress, and health-adverse behaviors, but the investigators noted that there has been no prior research on the topic.
 

Assessing behaviors, attitudes, and outcomes

Between August and September 2020, the researchers surveyed 1,328 adult cancer patients who had visited Huntsman in the previous 4 years and who were enrolled in Huntsman’s Total Cancer Care or Precision Exercise Prescription studies.

Patients completed questionnaires that encompassed demographic and clinical factors, employment status, health behaviors, and infection preventive measures. Questionnaires were provided in electronic, paper, or phone-based formats. Information regarding age, race, ethnicity, and tumor stage was abstracted from Huntsman’s electronic health record.

Modifications in daily life and social interaction were assessed on a 5-point scale. Changes in exercise habits and alcohol consumption were assessed on a 3-point scale. Infection mitigation measures (the use of face masks and hand sanitizer) and perceptions about the likelihood of SARS-CoV-2 infection were measured.

The rural-urban community area codes system, which classifies U.S. census tracts by measures of population density, urbanization, and daily commuting, was utilized to categorize patients into rural and urban residences.
 

Characteristics of urban and rural cancer patients

There were 997 urban and 331 rural participants. The mean age was 60.1 years in the urban population and 62.6 years in the rural population (P = .01). There were no urban-rural differences in sex, ethnicity, cancer stage, or body mass index.

More urban than rural participants were employed full- or part-time (45% vs. 37%; P = .045). The rural counties had more patients who were not currently employed, primarily due to retirement (77% vs. 69% urban; P < .001).

“No health insurance coverage” was reported by 2% of urban and 4% of rural participants (P = .009), and 85% of all patients reported “good” to “excellent” overall health. Cancer patients in rural counties were significantly more likely to have ever smoked (37% vs. 25% urban; P = .001). In addition, alcohol consumption in the previous year was higher in rural patients. “Every day to less than once monthly” alcohol usage was reported by 44% of urban and 60% of rural patients (P < .001).
 

Changes in daily life and health-related behavior during the pandemic

Urban patients were more likely to report changes in their daily lives due to the pandemic. Specifically, 35% of urban patients and 26% of rural patients said the pandemic had changed their daily life “a lot” (P = .001).

However, there were no major differences between urban and rural patients when it came to changes in social interaction in the past month or feeling lonely in the past month (P = .45 and P = .88, respectively). Similarly, there were no significant differences for changes in alcohol consumption between the groups (P = .90).

Changes in exercise habits due to the pandemic were more common among patients in urban counties (51% vs. 39% rural; P < .001), though similar percentages of patients reported exercising less (44% urban vs. 45% rural) or more frequently (24% urban vs. 20% rural).

In terms of infection mitigation measures, urban patients were more likely to use face masks “very often” (83% vs. 66% rural; P < .001), while hand sanitizer was used “very often” among 66% of urban and 57% of rural participants (P = .05).

Urban participants were more likely than were their rural counterparts to think themselves “somewhat” or “very” likely to develop COVID-19 (22% vs. 14%; P = .04).

It might be short-sighted for oncology and public health specialists to be dismissive of differences in infection mitigation behaviors and perceptions of vulnerability to SARS-CoV-2 infection. Those behaviors and perceptions of risk could lead to lower vaccination rates in rural areas. If that occurs, there would be major negative consequences for the long-term health of rural communities and their medically vulnerable residents.
 

Future directions

Although the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties, the reasons for the disparities are complex and not easily explained by this study.

It is possible that sequential administration of the survey during the pandemic would have uncovered greater variances in attitude and health-related behaviors.

As Ms. Daniels noted, when the survey was performed, Utah had not experienced a high frequency of COVID-19 cases. Furthermore, different levels of restrictions were implemented on a county-by-county basis, potentially influencing patients’ behaviors, psychosocial adjustment, and perceptions of risk.

In addition, there may have been differences in unmeasured endpoints (infection rates, medical care utilization via telemedicine, hospitalization rates, late effects, and mortality) between the urban and rural populations.

As the investigators concluded, further research is needed to better characterize the pandemic’s short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Such studies may yield insights into the various facets of the well-documented “rural health gap” in cancer outcomes and interventions that could narrow the gap in spheres beyond the COVID-19 pandemic.

Ms. Daniels reported having no relevant disclosures.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research has shown that, compared with their urban counterparts, rural cancer patients have higher cancer-related mortality and other negative treatment outcomes.

Among other explanations, the disparity has been attributed to lower education and income levels, medical and behavioral risk factors, differences in health literacy, and lower confidence in the medical system among rural residents (JCO Oncol Pract. 2020 Jul;16(7):422-30).

The COVID-19 and Oncology Patient Experience Consortium

Ms. Daniels explained that the COVID-19 and Oncology Patient Experience (COPES) Consortium was created to investigate various aspects of the patient experience during the pandemic. Three cancer centers – Moffitt Cancer Center, Huntsman Cancer Institute, and the Sylvester Comprehensive Cancer Center – participate in COPES.

At Huntsman, investigators studied social and health behaviors of cancer patients to assess whether there was a difference between those from rural and urban areas. The researchers looked at the impact of the pandemic on psychosocial outcomes, preventive measures patients implemented, and their perceptions of the risk of SARS-CoV-2 infection.

The team’s hypothesis was that rural patients might be more vulnerable than urban patients to the effects of social isolation, emotional distress, and health-adverse behaviors, but the investigators noted that there has been no prior research on the topic.
 

Assessing behaviors, attitudes, and outcomes

Between August and September 2020, the researchers surveyed 1,328 adult cancer patients who had visited Huntsman in the previous 4 years and who were enrolled in Huntsman’s Total Cancer Care or Precision Exercise Prescription studies.

Patients completed questionnaires that encompassed demographic and clinical factors, employment status, health behaviors, and infection preventive measures. Questionnaires were provided in electronic, paper, or phone-based formats. Information regarding age, race, ethnicity, and tumor stage was abstracted from Huntsman’s electronic health record.

Modifications in daily life and social interaction were assessed on a 5-point scale. Changes in exercise habits and alcohol consumption were assessed on a 3-point scale. Infection mitigation measures (the use of face masks and hand sanitizer) and perceptions about the likelihood of SARS-CoV-2 infection were measured.

The rural-urban community area codes system, which classifies U.S. census tracts by measures of population density, urbanization, and daily commuting, was utilized to categorize patients into rural and urban residences.
 

Characteristics of urban and rural cancer patients

There were 997 urban and 331 rural participants. The mean age was 60.1 years in the urban population and 62.6 years in the rural population (P = .01). There were no urban-rural differences in sex, ethnicity, cancer stage, or body mass index.

More urban than rural participants were employed full- or part-time (45% vs. 37%; P = .045). The rural counties had more patients who were not currently employed, primarily due to retirement (77% vs. 69% urban; P < .001).

“No health insurance coverage” was reported by 2% of urban and 4% of rural participants (P = .009), and 85% of all patients reported “good” to “excellent” overall health. Cancer patients in rural counties were significantly more likely to have ever smoked (37% vs. 25% urban; P = .001). In addition, alcohol consumption in the previous year was higher in rural patients. “Every day to less than once monthly” alcohol usage was reported by 44% of urban and 60% of rural patients (P < .001).
 

Changes in daily life and health-related behavior during the pandemic

Urban patients were more likely to report changes in their daily lives due to the pandemic. Specifically, 35% of urban patients and 26% of rural patients said the pandemic had changed their daily life “a lot” (P = .001).

However, there were no major differences between urban and rural patients when it came to changes in social interaction in the past month or feeling lonely in the past month (P = .45 and P = .88, respectively). Similarly, there were no significant differences for changes in alcohol consumption between the groups (P = .90).

Changes in exercise habits due to the pandemic were more common among patients in urban counties (51% vs. 39% rural; P < .001), though similar percentages of patients reported exercising less (44% urban vs. 45% rural) or more frequently (24% urban vs. 20% rural).

In terms of infection mitigation measures, urban patients were more likely to use face masks “very often” (83% vs. 66% rural; P < .001), while hand sanitizer was used “very often” among 66% of urban and 57% of rural participants (P = .05).

Urban participants were more likely than were their rural counterparts to think themselves “somewhat” or “very” likely to develop COVID-19 (22% vs. 14%; P = .04).

It might be short-sighted for oncology and public health specialists to be dismissive of differences in infection mitigation behaviors and perceptions of vulnerability to SARS-CoV-2 infection. Those behaviors and perceptions of risk could lead to lower vaccination rates in rural areas. If that occurs, there would be major negative consequences for the long-term health of rural communities and their medically vulnerable residents.
 

Future directions

Although the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties, the reasons for the disparities are complex and not easily explained by this study.

It is possible that sequential administration of the survey during the pandemic would have uncovered greater variances in attitude and health-related behaviors.

As Ms. Daniels noted, when the survey was performed, Utah had not experienced a high frequency of COVID-19 cases. Furthermore, different levels of restrictions were implemented on a county-by-county basis, potentially influencing patients’ behaviors, psychosocial adjustment, and perceptions of risk.

In addition, there may have been differences in unmeasured endpoints (infection rates, medical care utilization via telemedicine, hospitalization rates, late effects, and mortality) between the urban and rural populations.

As the investigators concluded, further research is needed to better characterize the pandemic’s short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Such studies may yield insights into the various facets of the well-documented “rural health gap” in cancer outcomes and interventions that could narrow the gap in spheres beyond the COVID-19 pandemic.

Ms. Daniels reported having no relevant disclosures.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research has shown that, compared with their urban counterparts, rural cancer patients have higher cancer-related mortality and other negative treatment outcomes.

Among other explanations, the disparity has been attributed to lower education and income levels, medical and behavioral risk factors, differences in health literacy, and lower confidence in the medical system among rural residents (JCO Oncol Pract. 2020 Jul;16(7):422-30).

The COVID-19 and Oncology Patient Experience Consortium

Ms. Daniels explained that the COVID-19 and Oncology Patient Experience (COPES) Consortium was created to investigate various aspects of the patient experience during the pandemic. Three cancer centers – Moffitt Cancer Center, Huntsman Cancer Institute, and the Sylvester Comprehensive Cancer Center – participate in COPES.

At Huntsman, investigators studied social and health behaviors of cancer patients to assess whether there was a difference between those from rural and urban areas. The researchers looked at the impact of the pandemic on psychosocial outcomes, preventive measures patients implemented, and their perceptions of the risk of SARS-CoV-2 infection.

The team’s hypothesis was that rural patients might be more vulnerable than urban patients to the effects of social isolation, emotional distress, and health-adverse behaviors, but the investigators noted that there has been no prior research on the topic.
 

Assessing behaviors, attitudes, and outcomes

Between August and September 2020, the researchers surveyed 1,328 adult cancer patients who had visited Huntsman in the previous 4 years and who were enrolled in Huntsman’s Total Cancer Care or Precision Exercise Prescription studies.

Patients completed questionnaires that encompassed demographic and clinical factors, employment status, health behaviors, and infection preventive measures. Questionnaires were provided in electronic, paper, or phone-based formats. Information regarding age, race, ethnicity, and tumor stage was abstracted from Huntsman’s electronic health record.

Modifications in daily life and social interaction were assessed on a 5-point scale. Changes in exercise habits and alcohol consumption were assessed on a 3-point scale. Infection mitigation measures (the use of face masks and hand sanitizer) and perceptions about the likelihood of SARS-CoV-2 infection were measured.

The rural-urban community area codes system, which classifies U.S. census tracts by measures of population density, urbanization, and daily commuting, was utilized to categorize patients into rural and urban residences.
 

Characteristics of urban and rural cancer patients

There were 997 urban and 331 rural participants. The mean age was 60.1 years in the urban population and 62.6 years in the rural population (P = .01). There were no urban-rural differences in sex, ethnicity, cancer stage, or body mass index.

More urban than rural participants were employed full- or part-time (45% vs. 37%; P = .045). The rural counties had more patients who were not currently employed, primarily due to retirement (77% vs. 69% urban; P < .001).

“No health insurance coverage” was reported by 2% of urban and 4% of rural participants (P = .009), and 85% of all patients reported “good” to “excellent” overall health. Cancer patients in rural counties were significantly more likely to have ever smoked (37% vs. 25% urban; P = .001). In addition, alcohol consumption in the previous year was higher in rural patients. “Every day to less than once monthly” alcohol usage was reported by 44% of urban and 60% of rural patients (P < .001).
 

Changes in daily life and health-related behavior during the pandemic

Urban patients were more likely to report changes in their daily lives due to the pandemic. Specifically, 35% of urban patients and 26% of rural patients said the pandemic had changed their daily life “a lot” (P = .001).

However, there were no major differences between urban and rural patients when it came to changes in social interaction in the past month or feeling lonely in the past month (P = .45 and P = .88, respectively). Similarly, there were no significant differences for changes in alcohol consumption between the groups (P = .90).

Changes in exercise habits due to the pandemic were more common among patients in urban counties (51% vs. 39% rural; P < .001), though similar percentages of patients reported exercising less (44% urban vs. 45% rural) or more frequently (24% urban vs. 20% rural).

In terms of infection mitigation measures, urban patients were more likely to use face masks “very often” (83% vs. 66% rural; P < .001), while hand sanitizer was used “very often” among 66% of urban and 57% of rural participants (P = .05).

Urban participants were more likely than were their rural counterparts to think themselves “somewhat” or “very” likely to develop COVID-19 (22% vs. 14%; P = .04).

It might be short-sighted for oncology and public health specialists to be dismissive of differences in infection mitigation behaviors and perceptions of vulnerability to SARS-CoV-2 infection. Those behaviors and perceptions of risk could lead to lower vaccination rates in rural areas. If that occurs, there would be major negative consequences for the long-term health of rural communities and their medically vulnerable residents.
 

Future directions

Although the first 6 months of the COVID-19 pandemic had disparate effects on cancer patients living in rural and urban counties, the reasons for the disparities are complex and not easily explained by this study.

It is possible that sequential administration of the survey during the pandemic would have uncovered greater variances in attitude and health-related behaviors.

As Ms. Daniels noted, when the survey was performed, Utah had not experienced a high frequency of COVID-19 cases. Furthermore, different levels of restrictions were implemented on a county-by-county basis, potentially influencing patients’ behaviors, psychosocial adjustment, and perceptions of risk.

In addition, there may have been differences in unmeasured endpoints (infection rates, medical care utilization via telemedicine, hospitalization rates, late effects, and mortality) between the urban and rural populations.

As the investigators concluded, further research is needed to better characterize the pandemic’s short- and long-term effects on cancer patients in rural and urban settings and appropriate interventions. Such studies may yield insights into the various facets of the well-documented “rural health gap” in cancer outcomes and interventions that could narrow the gap in spheres beyond the COVID-19 pandemic.

Ms. Daniels reported having no relevant disclosures.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

Despite improvements in prevention of graft-versus-host disease, chronic GVHD still occurs in 10%-50% of patients who undergo an allogeneic hematopoietic stem cell transplant, and these patients may require prolonged treatment with multiple lines of therapy, said a hematologist and transplant researcher.

“More effective, less toxic therapies for chronic GVHD are needed,” Stephanie Lee, MD, MPH, from the Fred Hutchinson Cancer Research Center in Seattle said at the Transplant & Cellular Therapies Meetings.

Dr. Lee reviewed clinical trials for chronic GVHD at the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Although the incidence of chronic GVHD has gradually declined over the last 40 years and both relapse-free and overall survival following a chronic GVHD diagnosis have improved, “for patients who are diagnosed with chronic GVHD, they still will see many lines of therapy and many years of therapy,” she said.

Among 148 patients with chronic GVHD treated at her center, for example, 66% went on to two lines of therapy, 50% went on to three lines, 37% required four lines of therapy, and 20% needed five lines or more.

Salvage therapies for patients with chronic GVHD have evolved away from immunomodulators and immunosuppressants in the early 1990s, toward monoclonal antibodies such as rituximab in the early 2000s, to interleukin-2 and to tyrosine kinase inhibitors such as ruxolitinib (Jakafi) and ibrutinib (Imbruvica).

There are currently 36 agents that are FDA approved for at least one indication and can also be prescribed for the treatment of chronic GVHD, Dr. Lee noted.
 

Treatment goals

Dr. Lee laid out six goals for treating patients with chronic GVHD. They include:

• Controlling current signs and symptoms, measured by response rates and patient-reported outcomes
• Preventing further tissue and organ damage
• Minimizing toxicity
• Maintaining graft-versus-tumor effect
• Achieving graft tolerance and stopping immunosuppression
• Decreasing nonrelapse mortality and improving survival

Active trials

Dr. Lee identified 33 trials with chronic GVHD as an indication that are currently recruiting, and an additional 13 trials that are active but closed to recruiting. The trials can be generally grouped by mechanism of action, and involve agents targeting T-regulatory cells, B cells and/or B-cell receptor (BCR) signaling, monocytes/macrophages, costimulatory blockage, a proteasome inhibition, Janus kinase (JAK) 1/2 inhibitors, ROCK2 inhibitors, hedgehog pathway inhibition, cellular therapy, and organ-targeted therapy.

Most of the trials have overall response rate as the primary endpoint, and all but five are currently in phase 1 or 2. The currently active phase 3 trials include two with ibrutinib, one with the investigational agent itacitinib, one with ruxolitinib, and one with mesenchymal stem cells.

“I’ll note that, when results are reported, the denominator really matters for the overall response rate, especially if you’re talking about small trials, because if you require the patient to be treated with an agent for a certain period of time, and you take out all the people who didn’t make it to that time point, then your overall response rate looks better,” she said.
 

BTK inhibitors

The first-in-class Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first and thus far only agent approved by the Food and Drug Administration for chronic GVHD. The approval was based on a single-arm, multicenter trial with 42 patients.

The ORR in this trial was 69%, consisting of 31% complete responses and 38% partial responses, with a duration of response longer than 10 months in slightly more than half of all patients. In all, 24% of patients had improvement of symptoms in two consecutive visits, and 29% continued on ibrutinib at the time of the primary analysis in 2017.

Based on these promising results, acalabrutinib, which is more potent and selective for BTK than ibrutinib, with no effect on either platelets or natural killer cells, is currently under investigation in a phase 2 trial in 50 patients at a dose of 100 mg orally twice daily.
 

JAK1/2 inhibition

The JAK1 inhibitor itacitinib failed to meet its primary ORR endpoint in the phase 3 GRAVITAS-301 study, according to a press release, but the manufacturer (Incyte) said that it is continuing its commitment to JAK inhibitors with ruxolitinib, which has shown activity against acute, steroid-refractory GVHD, and is being explored for prevention of chronic GVHD in the randomized, phase 3 REACH3 study.

The trial met its primary endpoint for a higher ORR at week 24 with ruxolitinib versus best available therapy, at 49.7% versus 25.6%, respectively, which translated into an odds ratio for response with the JAK inhibitor of 2.99 (P < .0001).
 

Selective T-cell expansion

Efavaleukin alfa is an IL-2-mutated protein (mutein), with a mutation in the IL-2RB-binding portion of IL-2 causing increased selectivity for regulatory T-cell expansion. It is bound to an IgG-Fc domain that is itself mutated, with reduced Fc receptor binding and IgG effector function to give it a longer half life. This agent is being studied in a phase 1/2 trial in a subcutaneous formulation delivered every 1 or 2 weeks to 68 patients.

Monocyte/macrophage depletion

Axatilimab is a high-affinity antibody targeting colony stimulating factor–1 receptor (CSF-1R) expressed on monocytes and macrophages. By blocking CSF-1R, it depletes circulation of nonclassical monocytes and prevents the differentiation and survival of M2 macrophages in tissue.

It is currently being investigated 30 patients in a phase 1/2 study in an intravenous formulation delivered over 30 minutes every 2-4 weeks.
 

Hedgehog pathway inhibition

There is evidence suggesting that hedgehog pathway inhibition can lessen fibrosis. Glasdegib (Daurismo) a potent selective oral inhibitor of the hedgehog signaling pathway, is approved for use with low-dose cytarabine for patients with newly diagnosed acute myeloid leukemia aged older than 75 years or have comorbidities precluding intensive chemotherapy.

This agent is associated with drug intolerance because of muscle spasms, dysgeusia, and alopecia, however.

The drug is currently in phase 1/2 at a dose of 50 mg orally per day in 20 patients.
 

ROCK2 inhibition

Belumosudil (formerly KD025) “appears to rebalance the immune system,” Dr. Lee said. Investigators think that the drug dampens an autoaggressive inflammatory response by selective inhibition of ROCK2.

This drug has been studied in a dose-escalation study and a phase 2 trial, in which 132 participants were randomized to receive belumosudil 200 mg either once or twice daily.

At a median follow-up of 8 months, the ORR with belumosudil 200 mg once and twice daily was 73% and 74%, respectively. Similar results were seen in patients who had previously received either ruxolitinib or ibrutinib. High response rates were seen in patients with severe chronic GVHD, involvement of four or more organs and a refractory response to their last line of therapy.
 

Hard-to-manage patients

“We’re very hopeful for many of these agents, but we have to acknowledge that there are still many management dilemmas, patients that we just don’t really know what to do with,” Dr. Lee said. “These include patients who have bad sclerosis and fasciitis, nonhealing skin ulcers, bronchiolitis obliterans, serositis that can be very difficult to manage, severe keratoconjunctivitis that can be eyesight threatening, nonhealing mouth ulcers, esophageal structures, and always patients who have frequent infections.

“We are hopeful that some these agents will be useful for our patients who have severe manifestations, but often the number of patients with these manifestations in the trials is too low to say something specific about them,” she added.
 

‘Exciting time’

“It’s an exciting time because there are a lot of different drugs that are being studied for chronic GVHD,” commented Betty Hamilton, MD, a hematologist/oncologist at the Cleveland Clinic.

“I think that where the field is going in terms of treatment is recognizing that chronic GVHD is a pretty heterogeneous disease, and we have to learn even more about the underlying biologic pathways to be able to determine which class of drugs to use and when,” she said in an interview.

She agreed with Dr. Lee that the goals of treating patients with chronic GVHD include improving symptoms and quality, preventing progression, ideally tapering patients off immunosuppression, and achieving a balance between preventing negative consequences of GVHD while maintain the benefits of a graft-versus-leukemia effect.

“In our center, drug choice is based on physician preference and comfort with how often they’ve used the drug, patients’ comorbidities, toxicities of the drug, and logistical considerations,” Dr. Hamilton said.

Dr. Lee disclosed consulting activities for Pfizer and Kadmon, travel and lodging from Amgen, and research funding from those companies and others. Dr. Hamilton disclosed consulting for Syndax and Incyte.

The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Courtesy of Memorial Sloan Kettering Cancer Center

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
 

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
 

Which combination, which sequence?

“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.

“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”

The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.

“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”

The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Courtesy of Memorial Sloan Kettering Cancer Center

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
 

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
 

Which combination, which sequence?

“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.

“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”

The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.

“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”

The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

The combination of lenvatinib and pembrolizumab outperforms sunitinib as first-line therapy for advanced clear-cell renal cell carcinoma (RCC), based on findings of the CLEAR trial.

Courtesy of Memorial Sloan Kettering Cancer Center

Results from the phase 3 trial were reported at the 2021 Genitourinary Cancers Symposium (Abstract 269) and simultaneously published in the New England Journal of Medicine.

Early-phase trials have shown the promise of targeting RCC from two angles, with both antiangiogenic therapy and immunotherapy, said presenter Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York.

The CLEAR trial was designed to compare monotherapy with sunitinib to treatment with lenvatinib plus either pembrolizumab or everolimus.

The risk of progression-free survival events was 61% lower with lenvatinib-pembrolizumab and 35% lower with lenvatinib-everolimus, compared with sunitinib. However, only the first combination significantly reduced the risk of death.

Treatment-related adverse events were more common with both combinations but manageable with dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Dr. Motzer said.

Oncologists will likely soon have a handful of first-line options from which to choose, he acknowledged.

“It is a great situation, that we have made such progress in RCC with IO [immuno-oncology] therapy in the first line with ipilimumab-nivolumab, and now with the IO-TKI [tyrosine kinase inhibitor] combinations,” Dr. Motzer said.

The choice will probably come down to personal preference, experience with the various combinations, and side effect profiles, he speculated.

“I will say, however, that the data with lenvatinib-pembrolizumab is very impressive in terms of the long progression-free survival, in terms of the doubling of response rate to over 70%, in terms of the 16% complete response rate,” he said.
 

Trial details

The CLEAR investigators evenly randomized 1,069 patients with advanced clear-cell RCC who had not received prior systemic therapy to treatment with lenvatinib-pembrolizumab, lenvatinib-everolimus, or sunitinib.

The primary analysis was conducted at a median follow-up of 27 months.

The median progression-free survival was 9.2 months with sunitinib, 23.9 months with lenvatinib-pembrolizumab (hazard ratio, 0.39; P < .001), and 14.7 months with lenvatinib-everolimus (HR for events, 0.65; P < .001).

Findings were similar across key subgroups, including International Metastatic RCC Database Consortium risk groups.

An interim analysis of overall survival showed that patients lived significantly longer with lenvatinib-pembrolizumab versus sunitinib (HR, 0.66; P = .005), with similar benefit across subgroups, except for the favorable risk group.

In contrast, lenvatinib-everolimus did not significantly improve overall survival (HR, 1.15; P = .3). The median overall survival was not reached in any treatment arm.

“To me, this emphasizes the role of IO therapy combinations in the first line. I think you need the IO in the first line to get the dramatic efficacy results that we saw in the CLEAR study,” Dr. Motzer said.

The confirmed objective response rate was 36.1% with sunitinib, 71.0% with lenvatinib-pembrolizumab (relative risk, 1.97; P < .001), and 53.5% with lenvatinib-everolimus (RR, 1.48; P <.001). The median duration of response was 14.6 months, 25.8 months, and 16.6 months, respectively.

Grade 3 or higher treatment-related adverse events occurred in 58.8% of patients in the sunitinib group, 71.6% of the lenvatinib-pembrolizumab group, and 73.0% of the lenvatinib-everolimus group. The higher rates with the combinations likely reflected longer treatment durations, according to Dr. Motzer.

The most common grade 3 or higher events with lenvatinib-pembrolizumab were hypertension (25.3%), diarrhea (8.2%), and proteinuria (7.4%). The most common grade 3 or higher events with lenvatinib-everolimus were hypertension (20.8%), hypertriglyceridemia (10.1%), and diarrhea (9.6%).

“The relatively low rates of hepatic toxicity, lack of myelosuppression, and low rate of high-grade hand-foot syndrome is an attractive feature for lenvatinib in combination,” Dr. Motzer said.
 

Which combination, which sequence?

“Lenvatinib plus pembrolizumab is another novel combination to have in our armamentarium now for first-line clear-cell RCC,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

CLEAR is the fourth positive trial of combination tyrosine kinase inhibitor therapy and immunotherapy in this setting, although findings and study populations differ somewhat, and longer follow-up is needed, she said.

“None of these combinations have been directly compared to one another, and I don’t believe they will be compared head to head,” Dr. Berg said. “But other characteristics – for example, health-related quality of life, familiarity of the agents for clinicians, and high tumor burden versus slow-growing disease – may become important to choose the best first-line option for our patients.”

The emerging first-line options also raise some questions about the optimal sequencing of agents, according to Dr. Berg.

“If one starts with combination immunotherapy, it becomes an automatic choice to use a VEGF tyrosine kinase inhibitor second line,” she elaborated. “These trials establish that immuno-oncology–tyrosine kinase inhibitor combination therapy is now standard of care, but our second-line choice is less clear. Therefore, data is needed on the most suitable order of therapy for the entire population, as well as specific groups in the future.”

The CLEAR trial was sponsored by Eisai Inc. and Merck Sharp & Dohme Corp. Dr. Motzer disclosed relationships with Eisai, Merck, and many other companies. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.

ogichobanov/iStock/Getty Images Plus

The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
 

Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?

However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.

“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.

He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
 

Potency of romosozumab

Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.

“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.

In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.

Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.

Updated Endocrine Society guidelines

Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.

Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.

The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”

“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.

Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.

bjancin@mdedge.com

The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.

ogichobanov/iStock/Getty Images Plus

The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
 

Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?

However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.

“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.

He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
 

Potency of romosozumab

Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.

“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.

In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.

Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.

Updated Endocrine Society guidelines

Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.

Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.

The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”

“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.

Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.

bjancin@mdedge.com

The potent anabolic, antiosteoporosis agent romosozumab has been saddled with an Food and Drug Administration–mandated black-box warning for increased cardiovascular risk that may not be warranted, Glenn Haugeberg, MD, PhD, asserted at the 2021 Rheumatology Winter Clinical Symposium.

ogichobanov/iStock/Getty Images Plus

The black-box warning states that romosozumab (Evenity), a monoclonal antibody approved in 2019 for fracture prevention in patients with osteoporosis, may increase the risk of MI, stroke, and cardiovascular death. The warning arose from FDA concerns raised by the results of the phase 3 ARCH trial in which 4,093 postmenopausal women at high fracture risk were randomized to monthly subcutaneous injections of romosozumab or weekly dosing of the oral bisphosphonate alendronate (Fosamax) for 1 year, followed by 12 months of open-label alendronate for all. Alarm bells went off at the FDA because during year 1, the incidence of adjudicated major adverse cardiovascular events was 2.5% in the romosozumab arm, compared with 1.9% with alendronate.
 

Could a cardioprotective effect of bisphosphonates explain cardiovascular concerns?

However, evidence from multiple animal and human studies suggests that bisphosphonates actually have a cardioprotective effect. For example, a Taiwanese population-based cohort study of 1,548 patients on bisphosphonate therapy for osteoporotic fractures and 4,644 individuals with hip or vertebral fractures who were not on a bisphosphonate showed a 65% reduction in the risk of acute MI during 2 years of follow-up in those who received a bisphosphonate.

“That may explain the ARCH finding. It may – I say may – be that this concern in the ARCH study can be explained by the positive effect of the bisphosphonates on cardiovascular events,” according to Dr. Haugeberg, head of the division of rheumatology at the Southern Norway Hospital Trust, Kristiansand, and professor of medicine at the Norwegian University of Science and Technology, Trondheim.

He noted that, in the FRAME trial, another pivotal phase 3 trial of romosozumab, there was no signal of increased cardiovascular risk, compared with placebo. In FRAME, which included 7,180 osteoporotic postmenopausal women, rates of major adverse cardiovascular events and other adverse events were balanced between the two study arms at 12 months. Indeed, the incidence of adjudicated serious cardiovascular events was 0.5% with romosozumab and 0.4% with placebo injections. After 12 months, all participants were transitioned to denosumab (Prolia) for another 12 months. At 24 months, there remained no significant between-group difference in cardiovascular events, cancer, osteoarthritis, hyperostosis, or other major adverse events.
 

Potency of romosozumab

Romosozumab’s efficacy for fracture prevention in these two pivotal trials was striking. The risk of new vertebral fractures was reduced by 73% with romosozumab, compared with placebo at 12 months in FRAME, and by 75% at 24 months in the romosozumab-to-denosumab group.

“FRAME was a 12-month study for the primary endpoint. The bisphosphonate studies typically had a 3-year design in order to show benefit, but here you see only 12-month follow-up. This illustrates the potency of this drug. We saw rapid increase in bone density and a huge decrease in new vertebral fractures versus placebo in the first 12 months, then during follow-up with denosumab the reduction in fractures was maintained,” the rheumatologist commented.

In the ARCH trial, where romosozumab went head to head with a very effective oral bisphosphonate, the risk of new vertebral fractures was 48% lower at 24 months in the romosozumab-to-alendronate group than in women on alendronate for the full 24 months, while the risk of hip fractures was reduced by 38%.

Romosozumab is a humanized monoclonal antibody with a novel mechanism of anabolic action: This agent binds to sclerostin, which is produced in osteocytes. When sclerostin binds to receptors on osteoblasts it reduces their activity, thereby inhibiting bone formation. Romosozumab takes away this inhibition of osteoblasts, boosting their activity. The result is increased bone formation accompanied by decreased bone resorption. This allows for a logical treatment approach: first using an anabolic agent – in this instance, subcutaneously injected romosozumab at 210 mg once monthly for 12 months – then switching to an antiresorptive agent in order to maintain the gain in bone mineral density and decrease fracture risk. This is the same treatment strategy recommended when using the anabolic agents teriparatide (Forteo) and abaloparatide (Tymlos); however, those parathyroid hormone and parathyroid hormone–related protein analogs are seldom used in Norway because their cost is substantially greater than for romosozumab, he explained.

Updated Endocrine Society guidelines

Dr. Haugeberg called romosozumab “a new and wonderful drug.” The Endocrine Society also considers romosozumab an important new drug, as evidenced by the release of an 8-page update of the group’s clinical practice guideline on the pharmacologic management of osteoporosis in postmenopausal women; the update was devoted specifically to the use of romosozumab. The update, published in response to the biologic’s recent approval by U.S., Canadian, and European regulatory agencies, came just 10 months after release of the Endocrine Society’s comprehensive 28-page clinical practice guideline.

Dr. Haugeberg is a fan of the Endocrine Society guideline, which recommends romosozumab as a first-line therapy in postmenopausal women at very high risk of osteoporotic fracture, defined as those with a history of multiple vertebral fractures or severe osteoporosis with a T score of –2.5 or less at the hip or spine plus fractures. The updated guideline also recommends consideration of the antisclerostin biologic in high-risk patients who have failed on antiresorptive treatments.

The practice guideline states that the issue of a possible cardioprotective effect of alendronate in the ARCH trial “remains uncertain at this time.”

“Women at high risk of cardiovascular disease and stroke should not be considered for romosozumab pending further studies on cardiovascular risk associated with this treatment,” according to the Endocrine Society.

Dr. Haugeberg reported receiving research grants from Pfizer and Biogen and serving as a consultant to and/or on speakers’ bureaus for Amgen, which markets romosozumab, and more than a dozen other pharmaceutical companies.

bjancin@mdedge.com

Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.

“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.

“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”

A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.

“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
 

SCIg advantages

SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.

French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.

“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
 

Available products

Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.

The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.

Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.

“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.

More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.

Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.

Dr. Postolova reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.

“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.

“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”

A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.

“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
 

SCIg advantages

SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.

French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.

“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
 

Available products

Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.

The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.

Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.

“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.

More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.

Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.

Dr. Postolova reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

Home-based subcutaneous immune globulin therapy is a promising alternative to intravenous immune globulin therapy for patients with refractory dermatomyositis or polymyositis, Anna Postolova, MD, MPH, declared at the 2021 Rheumatology Winter Clinical Symposium.

“This is really exciting. I think in the years to come we may see a change to having our patients be able to do immune globulin therapy at home,” said Dr. Postolova, a rheumatologist and allergist/immunologist at Stanford (Calif.) Health Care.

“The technology is there. I think our patients might feel more comfortable getting immune globulin at home,” she said. “I would love to switch more patients from IVIg to SCIg [subcutaneous immune globulin] in my practice.”

A few caveats: SCIg remains off label for treatment of dermatomyositis (DM) or polymyositis (PM). Its approved indication is as replacement therapy in patients with primary or secondary immunodeficiency diseases. IVIg is approved for this indication, but is also approved for DM/PM refractory to high-dose corticosteroids and immunosuppressants. Yet SCIg is clearly effective for these autoimmune inflammatory diseases, albeit to date the supporting evidence comes chiefly from observational studies and anecdotal experience.

“I don’t know if insurers will cover it, but they should because it’s obviously a lot cheaper to do it at home,” she noted.
 

SCIg advantages

SCIg offers compelling advantages over IVIg in addition to its substantially lower cost. These include far fewer systemic side effects, shorter infusion time, greater bioavailability, and better quality of life. Patients self-administer SCIg at home, avoiding the inconvenience of IVIg therapy, which entails travel time for once-monthly hospitalization or long hours spent in an infusion center, she explained.

French investigators recently documented a previously unappreciated further advantage of home-based SCIg. They convened a focus group of patients with DM or PM experienced with both IVIg and home SCIg and determined that participants uniformly preferred home SCIg. The patients cited a new and welcome feeling of autonomy and control.

“All patients with experience of IVIg and SCIg expressed a clear preference for SCIg, which was described to be easy, less disruptive for daily life, well tolerated, and less time-consuming. Preference was mainly related to a restoration of autonomy. Home-based self-administration reinforced the feeling of independence,” according to the investigators.
 

Available products

Six preparations of SCIg are commercially available. Most are in 10% concentration, as are all IVIg products. However, a 20% formulation of SCIg known as Hizentra allows for a smaller infusion volume and quicker completion of a treatment session. And one SCIg product, HyQvia, uses recombinant human hyaluronidase-facilitated 10% immune globulin, allowing home infusion of large volumes of sustained-release immune globulin on a once-monthly basis.

The relatively recent introduction of home SCIg for treatment of autoimmune inflammatory diseases, including DM, PM, and chronic inflammatory demyelinating polyneuropathy, has been pioneered mainly by European investigators. The treatment is often given by programmable mechanical pump once weekly. Italian investigators have reported efficacy in DM using 0.2 g/kg per week, which is about half the monthly total dose of IVIg employed. The infusion rate is 10-40 mL/hour, with a volume of around 35 mL per injection site.

Alternatively, SCIg can be delivered by rapid push infusions of smaller volumes with a syringe two or three times per week; that’s the regimen that was used at 2 g/kg over the course of a month by patients in the French focus group study, who didn’t mind the more frequent dosing.

“As they have had severe long-lasting symptoms, SCIg was perceived as a curative rather than a preventive therapy,” according to the French investigators.

More than 40% of patients experience adverse reactions to IVIg. These often involve headaches, nausea, back or abdominal pain, arthralgias, and/or difficulty breathing. Thromboembolic events and acute renal failure occur occasionally. For this reason, many physicians give a prophylactic dose of corticosteroids an hour before a patient’s first dose of IVIg. These systemic side effects are so rare with SCIg that Dr. Postolova has never pretreated with steroids, even though the main reason she resorts to the home therapy is a patient’s track record of poor tolerance of IVIg. The lower abdomen and thigh are the most commonly used subcutaneous infusion sites. Mild local infusion site reactions are fairly common.

Formulating IVIg and SCIg is a complex process that entails plasma procurement and pooling, fractionation, and purification. It takes 10,000-60,000 plasma donations to make one lot of IVIg. Donations are accepted only from repeated donors. Samples are held for 6 months and tested for infectious agents. However, efforts are underway to develop bioengineered recombinant immune globulin products that don’t require donated plasma. These products are being designed to capture and enhance the most important mechanisms of benefit of plasma-derived immunoglobulins using Fc fragments that target key receptors, rather than relying on full-length immune globulin. The goal is enhanced efficacy at much lower doses than with IVIg or SCIg.

Dr. Postolova reported having no financial conflicts regarding her presentation.

bjancin@mdedge.com

When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.

Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.

“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.

Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.

The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.

Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.

“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.

Dr. Pal noted that current evidence supports only monotherapy in papillary disease.

“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.

Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
 

SWOG 1500 details

The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.

Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.

The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.

For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.

The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.

The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.

The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.

The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.

There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
 

MET alterations may be key

“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.

“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”

SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.

Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.

“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.

Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.

The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.

Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.

“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.

Dr. Pal noted that current evidence supports only monotherapy in papillary disease.

“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.

Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
 

SWOG 1500 details

The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.

Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.

The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.

For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.

The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.

The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.

The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.

The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.

There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
 

MET alterations may be key

“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.

“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”

SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

When treating metastatic papillary renal cell carcinoma (RCC), cabozantinib outperforms the current standard of care, according to results from the Southwest Oncology Group (SWOG) 1500 trial.

Compared with the VEGFR-2 inhibitor sunitinib, the MET inhibitor cabozantinib improved both response rate and progression-free survival. Two other MET inhibitors, crizotinib and savolitinib, were not more efficacious than sunitinib.

“To date, there have been no randomized data specifically in papillary RCC showing an advantage of one systemic therapy over another,” said Sumanta K. Pal, MD, of City of Hope National Medical Center, Duarte, Calif., when presenting results from SWOG 1500.

Dr. Pal presented the results at the 2021 Genitourinary Cancers Symposium (Abstract 270), and they were published simultaneously in The Lancet.

The SWOG 1500 trial, also known as the PAPMET trial, was undertaken given evidence that signaling in the MET pathway is a driver in a sizable proportion of papillary RCCs, Dr. Pal explained.

Compared with sunitinib, cabozantinib reduced the risk of progression-free survival events by 40% and netted a response rate that was almost six times higher. On the other hand, the crizotinib and savolitinib arms of the trial were stopped early because of futility.

“Cabozantinib should be considered the new reference standard for systemic therapy in patients with metastatic papillary RCC,” Dr. Pal recommended. At present, VEGF-directed therapy is used as standard of care.

Dr. Pal noted that current evidence supports only monotherapy in papillary disease.

“There may be a temptation to put a patient on a combination of cabozantinib with immunotherapy, and certainly there is data in the context of clear-cell disease to support that. But we have to stop and think. We don’t know yet if that actually results in benefit for our patients, and obviously, it could extend the spectrum of toxicities that they incur,” he added.

Dr. Pal therefore encouraged oncologists and their patients with papillary RCC to consider the planned PAPMET-2 trial, which will explore the benefits and risks of adding immunotherapy to cabozantinib for this patient population.
 

SWOG 1500 details

The phase 2 SWOG 1500 trial was conducted in 65 U.S. and Canadian centers. It enrolled 152 patients with metastatic papillary RCC who had received up to one prior systemic therapy, excluding sunitinib. The trial is the first exclusively in this patient population to complete accrual, Dr. Pal noted.

Patients were randomized evenly to sunitinib, cabozantinib, crizotinib, or savolitinib.

The investigators stopped accrual to the savolitinib and crizotinib arms early based on a prespecified futility analysis showing that the hazard ratios for progression-free survival, compared with sunitinib, exceeded 1.

For the remaining arms, the median progression-free survival was 9.0 months with cabozantinib and 5.6 months with sunitinib (hazard ratio for events, 0.60; one-sided P = .019), meeting the trial’s primary endpoint. Subgroup analyses numerically favored cabozantinib in both type I and type II disease.

The confirmed overall response rate was 23% with cabozantinib and 4% with sunitinib (two-sided P = .010). Respective rates of complete response were 5% and 0%.

The median overall survival was 20.0 months with cabozantinib and 16.4 months with sunitinib, a nonsignificant difference.

The investigators are conducting exploratory analyses of MET mutational status and MET expression, and their associations with outcomes, according to Dr. Pal. Findings of other studies are suggesting that MET-altered papillary RCC may be a distinct entity, which would support genomically driven studies, he noted.

The rate of grade 3-4 toxicity was 68% in the sunitinib group, 74% in the cabozantinib group, 37% in the crizotinib group, and 39% in the savolitinib group. The types of toxicities seen were similar to those observed with each agent in larger trials, Dr. Pal observed.

There was a single grade 5 event, a death secondary to thromboembolism in the cabozantinib arm.
 

MET alterations may be key

“We should consider cabozantinib as another first-line option for papillary kidney cancer,” said invited discussant Stephanie A. Berg, DO, of Loyola University Medical Center in Maywood, Ill.

Courtesy of Loyola University

Dr. Berg noted that the phase 3 SAVOIR trial, recently published in JAMA Oncology, compared savolitinib against sunitinib in MET-driven papillary RCC and stopped recruitment early. Although the trial did not meet its primary endpoint of progression-free survival, it did show numerically better results with the MET inhibitor.

“I question if the savolitinib arm in SWOG 1500 may have fared better if tumors were exclusively MET driven, especially as type II papillary patients represented almost half of the total patient population, and typically, 40% express alterations in MET,” Dr. Berg commented. “We will have to wait for further exploratory analysis regarding MET mutational status to tease out these differences.”

SWOG 1500 was sponsored by the National Cancer Institute. Dr. Pal disclosed a consulting or advisory role with Astellas Pharma, Aveo, Bristol-Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer. Dr. Berg disclosed a consulting or advisory role with Bristol-Myers Squibb.

Artificial intelligence (AI) is expected to one day affect the entire continuum of cancer care – from screening and risk prediction to diagnosis, risk stratification, treatment selection, and follow-up, according to an expert in the field.

Hugo J.W.L. Aerts, PhD, director of the AI in Medicine Program at Brigham and Women’s Hospital in Boston, described studies using AI for some of these purposes during a presentation at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (Abstract IA-06).

In one study, Dr. Aerts and colleagues set out to determine whether a convolutional neural network (CNN) could extract prognostic information from chest radiographs. The researchers tested this theory using patients from two trials – the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the National Lung Screening Trial (NLST).

The team developed a CNN, called CXR-risk, and tested whether it could predict the longevity and prognosis of patients in the PLCO (n = 52,320) and NLST (n = 5,493) trials over a 12-year time period, based only on chest radiographs. No clinical information, demographics, radiographic interpretations, duration of follow-up, or censoring were provided to the deep-learning system.

CXR-risk output was stratified into five categories of radiographic risk scores for probability of death, from 0 (very low likelihood of mortality) to 1 (very high likelihood of mortality).

The investigators found a graded association between radiographic risk score and mortality. The very-high-risk group had mortality rates of 53.0% (PLCO) and 33.9% (NLST). In both trials, this was significantly higher than for the very-low-risk group. The unadjusted hazard ratio was 18.3 in the PCLO data set and 15.2 in the NLST data set (P < .001 for both).

This association was maintained after adjustment for radiologists’ findings (e.g., a lung nodule) and risk factors such as age, gender, and comorbid illnesses like diabetes. The adjusted HR was 4.8 in the PCLO data set and 7.0 in the NLST data set (P < .001 for both).

In both data sets, individuals in the very-high-risk group were significantly more likely to die of lung cancer. The aHR was 11.1 in the PCLO data set and 8.4 in the NSLT data set (P < .001 for both).

This might be expected for people who were interested in being screened for lung cancer. However, patients in the very-high-risk group were also more likely to die of cardiovascular illness (aHR, 3.6 for PLCO and 47.8 for NSLT; P < .001 for both) and respiratory illness (aHR, 27.5 for PLCO and 31.9 for NLST; P ≤ .001 for both).

With this information, a clinician could initiate additional testing and/or utilize more aggressive surveillance measures. If an oncologist considered therapy for a patient with newly diagnosed cancer, treatment choices and stratification for adverse events would be more intelligently planned.
 

Using AI to predict the risk of lung cancer

In another study, Dr. Aerts and colleagues developed and validated a CNN called CXR-LC, which was based on CXR-risk. The goal of this study was to see if CXR-LC could predict long-term incident lung cancer using data available in the EHR, including chest radiographs, age, sex, and smoking status.

The CXR-LC model was developed using data from the PLCO trial (n = 41,856) and was validated in smokers from the PLCO trial (n = 5,615; 12-year follow-up) as well as heavy smokers from the NLST trial (n = 5,493; 6-year follow-up).

Results showed that CXR-LC was able to predict which patients were at highest risk for developing lung cancer.

CXR-LC had better discrimination for incident lung cancer than did Medicare eligibility in the PLCO data set (area under the curve, 0.755 vs. 0.634; P < .001). And the performance of CXR-LC was similar to that of the PLCO_M2012 risk score in both the PLCO data set (AUC, 0.755 vs. 0.751) and the NLST data set (AUC, 0.659 vs. 0.650).

When they were compared in screening populations of equal size, CXR-LC was more sensitive than Medicare eligibility criteria in the PLCO data set (74.9% vs. 63.8%; P = .012) and missed 30.7% fewer incident lung cancer diagnoses.
 

AI as a substitute for specialized testing and consultation

In a third study, Dr. Aerts and colleagues used a CNN to predict cardiovascular risk by assessing coronary artery calcium (CAC) from clinically obtained, readily available CT scans.

Ordinarily, identifying CAC – an accurate predictor of cardiovascular events – requires specialized expertise (manual measurement and cardiologist interpretation), time (estimated at 20 minutes/scan), and equipment (ECG-gated cardiac CT scan and special software).

In this study, the researchers used a fully end-to-end automated system with analytic time measured in less than 2 seconds.

The team trained and tuned their CNN using the Framingham Heart Study Offspring and Third Generation cohorts (n = 1,636), which included asymptomatic patients with high-quality, cardiac-gated CT scans for CAC quantification.

The researchers then tested the CNN on two asymptomatic and two symptomatic cohorts:

• Asymptomatic Framingham Heart Study participants (n = 663) in whom the outcome measures were cardiovascular disease and death.
• Asymptomatic NLST participants (n = 14,959) in whom the outcome measure was atherosclerotic cardiovascular death.
• Symptomatic PROMISE study participants with stable chest pain (n = 4,021) in whom the outcome measures were all-cause mortality, MI, and hospitalization for unstable angina.
• Symptomatic ROMICAT-II study patients with acute chest pain (n = 441) in whom the outcome measure was acute coronary syndrome at 28 days.

Among 5,521 subjects across all testing cohorts with cardiac-gated and nongated chest CT scans, the CNN and expert reader interpretations agreed on the CAC risk scores with a high level of concordance (kappa, 0.71; concordance rate, 0.79).

There was a very high Spearman’s correlation of 0.92 (P < .0001) and substantial agreement between automatically and manually calculated CAC risk groups, substantiating robust risk prediction for cardiovascular disease across multiple clinical scenarios.

Dr. Aerts commented that, among the NLST participants who had the highest risk of developing lung cancer, the risk of cardiovascular death was as high as the risk of death from lung cancer.
 

Using AI to assess patient outcomes

In an unpublished study, Dr. Aerts and colleagues used AI in an attempt to determine whether changes in measurements of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle mass would provide clues about treatment outcomes in lung cancer patients.

The researchers developed a deep learning model using data from 1,129 patients at Massachusetts General and Brigham and Women’s Hospitals, measuring SAT, VAT, and muscle mass. The team applied the measurement system to a population of 12,128 outpatients and calculated z scores for SAT, VAT, and muscle mass to determine “normal” values.

When they applied the norms to surgical lung cancer data sets from the Boston Lung Cancer Study (n = 437) and TRACERx study (n = 394), the researchers found that smokers had lower adiposity and lower muscle mass than never-smokers.

More importantly, over time, among lung cancer patients who lost greater than 5% of VAT, SAT, and muscle mass, those patients with the greatest SAT loss (P < .0001) or VAT loss (P = .0015) had the lowest lung cancer–specific survival in the TRACERx study. There was no significant impairment of lung cancer-specific survival for patients who experienced skeletal muscle loss (P = .23).

The same observation was made for overall survival among patients enrolled in the Boston Lung Cancer Study, using the 5% threshold. Overall survival was significantly worse with increasing VAT loss (P = .0023) and SAT loss (P = .0082) but not with increasing skeletal muscle loss (P = .3).

The investigators speculated about whether the correlation between body composition and clinical outcome could yield clues about tumor biology. To test this, the researchers used the RNA sequencing–based ORACLE risk score in lung cancer patients from TRACERx. There was a high correlation between higher ORACLE risk scores and lower VAT and SAT, suggesting that measures of adiposity on CT were reflected in tumor biology patterns on an RNA level in lung cancer patients. There was no such correlation between ORACLE risk scores and skeletal muscle mass.
 

Wonderment ... tempered by concern and challenges

AI has awe-inspiring potential to yield actionable and prognostically important information from data mining the EHR and extracting the vast quantities of information from images. In some cases (like CAC), it is information that is “hiding in plain sight.” However, Dr. Aerts expressed several cautions, some of which have already plagued AI.

He referenced the Gartner Hype Cycle, which provides a graphic representation of five phases in the life cycle of emerging technologies. The “innovation trigger” is followed by a “peak of inflated expectations,” a “trough of disillusionment,” a “slope of enlightenment,” and a “plateau of productivity.”

Dr. Aerts noted that, in recent years, AI has seemed to fall into the trough of disillusionment, but it may be entering the slope of enlightenment on the way to the plateau of productivity.

His research highlighted several examples of productivity in radiomics in cancer patients and those who are at high risk of developing cancer.

In Dr. Aerts’s opinion, a second concern is replication of AI research results. He noted that, among 400 published studies, only 6% of authors shared the codes that would enable their findings to be corroborated. About 30% shared test data, and 54% shared “pseudocodes,” but transparency and reproducibility are problems for the acceptance and broad implementation of AI.

Dr. Aerts endorsed the Modelhub initiative (www.modelhub.ai), a multi-institutional initiative to advance reproducibility in the AI field and advance its full potential.

However, there are additional concerns about the implementation of radiomics and, more generally, data mining from clinicians’ EHRs to personalize care.

Firstly, it may be laborious and difficult to explain complex, computer-based risk stratification models to patients. Hereditary cancer testing is an example of a risk assessment test that requires complicated explanations that many clinicians relegate to genetics counselors – when patients elect to see them. When a model is not explainable, it undermines the confidence of patients and their care providers, according to an editorial related to the CXR-LC study.

Another issue is that uptake of lung cancer screening, in practice, has been underutilized by individuals who meet current, relatively straightforward Medicare criteria. Despite the apparently better accuracy of the CXR-LC deep-learning model, its complexity and limited access could constitute an additional barrier for the at-risk individuals who should avail themselves of screening.

Furthermore, although age and gender are accurate in most circumstances, there is legitimate concern about the accuracy of, for example, smoking history data and comorbid conditions in current EHRs. Who performs the laborious curation of the input in an AI model to assure its accuracy for individual patients?

Finally, it is unclear how scalable and applicable AI will be to medically underserved populations (e.g., smaller, community-based, free-standing, socioeconomically disadvantaged or rural health care institutions). There are substantial initial and maintenance costs that may limit AI’s availability to some academic institutions and large health maintenance organizations.

As the concerns and challenges are addressed, it will be interesting to see where and when the plateau of productivity for AI in cancer care occurs. When it does, many cancer patients will benefit from enhanced care along the continuum of the complex disease they and their caregivers seek to master.

Dr. Aerts disclosed relationships with Onc.AI outside the presented work.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Artificial intelligence (AI) is expected to one day affect the entire continuum of cancer care – from screening and risk prediction to diagnosis, risk stratification, treatment selection, and follow-up, according to an expert in the field.

Hugo J.W.L. Aerts, PhD, director of the AI in Medicine Program at Brigham and Women’s Hospital in Boston, described studies using AI for some of these purposes during a presentation at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (Abstract IA-06).

In one study, Dr. Aerts and colleagues set out to determine whether a convolutional neural network (CNN) could extract prognostic information from chest radiographs. The researchers tested this theory using patients from two trials – the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the National Lung Screening Trial (NLST).

The team developed a CNN, called CXR-risk, and tested whether it could predict the longevity and prognosis of patients in the PLCO (n = 52,320) and NLST (n = 5,493) trials over a 12-year time period, based only on chest radiographs. No clinical information, demographics, radiographic interpretations, duration of follow-up, or censoring were provided to the deep-learning system.

CXR-risk output was stratified into five categories of radiographic risk scores for probability of death, from 0 (very low likelihood of mortality) to 1 (very high likelihood of mortality).

The investigators found a graded association between radiographic risk score and mortality. The very-high-risk group had mortality rates of 53.0% (PLCO) and 33.9% (NLST). In both trials, this was significantly higher than for the very-low-risk group. The unadjusted hazard ratio was 18.3 in the PCLO data set and 15.2 in the NLST data set (P < .001 for both).

This association was maintained after adjustment for radiologists’ findings (e.g., a lung nodule) and risk factors such as age, gender, and comorbid illnesses like diabetes. The adjusted HR was 4.8 in the PCLO data set and 7.0 in the NLST data set (P < .001 for both).

In both data sets, individuals in the very-high-risk group were significantly more likely to die of lung cancer. The aHR was 11.1 in the PCLO data set and 8.4 in the NSLT data set (P < .001 for both).

This might be expected for people who were interested in being screened for lung cancer. However, patients in the very-high-risk group were also more likely to die of cardiovascular illness (aHR, 3.6 for PLCO and 47.8 for NSLT; P < .001 for both) and respiratory illness (aHR, 27.5 for PLCO and 31.9 for NLST; P ≤ .001 for both).

With this information, a clinician could initiate additional testing and/or utilize more aggressive surveillance measures. If an oncologist considered therapy for a patient with newly diagnosed cancer, treatment choices and stratification for adverse events would be more intelligently planned.
 

Using AI to predict the risk of lung cancer

In another study, Dr. Aerts and colleagues developed and validated a CNN called CXR-LC, which was based on CXR-risk. The goal of this study was to see if CXR-LC could predict long-term incident lung cancer using data available in the EHR, including chest radiographs, age, sex, and smoking status.

The CXR-LC model was developed using data from the PLCO trial (n = 41,856) and was validated in smokers from the PLCO trial (n = 5,615; 12-year follow-up) as well as heavy smokers from the NLST trial (n = 5,493; 6-year follow-up).

Results showed that CXR-LC was able to predict which patients were at highest risk for developing lung cancer.

CXR-LC had better discrimination for incident lung cancer than did Medicare eligibility in the PLCO data set (area under the curve, 0.755 vs. 0.634; P < .001). And the performance of CXR-LC was similar to that of the PLCO_M2012 risk score in both the PLCO data set (AUC, 0.755 vs. 0.751) and the NLST data set (AUC, 0.659 vs. 0.650).

When they were compared in screening populations of equal size, CXR-LC was more sensitive than Medicare eligibility criteria in the PLCO data set (74.9% vs. 63.8%; P = .012) and missed 30.7% fewer incident lung cancer diagnoses.
 

AI as a substitute for specialized testing and consultation

In a third study, Dr. Aerts and colleagues used a CNN to predict cardiovascular risk by assessing coronary artery calcium (CAC) from clinically obtained, readily available CT scans.

Ordinarily, identifying CAC – an accurate predictor of cardiovascular events – requires specialized expertise (manual measurement and cardiologist interpretation), time (estimated at 20 minutes/scan), and equipment (ECG-gated cardiac CT scan and special software).

In this study, the researchers used a fully end-to-end automated system with analytic time measured in less than 2 seconds.

The team trained and tuned their CNN using the Framingham Heart Study Offspring and Third Generation cohorts (n = 1,636), which included asymptomatic patients with high-quality, cardiac-gated CT scans for CAC quantification.

The researchers then tested the CNN on two asymptomatic and two symptomatic cohorts:

• Asymptomatic Framingham Heart Study participants (n = 663) in whom the outcome measures were cardiovascular disease and death.
• Asymptomatic NLST participants (n = 14,959) in whom the outcome measure was atherosclerotic cardiovascular death.
• Symptomatic PROMISE study participants with stable chest pain (n = 4,021) in whom the outcome measures were all-cause mortality, MI, and hospitalization for unstable angina.
• Symptomatic ROMICAT-II study patients with acute chest pain (n = 441) in whom the outcome measure was acute coronary syndrome at 28 days.

Among 5,521 subjects across all testing cohorts with cardiac-gated and nongated chest CT scans, the CNN and expert reader interpretations agreed on the CAC risk scores with a high level of concordance (kappa, 0.71; concordance rate, 0.79).

There was a very high Spearman’s correlation of 0.92 (P < .0001) and substantial agreement between automatically and manually calculated CAC risk groups, substantiating robust risk prediction for cardiovascular disease across multiple clinical scenarios.

Dr. Aerts commented that, among the NLST participants who had the highest risk of developing lung cancer, the risk of cardiovascular death was as high as the risk of death from lung cancer.
 

Using AI to assess patient outcomes

In an unpublished study, Dr. Aerts and colleagues used AI in an attempt to determine whether changes in measurements of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle mass would provide clues about treatment outcomes in lung cancer patients.

The researchers developed a deep learning model using data from 1,129 patients at Massachusetts General and Brigham and Women’s Hospitals, measuring SAT, VAT, and muscle mass. The team applied the measurement system to a population of 12,128 outpatients and calculated z scores for SAT, VAT, and muscle mass to determine “normal” values.

When they applied the norms to surgical lung cancer data sets from the Boston Lung Cancer Study (n = 437) and TRACERx study (n = 394), the researchers found that smokers had lower adiposity and lower muscle mass than never-smokers.

More importantly, over time, among lung cancer patients who lost greater than 5% of VAT, SAT, and muscle mass, those patients with the greatest SAT loss (P < .0001) or VAT loss (P = .0015) had the lowest lung cancer–specific survival in the TRACERx study. There was no significant impairment of lung cancer-specific survival for patients who experienced skeletal muscle loss (P = .23).

The same observation was made for overall survival among patients enrolled in the Boston Lung Cancer Study, using the 5% threshold. Overall survival was significantly worse with increasing VAT loss (P = .0023) and SAT loss (P = .0082) but not with increasing skeletal muscle loss (P = .3).

The investigators speculated about whether the correlation between body composition and clinical outcome could yield clues about tumor biology. To test this, the researchers used the RNA sequencing–based ORACLE risk score in lung cancer patients from TRACERx. There was a high correlation between higher ORACLE risk scores and lower VAT and SAT, suggesting that measures of adiposity on CT were reflected in tumor biology patterns on an RNA level in lung cancer patients. There was no such correlation between ORACLE risk scores and skeletal muscle mass.
 

Wonderment ... tempered by concern and challenges

AI has awe-inspiring potential to yield actionable and prognostically important information from data mining the EHR and extracting the vast quantities of information from images. In some cases (like CAC), it is information that is “hiding in plain sight.” However, Dr. Aerts expressed several cautions, some of which have already plagued AI.

He referenced the Gartner Hype Cycle, which provides a graphic representation of five phases in the life cycle of emerging technologies. The “innovation trigger” is followed by a “peak of inflated expectations,” a “trough of disillusionment,” a “slope of enlightenment,” and a “plateau of productivity.”

Dr. Aerts noted that, in recent years, AI has seemed to fall into the trough of disillusionment, but it may be entering the slope of enlightenment on the way to the plateau of productivity.

His research highlighted several examples of productivity in radiomics in cancer patients and those who are at high risk of developing cancer.

In Dr. Aerts’s opinion, a second concern is replication of AI research results. He noted that, among 400 published studies, only 6% of authors shared the codes that would enable their findings to be corroborated. About 30% shared test data, and 54% shared “pseudocodes,” but transparency and reproducibility are problems for the acceptance and broad implementation of AI.

Dr. Aerts endorsed the Modelhub initiative (www.modelhub.ai), a multi-institutional initiative to advance reproducibility in the AI field and advance its full potential.

However, there are additional concerns about the implementation of radiomics and, more generally, data mining from clinicians’ EHRs to personalize care.

Firstly, it may be laborious and difficult to explain complex, computer-based risk stratification models to patients. Hereditary cancer testing is an example of a risk assessment test that requires complicated explanations that many clinicians relegate to genetics counselors – when patients elect to see them. When a model is not explainable, it undermines the confidence of patients and their care providers, according to an editorial related to the CXR-LC study.

Another issue is that uptake of lung cancer screening, in practice, has been underutilized by individuals who meet current, relatively straightforward Medicare criteria. Despite the apparently better accuracy of the CXR-LC deep-learning model, its complexity and limited access could constitute an additional barrier for the at-risk individuals who should avail themselves of screening.

Furthermore, although age and gender are accurate in most circumstances, there is legitimate concern about the accuracy of, for example, smoking history data and comorbid conditions in current EHRs. Who performs the laborious curation of the input in an AI model to assure its accuracy for individual patients?

Finally, it is unclear how scalable and applicable AI will be to medically underserved populations (e.g., smaller, community-based, free-standing, socioeconomically disadvantaged or rural health care institutions). There are substantial initial and maintenance costs that may limit AI’s availability to some academic institutions and large health maintenance organizations.

As the concerns and challenges are addressed, it will be interesting to see where and when the plateau of productivity for AI in cancer care occurs. When it does, many cancer patients will benefit from enhanced care along the continuum of the complex disease they and their caregivers seek to master.

Dr. Aerts disclosed relationships with Onc.AI outside the presented work.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Artificial intelligence (AI) is expected to one day affect the entire continuum of cancer care – from screening and risk prediction to diagnosis, risk stratification, treatment selection, and follow-up, according to an expert in the field.

Hugo J.W.L. Aerts, PhD, director of the AI in Medicine Program at Brigham and Women’s Hospital in Boston, described studies using AI for some of these purposes during a presentation at the AACR Virtual Special Conference: Artificial Intelligence, Diagnosis, and Imaging (Abstract IA-06).

In one study, Dr. Aerts and colleagues set out to determine whether a convolutional neural network (CNN) could extract prognostic information from chest radiographs. The researchers tested this theory using patients from two trials – the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the National Lung Screening Trial (NLST).

The team developed a CNN, called CXR-risk, and tested whether it could predict the longevity and prognosis of patients in the PLCO (n = 52,320) and NLST (n = 5,493) trials over a 12-year time period, based only on chest radiographs. No clinical information, demographics, radiographic interpretations, duration of follow-up, or censoring were provided to the deep-learning system.

CXR-risk output was stratified into five categories of radiographic risk scores for probability of death, from 0 (very low likelihood of mortality) to 1 (very high likelihood of mortality).

The investigators found a graded association between radiographic risk score and mortality. The very-high-risk group had mortality rates of 53.0% (PLCO) and 33.9% (NLST). In both trials, this was significantly higher than for the very-low-risk group. The unadjusted hazard ratio was 18.3 in the PCLO data set and 15.2 in the NLST data set (P < .001 for both).

This association was maintained after adjustment for radiologists’ findings (e.g., a lung nodule) and risk factors such as age, gender, and comorbid illnesses like diabetes. The adjusted HR was 4.8 in the PCLO data set and 7.0 in the NLST data set (P < .001 for both).

In both data sets, individuals in the very-high-risk group were significantly more likely to die of lung cancer. The aHR was 11.1 in the PCLO data set and 8.4 in the NSLT data set (P < .001 for both).

This might be expected for people who were interested in being screened for lung cancer. However, patients in the very-high-risk group were also more likely to die of cardiovascular illness (aHR, 3.6 for PLCO and 47.8 for NSLT; P < .001 for both) and respiratory illness (aHR, 27.5 for PLCO and 31.9 for NLST; P ≤ .001 for both).

With this information, a clinician could initiate additional testing and/or utilize more aggressive surveillance measures. If an oncologist considered therapy for a patient with newly diagnosed cancer, treatment choices and stratification for adverse events would be more intelligently planned.
 

Using AI to predict the risk of lung cancer

In another study, Dr. Aerts and colleagues developed and validated a CNN called CXR-LC, which was based on CXR-risk. The goal of this study was to see if CXR-LC could predict long-term incident lung cancer using data available in the EHR, including chest radiographs, age, sex, and smoking status.

The CXR-LC model was developed using data from the PLCO trial (n = 41,856) and was validated in smokers from the PLCO trial (n = 5,615; 12-year follow-up) as well as heavy smokers from the NLST trial (n = 5,493; 6-year follow-up).

Results showed that CXR-LC was able to predict which patients were at highest risk for developing lung cancer.

CXR-LC had better discrimination for incident lung cancer than did Medicare eligibility in the PLCO data set (area under the curve, 0.755 vs. 0.634; P < .001). And the performance of CXR-LC was similar to that of the PLCO_M2012 risk score in both the PLCO data set (AUC, 0.755 vs. 0.751) and the NLST data set (AUC, 0.659 vs. 0.650).

When they were compared in screening populations of equal size, CXR-LC was more sensitive than Medicare eligibility criteria in the PLCO data set (74.9% vs. 63.8%; P = .012) and missed 30.7% fewer incident lung cancer diagnoses.
 

AI as a substitute for specialized testing and consultation

In a third study, Dr. Aerts and colleagues used a CNN to predict cardiovascular risk by assessing coronary artery calcium (CAC) from clinically obtained, readily available CT scans.

Ordinarily, identifying CAC – an accurate predictor of cardiovascular events – requires specialized expertise (manual measurement and cardiologist interpretation), time (estimated at 20 minutes/scan), and equipment (ECG-gated cardiac CT scan and special software).

In this study, the researchers used a fully end-to-end automated system with analytic time measured in less than 2 seconds.

The team trained and tuned their CNN using the Framingham Heart Study Offspring and Third Generation cohorts (n = 1,636), which included asymptomatic patients with high-quality, cardiac-gated CT scans for CAC quantification.

The researchers then tested the CNN on two asymptomatic and two symptomatic cohorts:

• Asymptomatic Framingham Heart Study participants (n = 663) in whom the outcome measures were cardiovascular disease and death.
• Asymptomatic NLST participants (n = 14,959) in whom the outcome measure was atherosclerotic cardiovascular death.
• Symptomatic PROMISE study participants with stable chest pain (n = 4,021) in whom the outcome measures were all-cause mortality, MI, and hospitalization for unstable angina.
• Symptomatic ROMICAT-II study patients with acute chest pain (n = 441) in whom the outcome measure was acute coronary syndrome at 28 days.

Among 5,521 subjects across all testing cohorts with cardiac-gated and nongated chest CT scans, the CNN and expert reader interpretations agreed on the CAC risk scores with a high level of concordance (kappa, 0.71; concordance rate, 0.79).

There was a very high Spearman’s correlation of 0.92 (P < .0001) and substantial agreement between automatically and manually calculated CAC risk groups, substantiating robust risk prediction for cardiovascular disease across multiple clinical scenarios.

Dr. Aerts commented that, among the NLST participants who had the highest risk of developing lung cancer, the risk of cardiovascular death was as high as the risk of death from lung cancer.
 

Using AI to assess patient outcomes

In an unpublished study, Dr. Aerts and colleagues used AI in an attempt to determine whether changes in measurements of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle mass would provide clues about treatment outcomes in lung cancer patients.

The researchers developed a deep learning model using data from 1,129 patients at Massachusetts General and Brigham and Women’s Hospitals, measuring SAT, VAT, and muscle mass. The team applied the measurement system to a population of 12,128 outpatients and calculated z scores for SAT, VAT, and muscle mass to determine “normal” values.

When they applied the norms to surgical lung cancer data sets from the Boston Lung Cancer Study (n = 437) and TRACERx study (n = 394), the researchers found that smokers had lower adiposity and lower muscle mass than never-smokers.

More importantly, over time, among lung cancer patients who lost greater than 5% of VAT, SAT, and muscle mass, those patients with the greatest SAT loss (P < .0001) or VAT loss (P = .0015) had the lowest lung cancer–specific survival in the TRACERx study. There was no significant impairment of lung cancer-specific survival for patients who experienced skeletal muscle loss (P = .23).

The same observation was made for overall survival among patients enrolled in the Boston Lung Cancer Study, using the 5% threshold. Overall survival was significantly worse with increasing VAT loss (P = .0023) and SAT loss (P = .0082) but not with increasing skeletal muscle loss (P = .3).

The investigators speculated about whether the correlation between body composition and clinical outcome could yield clues about tumor biology. To test this, the researchers used the RNA sequencing–based ORACLE risk score in lung cancer patients from TRACERx. There was a high correlation between higher ORACLE risk scores and lower VAT and SAT, suggesting that measures of adiposity on CT were reflected in tumor biology patterns on an RNA level in lung cancer patients. There was no such correlation between ORACLE risk scores and skeletal muscle mass.
 

Wonderment ... tempered by concern and challenges

AI has awe-inspiring potential to yield actionable and prognostically important information from data mining the EHR and extracting the vast quantities of information from images. In some cases (like CAC), it is information that is “hiding in plain sight.” However, Dr. Aerts expressed several cautions, some of which have already plagued AI.

He referenced the Gartner Hype Cycle, which provides a graphic representation of five phases in the life cycle of emerging technologies. The “innovation trigger” is followed by a “peak of inflated expectations,” a “trough of disillusionment,” a “slope of enlightenment,” and a “plateau of productivity.”

Dr. Aerts noted that, in recent years, AI has seemed to fall into the trough of disillusionment, but it may be entering the slope of enlightenment on the way to the plateau of productivity.

His research highlighted several examples of productivity in radiomics in cancer patients and those who are at high risk of developing cancer.

In Dr. Aerts’s opinion, a second concern is replication of AI research results. He noted that, among 400 published studies, only 6% of authors shared the codes that would enable their findings to be corroborated. About 30% shared test data, and 54% shared “pseudocodes,” but transparency and reproducibility are problems for the acceptance and broad implementation of AI.

Dr. Aerts endorsed the Modelhub initiative (www.modelhub.ai), a multi-institutional initiative to advance reproducibility in the AI field and advance its full potential.

However, there are additional concerns about the implementation of radiomics and, more generally, data mining from clinicians’ EHRs to personalize care.

Firstly, it may be laborious and difficult to explain complex, computer-based risk stratification models to patients. Hereditary cancer testing is an example of a risk assessment test that requires complicated explanations that many clinicians relegate to genetics counselors – when patients elect to see them. When a model is not explainable, it undermines the confidence of patients and their care providers, according to an editorial related to the CXR-LC study.

Another issue is that uptake of lung cancer screening, in practice, has been underutilized by individuals who meet current, relatively straightforward Medicare criteria. Despite the apparently better accuracy of the CXR-LC deep-learning model, its complexity and limited access could constitute an additional barrier for the at-risk individuals who should avail themselves of screening.

Furthermore, although age and gender are accurate in most circumstances, there is legitimate concern about the accuracy of, for example, smoking history data and comorbid conditions in current EHRs. Who performs the laborious curation of the input in an AI model to assure its accuracy for individual patients?

Finally, it is unclear how scalable and applicable AI will be to medically underserved populations (e.g., smaller, community-based, free-standing, socioeconomically disadvantaged or rural health care institutions). There are substantial initial and maintenance costs that may limit AI’s availability to some academic institutions and large health maintenance organizations.

As the concerns and challenges are addressed, it will be interesting to see where and when the plateau of productivity for AI in cancer care occurs. When it does, many cancer patients will benefit from enhanced care along the continuum of the complex disease they and their caregivers seek to master.

Dr. Aerts disclosed relationships with Onc.AI outside the presented work.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

When early-stage seminoma metastasizes to one or two retroperitoneal lymph nodes, surgical excision is an “attractive” alternative to standard chemotherapy or radiation, according to an investigator from the phase 2 SEMS trial.

The trial enrolled 55 men with early-stage seminoma and isolated retroperitoneal disease, and all of them underwent retroperitoneal lymph node dissection (RPLND). At 2 years, the recurrence rate was 18%, the recurrence-free survival rate was 84%, and the overall survival rate was 100%. Surgical complications occurred in 13% of patients.

“The SEMS trial establishes RPLND as a first-line treatment alternative for testicular seminoma with isolated retroperitoneal lymphadenopathy up to 3 cm ... It’s an attractive option given the favorable long-term morbidity of RPLND,” said co-principal investigator Siamak Daneshmand, MD, of the University of Southern California (USC), Los Angeles.

“The whole point is to offer an alternative treatment that will avoid long-term toxicity ... It makes no sense treating isolated retroperitoneal lymphadenopathy with strong chemotherapy that’s meant for more widely disseminated disease,” Dr. Daneshmand said.

He presented results from the SEMS trial at the 2021 Genitourinary Cancers Symposium (Abstract 375).
 

Practice-changing?

Dr. Daneshmand called the trial results “practice-changing” and noted that surgery “makes sense” to patients and providers, especially because RPLND is already an established option for early-stage non-seminoma testicular cancer. In fact, USC has continued to offer RPLND for early-stage seminoma since this trial ended 2 years ago, Dr. Daneshmand said.

Study discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University in Turkey, offered a different viewpoint. She said the SEMS trial had an “excellent” design, but, due to the relatively short follow-up, she would recommend caution.

“We in Europe do not recommend primary retroperitoneal lymph node dissection in seminoma outside a trial or institutional study,” Dr. Laguna said.

Still, she said the SEMS trial “establishes a solid base” for ongoing prospective trials of primary RPLND in early-stage seminoma.
 

Trial details

The SEMS trial enrolled 55 patients with pure testicular seminoma. They had stage I disease with 1-3 cm relapse (25%) or stage IIA/B disease with no more than two lymph nodes in any dimension (75%). Imaging was done within 6 weeks of surgery to avoid under staging, and serum tumor markers could be no more than 1.5 times the upper limit of normal.

The majority of subjects were White, and the median age was 34 years (range, 21-64 years). Including USC, the trial was conducted at 12 North American sites.

Patients had open modified-template surgeries by surgeons who had performed at least eight open RPLNDs in 1 year or more than 24 in 3 years. Surgeries at USC used a midline approach, with a typical hospital stay of 1 day.

The median follow-up was 2 years. The overall recurrence rate was 18% (10/55), with a median time to recurrence of 8 months.

All 10 cases of recurrence were salvageable – 8 with chemotherapy and 2 with surgical resection. All of the recurrences were retroperitoneal.

“If you can cure 80% [of men] without radiation or chemotherapy, that’s very significant. These are young patients, and chemotherapy and radiation have long-term side effects. The important thing to remember is if men do recur, they are salvageable,” Dr. Daneshmand said.

Seven patients (13%) had surgical complications that were largely minor. The exceptions were one case of pulmonary embolism and one case of chylous ascites that required drainage. There were no long-term complications, including retrograde ejaculation.

The SEMS study was funded by the Think Different Foundation. Dr. Daneshmand and Dr. Laguna said they have no relevant disclosures.

aotto@mdedge.com

When early-stage seminoma metastasizes to one or two retroperitoneal lymph nodes, surgical excision is an “attractive” alternative to standard chemotherapy or radiation, according to an investigator from the phase 2 SEMS trial.

The trial enrolled 55 men with early-stage seminoma and isolated retroperitoneal disease, and all of them underwent retroperitoneal lymph node dissection (RPLND). At 2 years, the recurrence rate was 18%, the recurrence-free survival rate was 84%, and the overall survival rate was 100%. Surgical complications occurred in 13% of patients.

“The SEMS trial establishes RPLND as a first-line treatment alternative for testicular seminoma with isolated retroperitoneal lymphadenopathy up to 3 cm ... It’s an attractive option given the favorable long-term morbidity of RPLND,” said co-principal investigator Siamak Daneshmand, MD, of the University of Southern California (USC), Los Angeles.

“The whole point is to offer an alternative treatment that will avoid long-term toxicity ... It makes no sense treating isolated retroperitoneal lymphadenopathy with strong chemotherapy that’s meant for more widely disseminated disease,” Dr. Daneshmand said.

He presented results from the SEMS trial at the 2021 Genitourinary Cancers Symposium (Abstract 375).
 

Practice-changing?

Dr. Daneshmand called the trial results “practice-changing” and noted that surgery “makes sense” to patients and providers, especially because RPLND is already an established option for early-stage non-seminoma testicular cancer. In fact, USC has continued to offer RPLND for early-stage seminoma since this trial ended 2 years ago, Dr. Daneshmand said.

Study discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University in Turkey, offered a different viewpoint. She said the SEMS trial had an “excellent” design, but, due to the relatively short follow-up, she would recommend caution.

“We in Europe do not recommend primary retroperitoneal lymph node dissection in seminoma outside a trial or institutional study,” Dr. Laguna said.

Still, she said the SEMS trial “establishes a solid base” for ongoing prospective trials of primary RPLND in early-stage seminoma.
 

Trial details

The SEMS trial enrolled 55 patients with pure testicular seminoma. They had stage I disease with 1-3 cm relapse (25%) or stage IIA/B disease with no more than two lymph nodes in any dimension (75%). Imaging was done within 6 weeks of surgery to avoid under staging, and serum tumor markers could be no more than 1.5 times the upper limit of normal.

The majority of subjects were White, and the median age was 34 years (range, 21-64 years). Including USC, the trial was conducted at 12 North American sites.

Patients had open modified-template surgeries by surgeons who had performed at least eight open RPLNDs in 1 year or more than 24 in 3 years. Surgeries at USC used a midline approach, with a typical hospital stay of 1 day.

The median follow-up was 2 years. The overall recurrence rate was 18% (10/55), with a median time to recurrence of 8 months.

All 10 cases of recurrence were salvageable – 8 with chemotherapy and 2 with surgical resection. All of the recurrences were retroperitoneal.

“If you can cure 80% [of men] without radiation or chemotherapy, that’s very significant. These are young patients, and chemotherapy and radiation have long-term side effects. The important thing to remember is if men do recur, they are salvageable,” Dr. Daneshmand said.

Seven patients (13%) had surgical complications that were largely minor. The exceptions were one case of pulmonary embolism and one case of chylous ascites that required drainage. There were no long-term complications, including retrograde ejaculation.

The SEMS study was funded by the Think Different Foundation. Dr. Daneshmand and Dr. Laguna said they have no relevant disclosures.

aotto@mdedge.com

When early-stage seminoma metastasizes to one or two retroperitoneal lymph nodes, surgical excision is an “attractive” alternative to standard chemotherapy or radiation, according to an investigator from the phase 2 SEMS trial.

The trial enrolled 55 men with early-stage seminoma and isolated retroperitoneal disease, and all of them underwent retroperitoneal lymph node dissection (RPLND). At 2 years, the recurrence rate was 18%, the recurrence-free survival rate was 84%, and the overall survival rate was 100%. Surgical complications occurred in 13% of patients.

“The SEMS trial establishes RPLND as a first-line treatment alternative for testicular seminoma with isolated retroperitoneal lymphadenopathy up to 3 cm ... It’s an attractive option given the favorable long-term morbidity of RPLND,” said co-principal investigator Siamak Daneshmand, MD, of the University of Southern California (USC), Los Angeles.

“The whole point is to offer an alternative treatment that will avoid long-term toxicity ... It makes no sense treating isolated retroperitoneal lymphadenopathy with strong chemotherapy that’s meant for more widely disseminated disease,” Dr. Daneshmand said.

He presented results from the SEMS trial at the 2021 Genitourinary Cancers Symposium (Abstract 375).
 

Practice-changing?

Dr. Daneshmand called the trial results “practice-changing” and noted that surgery “makes sense” to patients and providers, especially because RPLND is already an established option for early-stage non-seminoma testicular cancer. In fact, USC has continued to offer RPLND for early-stage seminoma since this trial ended 2 years ago, Dr. Daneshmand said.

Study discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University in Turkey, offered a different viewpoint. She said the SEMS trial had an “excellent” design, but, due to the relatively short follow-up, she would recommend caution.

“We in Europe do not recommend primary retroperitoneal lymph node dissection in seminoma outside a trial or institutional study,” Dr. Laguna said.

Still, she said the SEMS trial “establishes a solid base” for ongoing prospective trials of primary RPLND in early-stage seminoma.
 

Trial details

The SEMS trial enrolled 55 patients with pure testicular seminoma. They had stage I disease with 1-3 cm relapse (25%) or stage IIA/B disease with no more than two lymph nodes in any dimension (75%). Imaging was done within 6 weeks of surgery to avoid under staging, and serum tumor markers could be no more than 1.5 times the upper limit of normal.

The majority of subjects were White, and the median age was 34 years (range, 21-64 years). Including USC, the trial was conducted at 12 North American sites.

Patients had open modified-template surgeries by surgeons who had performed at least eight open RPLNDs in 1 year or more than 24 in 3 years. Surgeries at USC used a midline approach, with a typical hospital stay of 1 day.

The median follow-up was 2 years. The overall recurrence rate was 18% (10/55), with a median time to recurrence of 8 months.

All 10 cases of recurrence were salvageable – 8 with chemotherapy and 2 with surgical resection. All of the recurrences were retroperitoneal.

“If you can cure 80% [of men] without radiation or chemotherapy, that’s very significant. These are young patients, and chemotherapy and radiation have long-term side effects. The important thing to remember is if men do recur, they are salvageable,” Dr. Daneshmand said.

Seven patients (13%) had surgical complications that were largely minor. The exceptions were one case of pulmonary embolism and one case of chylous ascites that required drainage. There were no long-term complications, including retrograde ejaculation.

The SEMS study was funded by the Think Different Foundation. Dr. Daneshmand and Dr. Laguna said they have no relevant disclosures.

aotto@mdedge.com

The checkpoint inhibitor nivolumab is efficacious and well tolerated when used as adjuvant therapy in patients who have undergone radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC), first results of the CheckMate 274 trial suggest.

The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
 

Trial details

The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.

By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).

The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.

At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).

In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.

The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).

Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.

Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.

The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
 

Awaited findings

Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.

“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.

“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.

“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.

Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.

Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”

The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.

The checkpoint inhibitor nivolumab is efficacious and well tolerated when used as adjuvant therapy in patients who have undergone radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC), first results of the CheckMate 274 trial suggest.

The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
 

Trial details

The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.

By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).

The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.

At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).

In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.

The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).

Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.

Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.

The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
 

Awaited findings

Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.

“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.

“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.

“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.

Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.

Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”

The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.

The checkpoint inhibitor nivolumab is efficacious and well tolerated when used as adjuvant therapy in patients who have undergone radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC), first results of the CheckMate 274 trial suggest.

The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
 

Trial details

The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.

By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).

The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.

At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).

In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.

The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).

Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.

Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.

The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
 

Awaited findings

Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.

“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.

“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.

“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.

Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.

Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”

The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.