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Chronic stress, especially race related, may hasten cancer death
The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.
It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.
Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.
To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.
Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”
In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.
In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.
After adjustment, the (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.
Dr. Moore has no relevant financial disclosures.
The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.
It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.
Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.
To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.
Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”
In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.
In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.
After adjustment, the (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.
Dr. Moore has no relevant financial disclosures.
The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.
It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.
Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.
To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.
Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”
In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.
In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.
After adjustment, the (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.
Dr. Moore has no relevant financial disclosures.
FROM SSM–POPULATION HEALTH
Third COVID booster benefits cancer patients
though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.
People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.
The research was published in the November issue of the European Journal of Cancer.
Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.
Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.
The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.
“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.
Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.
The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.
The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).
Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).
Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).
Dr. Lee has no relevant financial disclosures.
though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.
People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.
The research was published in the November issue of the European Journal of Cancer.
Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.
Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.
The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.
“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.
Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.
The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.
The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).
Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).
Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).
Dr. Lee has no relevant financial disclosures.
though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.
People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.
The research was published in the November issue of the European Journal of Cancer.
Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.
Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.
The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.
“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.
Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.
The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.
The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).
Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).
Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).
Dr. Lee has no relevant financial disclosures.
FROM THE EUROPEAN JOURNAL OF CANCER
Durvalumab combinations show tentative promise in NSCLC
in patients with unresectable stage 3 non–small-cell lung cancer.
Combinations of the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab led to improved overall response rate and progression-free survival compared to durvalumab alone.
The findings support further study in a phase 3 clinical trial, according to the authors of the study recently published in the Journal of Clinical Oncology.
Durvalumab is the standard treatment following consolidation therapy of chemoradiotherapy in unresectable stage 3 non–small-cell lung cancer (NSCLC). Although it extended progression-free survival (PFS) and overall survival in the PACIFIC phase 3 study, some patients experience a recurrence, which has led to exploration of immunotherapy combinations.
Oleclumab inhibits the enzyme CD73, found on the surfaces of both tumor and immune cells. Its activity leads to an immunosuppressive effect in the tumor microenvironment, and preclinical studies have shown that it can have an additive antitumor effect when combined with PD-1 or PD-L1 inhibitors. A phase 1 study also suggested efficacy. Monalizumab blocks interactions between major histocompatibility complex-E (HLA-E) and an inhibitor receptor. A number of tumors overexpress HLA-E, triggering inhibitor signals that inhibit natural killer and CD8+ T cells.
“COAST was an interesting study that, although not definitive, suggested that the combination of durvalumab with oleclumab or with monalizumab was more effective than durvalumab alone in the consolidation setting after definitive concurrent chemoradiation for patients with stage 3 unresectable NSCLC,” said Nathan Pennell, MD, PhD, who wrote an accompanying editorial.
Despite the positive signal, Dr. Pennell expressed some skepticism that the combinations would pass a phase 3 test. He questioned the choice of response rate as the primary endpoint of the phase 2 study, and noted that the durvalumab arm had worse progression-free survival (PFS) than the previous PACIFIC trial. It could be that the clinical characteristics of the study population differed between the two trials, in which case the improved objective response rate (ORR) and PFS results should be encouraging. It’s also possible the COAST trial’s small sample size led to a mismatch between the control and treatment group despite randomization, in which case the findings may not be valid.
“These are the kinds of issues that keep drug developers up at night. There really is no way to know which scenario is correct without doing the larger trial. I do hope though that the phase 3 trials have robust biomarker analysis including PDL1 to make sure the arms are as well matched for known prognostic and predictive markers as possible,” said Dr. Pennell, who is vice chair of clinical research at Taussig Cancer Institute.
The study details
The researchers randomized 189 patients to durvalumab, durvalumab plus oleclumab, or durvalumab plus monalizumab between January 2019 and July 2020. After a median follow-up of 11.5 months, there was a higher confirmed objective response rate in the durvalumab plus oleclumab group (30.0%; 95% confidence interval, 18.8%-43.2%) and the durvalumab plus monalizumab group (35.5%; 95% CI, 23.7%-48.7%) versus durvalumab alone (17.9%; 95% CI, 9.6%-29.2%).
Compared to durvalumab alone, there was improved PFS in both durvalumab plus oleclumab (stratified hazard ratio, 0.44; 95% CI, 0.26-0.75) and durvalumab plus monalizumab (HR, 0.42; 95% CI, 0.24-0.72). At 12 months, PFS was 62.6% (95% CI, 48.1-74.2%) for durvalumab plus oleclumab, 72.7% (95% CI, 58.8-82.6%) for durvalumab plus monalizumab, and 33.9% (95% CI, 21.2-47.1%) for durvalumab alone.
The study was funded by AstraZeneca.
in patients with unresectable stage 3 non–small-cell lung cancer.
Combinations of the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab led to improved overall response rate and progression-free survival compared to durvalumab alone.
The findings support further study in a phase 3 clinical trial, according to the authors of the study recently published in the Journal of Clinical Oncology.
Durvalumab is the standard treatment following consolidation therapy of chemoradiotherapy in unresectable stage 3 non–small-cell lung cancer (NSCLC). Although it extended progression-free survival (PFS) and overall survival in the PACIFIC phase 3 study, some patients experience a recurrence, which has led to exploration of immunotherapy combinations.
Oleclumab inhibits the enzyme CD73, found on the surfaces of both tumor and immune cells. Its activity leads to an immunosuppressive effect in the tumor microenvironment, and preclinical studies have shown that it can have an additive antitumor effect when combined with PD-1 or PD-L1 inhibitors. A phase 1 study also suggested efficacy. Monalizumab blocks interactions between major histocompatibility complex-E (HLA-E) and an inhibitor receptor. A number of tumors overexpress HLA-E, triggering inhibitor signals that inhibit natural killer and CD8+ T cells.
“COAST was an interesting study that, although not definitive, suggested that the combination of durvalumab with oleclumab or with monalizumab was more effective than durvalumab alone in the consolidation setting after definitive concurrent chemoradiation for patients with stage 3 unresectable NSCLC,” said Nathan Pennell, MD, PhD, who wrote an accompanying editorial.
Despite the positive signal, Dr. Pennell expressed some skepticism that the combinations would pass a phase 3 test. He questioned the choice of response rate as the primary endpoint of the phase 2 study, and noted that the durvalumab arm had worse progression-free survival (PFS) than the previous PACIFIC trial. It could be that the clinical characteristics of the study population differed between the two trials, in which case the improved objective response rate (ORR) and PFS results should be encouraging. It’s also possible the COAST trial’s small sample size led to a mismatch between the control and treatment group despite randomization, in which case the findings may not be valid.
“These are the kinds of issues that keep drug developers up at night. There really is no way to know which scenario is correct without doing the larger trial. I do hope though that the phase 3 trials have robust biomarker analysis including PDL1 to make sure the arms are as well matched for known prognostic and predictive markers as possible,” said Dr. Pennell, who is vice chair of clinical research at Taussig Cancer Institute.
The study details
The researchers randomized 189 patients to durvalumab, durvalumab plus oleclumab, or durvalumab plus monalizumab between January 2019 and July 2020. After a median follow-up of 11.5 months, there was a higher confirmed objective response rate in the durvalumab plus oleclumab group (30.0%; 95% confidence interval, 18.8%-43.2%) and the durvalumab plus monalizumab group (35.5%; 95% CI, 23.7%-48.7%) versus durvalumab alone (17.9%; 95% CI, 9.6%-29.2%).
Compared to durvalumab alone, there was improved PFS in both durvalumab plus oleclumab (stratified hazard ratio, 0.44; 95% CI, 0.26-0.75) and durvalumab plus monalizumab (HR, 0.42; 95% CI, 0.24-0.72). At 12 months, PFS was 62.6% (95% CI, 48.1-74.2%) for durvalumab plus oleclumab, 72.7% (95% CI, 58.8-82.6%) for durvalumab plus monalizumab, and 33.9% (95% CI, 21.2-47.1%) for durvalumab alone.
The study was funded by AstraZeneca.
in patients with unresectable stage 3 non–small-cell lung cancer.
Combinations of the PD-L1 inhibitor durvalumab (Imfinzi, AstraZeneca) with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab led to improved overall response rate and progression-free survival compared to durvalumab alone.
The findings support further study in a phase 3 clinical trial, according to the authors of the study recently published in the Journal of Clinical Oncology.
Durvalumab is the standard treatment following consolidation therapy of chemoradiotherapy in unresectable stage 3 non–small-cell lung cancer (NSCLC). Although it extended progression-free survival (PFS) and overall survival in the PACIFIC phase 3 study, some patients experience a recurrence, which has led to exploration of immunotherapy combinations.
Oleclumab inhibits the enzyme CD73, found on the surfaces of both tumor and immune cells. Its activity leads to an immunosuppressive effect in the tumor microenvironment, and preclinical studies have shown that it can have an additive antitumor effect when combined with PD-1 or PD-L1 inhibitors. A phase 1 study also suggested efficacy. Monalizumab blocks interactions between major histocompatibility complex-E (HLA-E) and an inhibitor receptor. A number of tumors overexpress HLA-E, triggering inhibitor signals that inhibit natural killer and CD8+ T cells.
“COAST was an interesting study that, although not definitive, suggested that the combination of durvalumab with oleclumab or with monalizumab was more effective than durvalumab alone in the consolidation setting after definitive concurrent chemoradiation for patients with stage 3 unresectable NSCLC,” said Nathan Pennell, MD, PhD, who wrote an accompanying editorial.
Despite the positive signal, Dr. Pennell expressed some skepticism that the combinations would pass a phase 3 test. He questioned the choice of response rate as the primary endpoint of the phase 2 study, and noted that the durvalumab arm had worse progression-free survival (PFS) than the previous PACIFIC trial. It could be that the clinical characteristics of the study population differed between the two trials, in which case the improved objective response rate (ORR) and PFS results should be encouraging. It’s also possible the COAST trial’s small sample size led to a mismatch between the control and treatment group despite randomization, in which case the findings may not be valid.
“These are the kinds of issues that keep drug developers up at night. There really is no way to know which scenario is correct without doing the larger trial. I do hope though that the phase 3 trials have robust biomarker analysis including PDL1 to make sure the arms are as well matched for known prognostic and predictive markers as possible,” said Dr. Pennell, who is vice chair of clinical research at Taussig Cancer Institute.
The study details
The researchers randomized 189 patients to durvalumab, durvalumab plus oleclumab, or durvalumab plus monalizumab between January 2019 and July 2020. After a median follow-up of 11.5 months, there was a higher confirmed objective response rate in the durvalumab plus oleclumab group (30.0%; 95% confidence interval, 18.8%-43.2%) and the durvalumab plus monalizumab group (35.5%; 95% CI, 23.7%-48.7%) versus durvalumab alone (17.9%; 95% CI, 9.6%-29.2%).
Compared to durvalumab alone, there was improved PFS in both durvalumab plus oleclumab (stratified hazard ratio, 0.44; 95% CI, 0.26-0.75) and durvalumab plus monalizumab (HR, 0.42; 95% CI, 0.24-0.72). At 12 months, PFS was 62.6% (95% CI, 48.1-74.2%) for durvalumab plus oleclumab, 72.7% (95% CI, 58.8-82.6%) for durvalumab plus monalizumab, and 33.9% (95% CI, 21.2-47.1%) for durvalumab alone.
The study was funded by AstraZeneca.
FROM JOURNAL OF CLINICAL ONCOLOGY
Mutation burden predicts ICI response in lung cancer
FROM JAMA ONCOLOGY
after treatment with PD-1 and PD-L1 inhibitors. The findings could supplement other biomarkers, and suggest that chemotherapy could be avoided in some patients.
“We found a TMB value … of 19 mutations per megabase was a strong discriminator of response and nonresponse, and that corresponds to approximately the 90th percentile for TMB in our dataset. That is a higher threshold than has been previously proposed to be used for a TMB cutoff across different datasets or in lung cancer, but it did seem to be a strong discriminator of response, and that also translated into an improvement in progression free survival and overall survival in patients treated with immunotherapy,” said study coauthor Mark Awad, MD, PhD, in a podcast hosted by JAMA. He is a cancer researcher at Harvard Medical School, Boston. The research was published online in JAMA Oncology.
The value was reinforced when the team looked at deciles of TMB, from the lowest 10%, 20%, up to 90%. “It did seem like there was an inflection point, but only at the really higher levels of TMB – above the 80th, or especially the 90th percentile for TMB. That’s where it seemed to make a big difference in terms of improvements in response rate, progression-free, and overall survival,” Dr. Awad said.
The values of TMB and levels of PD-L1 expression also interacted in a useful way. “If you’re looking at PD-L1 on one axis and TMB on the other, it does seem that higher PD-L1 and the higher TMB can really identify patients with strong and great outcomes to immune checkpoint inhibitors. By contrast, low PD-L1 and low TMB really identifies patients that are not likely to benefit from immunotherapy alone and obviously might need to escalate it or more intensified therapy,” he said.
The results could help inform clinical decisions, though Dr. Awad included a caveat that the study was retrospective. In particular, patients with high TMB levels who might not tolerate chemotherapy well could be candidates for immunotherapy alone, “if you feel like there would be time to try immunotherapy alone rather than chemoimmunotherapy, and hopefully spare or avoid some of the chemotherapy toxicities, with the understanding that you wouldn’t want a patient’s disease to rapidly progress. You have to choose these cases carefully,” he said.
Dr. Awad suggested that TMB can be used alongside other factors such as PD-L1 mutations, KRAS mutation status, STK-11, and KEAP1 mutations. “I think all of these features will start to tip the scales one way or the other in terms of using immunotherapy alone or immunotherapy in combination with chemotherapy, and hopefully as new trials are developed, TMB and other predictive biomarkers can be used to stratify populations within a trial to hopefully ensure balance between treatment arms, and also to identify cancers that are less likely to respond to immune checkpoint inhibitors, such that we can really develop more tailored regimens for patients that will or won’t be as likely to respond to immunotherapy.”
The study included 1,552 patients with advanced NSCLC, with a median age of 66; 53.5% were women. The median TMB was 9.82 mutations per megabase. The researchers categorized patients as low TMB (fewer than 19 mutations per megabase) or high TMB (19 or more mutations). The high TMB group associated with better outcomes after treatment with PD-1/PD-L1 inhibitors, including overall response rate, progression-free survival, and overall survival. The associations occurred in the discovery cohort as well as two other independent cohorts. The same relationship occurred in all PD-L1 tumor proportion score subgroups.
Patients with NSCLCs with high TMB as well as PD-L1 expression of 50% or higher had an overall response rate of 57% and had the longest PFS and OS with ICI treatment (18.1 months and 47.7 months, respectively). On the other hand, patients with low TMB and PD-L1–negative NSCLC had the lowest ORR at 8.7% and the shortest PFS and OS (2.1 months and 10.4 months, respectively).
Dr. Awad has consulted for Achilles, AbbVie, Neon, Maverick, Nektar, and Hegrui. He has received grants and personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, and Lilly. He has received personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDx, Mirati, NextCure, Novartis, EMD Serono, and NovaRx.
FROM JAMA ONCOLOGY
after treatment with PD-1 and PD-L1 inhibitors. The findings could supplement other biomarkers, and suggest that chemotherapy could be avoided in some patients.
“We found a TMB value … of 19 mutations per megabase was a strong discriminator of response and nonresponse, and that corresponds to approximately the 90th percentile for TMB in our dataset. That is a higher threshold than has been previously proposed to be used for a TMB cutoff across different datasets or in lung cancer, but it did seem to be a strong discriminator of response, and that also translated into an improvement in progression free survival and overall survival in patients treated with immunotherapy,” said study coauthor Mark Awad, MD, PhD, in a podcast hosted by JAMA. He is a cancer researcher at Harvard Medical School, Boston. The research was published online in JAMA Oncology.
The value was reinforced when the team looked at deciles of TMB, from the lowest 10%, 20%, up to 90%. “It did seem like there was an inflection point, but only at the really higher levels of TMB – above the 80th, or especially the 90th percentile for TMB. That’s where it seemed to make a big difference in terms of improvements in response rate, progression-free, and overall survival,” Dr. Awad said.
The values of TMB and levels of PD-L1 expression also interacted in a useful way. “If you’re looking at PD-L1 on one axis and TMB on the other, it does seem that higher PD-L1 and the higher TMB can really identify patients with strong and great outcomes to immune checkpoint inhibitors. By contrast, low PD-L1 and low TMB really identifies patients that are not likely to benefit from immunotherapy alone and obviously might need to escalate it or more intensified therapy,” he said.
The results could help inform clinical decisions, though Dr. Awad included a caveat that the study was retrospective. In particular, patients with high TMB levels who might not tolerate chemotherapy well could be candidates for immunotherapy alone, “if you feel like there would be time to try immunotherapy alone rather than chemoimmunotherapy, and hopefully spare or avoid some of the chemotherapy toxicities, with the understanding that you wouldn’t want a patient’s disease to rapidly progress. You have to choose these cases carefully,” he said.
Dr. Awad suggested that TMB can be used alongside other factors such as PD-L1 mutations, KRAS mutation status, STK-11, and KEAP1 mutations. “I think all of these features will start to tip the scales one way or the other in terms of using immunotherapy alone or immunotherapy in combination with chemotherapy, and hopefully as new trials are developed, TMB and other predictive biomarkers can be used to stratify populations within a trial to hopefully ensure balance between treatment arms, and also to identify cancers that are less likely to respond to immune checkpoint inhibitors, such that we can really develop more tailored regimens for patients that will or won’t be as likely to respond to immunotherapy.”
The study included 1,552 patients with advanced NSCLC, with a median age of 66; 53.5% were women. The median TMB was 9.82 mutations per megabase. The researchers categorized patients as low TMB (fewer than 19 mutations per megabase) or high TMB (19 or more mutations). The high TMB group associated with better outcomes after treatment with PD-1/PD-L1 inhibitors, including overall response rate, progression-free survival, and overall survival. The associations occurred in the discovery cohort as well as two other independent cohorts. The same relationship occurred in all PD-L1 tumor proportion score subgroups.
Patients with NSCLCs with high TMB as well as PD-L1 expression of 50% or higher had an overall response rate of 57% and had the longest PFS and OS with ICI treatment (18.1 months and 47.7 months, respectively). On the other hand, patients with low TMB and PD-L1–negative NSCLC had the lowest ORR at 8.7% and the shortest PFS and OS (2.1 months and 10.4 months, respectively).
Dr. Awad has consulted for Achilles, AbbVie, Neon, Maverick, Nektar, and Hegrui. He has received grants and personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, and Lilly. He has received personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDx, Mirati, NextCure, Novartis, EMD Serono, and NovaRx.
FROM JAMA ONCOLOGY
after treatment with PD-1 and PD-L1 inhibitors. The findings could supplement other biomarkers, and suggest that chemotherapy could be avoided in some patients.
“We found a TMB value … of 19 mutations per megabase was a strong discriminator of response and nonresponse, and that corresponds to approximately the 90th percentile for TMB in our dataset. That is a higher threshold than has been previously proposed to be used for a TMB cutoff across different datasets or in lung cancer, but it did seem to be a strong discriminator of response, and that also translated into an improvement in progression free survival and overall survival in patients treated with immunotherapy,” said study coauthor Mark Awad, MD, PhD, in a podcast hosted by JAMA. He is a cancer researcher at Harvard Medical School, Boston. The research was published online in JAMA Oncology.
The value was reinforced when the team looked at deciles of TMB, from the lowest 10%, 20%, up to 90%. “It did seem like there was an inflection point, but only at the really higher levels of TMB – above the 80th, or especially the 90th percentile for TMB. That’s where it seemed to make a big difference in terms of improvements in response rate, progression-free, and overall survival,” Dr. Awad said.
The values of TMB and levels of PD-L1 expression also interacted in a useful way. “If you’re looking at PD-L1 on one axis and TMB on the other, it does seem that higher PD-L1 and the higher TMB can really identify patients with strong and great outcomes to immune checkpoint inhibitors. By contrast, low PD-L1 and low TMB really identifies patients that are not likely to benefit from immunotherapy alone and obviously might need to escalate it or more intensified therapy,” he said.
The results could help inform clinical decisions, though Dr. Awad included a caveat that the study was retrospective. In particular, patients with high TMB levels who might not tolerate chemotherapy well could be candidates for immunotherapy alone, “if you feel like there would be time to try immunotherapy alone rather than chemoimmunotherapy, and hopefully spare or avoid some of the chemotherapy toxicities, with the understanding that you wouldn’t want a patient’s disease to rapidly progress. You have to choose these cases carefully,” he said.
Dr. Awad suggested that TMB can be used alongside other factors such as PD-L1 mutations, KRAS mutation status, STK-11, and KEAP1 mutations. “I think all of these features will start to tip the scales one way or the other in terms of using immunotherapy alone or immunotherapy in combination with chemotherapy, and hopefully as new trials are developed, TMB and other predictive biomarkers can be used to stratify populations within a trial to hopefully ensure balance between treatment arms, and also to identify cancers that are less likely to respond to immune checkpoint inhibitors, such that we can really develop more tailored regimens for patients that will or won’t be as likely to respond to immunotherapy.”
The study included 1,552 patients with advanced NSCLC, with a median age of 66; 53.5% were women. The median TMB was 9.82 mutations per megabase. The researchers categorized patients as low TMB (fewer than 19 mutations per megabase) or high TMB (19 or more mutations). The high TMB group associated with better outcomes after treatment with PD-1/PD-L1 inhibitors, including overall response rate, progression-free survival, and overall survival. The associations occurred in the discovery cohort as well as two other independent cohorts. The same relationship occurred in all PD-L1 tumor proportion score subgroups.
Patients with NSCLCs with high TMB as well as PD-L1 expression of 50% or higher had an overall response rate of 57% and had the longest PFS and OS with ICI treatment (18.1 months and 47.7 months, respectively). On the other hand, patients with low TMB and PD-L1–negative NSCLC had the lowest ORR at 8.7% and the shortest PFS and OS (2.1 months and 10.4 months, respectively).
Dr. Awad has consulted for Achilles, AbbVie, Neon, Maverick, Nektar, and Hegrui. He has received grants and personal fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, and Lilly. He has received personal fees from Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDx, Mirati, NextCure, Novartis, EMD Serono, and NovaRx.
Key Data on Early Non–Small Cell Lung Cancer From ESMO 2022
Dr Jack West of City of Hope Comprehensive Cancer Center in Duarte, California, discusses key presentations on early-stage non–small lung cancer (NSCLC) from the 2022 European Society for Medical Oncology Congress.
He begins by reporting on 2 years of additional follow-up from the ADAURA trial, which looked at osimertinib as adjuvant therapy in patients with resected EGFR-mutated disease. The results raise the question of whether the drug needs to be given indefinitely.
Next, he discusses an analysis of data from the ADAURA trial that looked at longitudinal monitoring of circulating tumor DNA (ctDNA) levels. This revealed that both baseline ctDNA and ctDNA clearance were predictive of later recurrence.
Dr West moves on to a large global study that demonstrated a clear link between air pollution and lung cancer. Pollution was shown to be a tumor promoter of rare driver mutations in normal lung tissue.
After discussing disappointing data from CANOPY-A indicating that adjuvant canakinumab does not improve survival outcomes, he closes with an examination of the PATHFINDER study. This involved more than 6600 patients who were screened for cancer after a single blood test. Although the study identified cancer in 1.4% of participants, the low positive predictive value raises questions over the wider application of this test.
--
Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, California; Medical Director, AccessHope, Los Angeles, California
Howard (Jack) West, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Amgen; AstraZeneca; Eli Lilly; EQRx; Genentech/Roche; Merck; Mirati; Pfizer; Regeneron; Takeda
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca; Merck
Dr Jack West of City of Hope Comprehensive Cancer Center in Duarte, California, discusses key presentations on early-stage non–small lung cancer (NSCLC) from the 2022 European Society for Medical Oncology Congress.
He begins by reporting on 2 years of additional follow-up from the ADAURA trial, which looked at osimertinib as adjuvant therapy in patients with resected EGFR-mutated disease. The results raise the question of whether the drug needs to be given indefinitely.
Next, he discusses an analysis of data from the ADAURA trial that looked at longitudinal monitoring of circulating tumor DNA (ctDNA) levels. This revealed that both baseline ctDNA and ctDNA clearance were predictive of later recurrence.
Dr West moves on to a large global study that demonstrated a clear link between air pollution and lung cancer. Pollution was shown to be a tumor promoter of rare driver mutations in normal lung tissue.
After discussing disappointing data from CANOPY-A indicating that adjuvant canakinumab does not improve survival outcomes, he closes with an examination of the PATHFINDER study. This involved more than 6600 patients who were screened for cancer after a single blood test. Although the study identified cancer in 1.4% of participants, the low positive predictive value raises questions over the wider application of this test.
--
Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, California; Medical Director, AccessHope, Los Angeles, California
Howard (Jack) West, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Amgen; AstraZeneca; Eli Lilly; EQRx; Genentech/Roche; Merck; Mirati; Pfizer; Regeneron; Takeda
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca; Merck
Dr Jack West of City of Hope Comprehensive Cancer Center in Duarte, California, discusses key presentations on early-stage non–small lung cancer (NSCLC) from the 2022 European Society for Medical Oncology Congress.
He begins by reporting on 2 years of additional follow-up from the ADAURA trial, which looked at osimertinib as adjuvant therapy in patients with resected EGFR-mutated disease. The results raise the question of whether the drug needs to be given indefinitely.
Next, he discusses an analysis of data from the ADAURA trial that looked at longitudinal monitoring of circulating tumor DNA (ctDNA) levels. This revealed that both baseline ctDNA and ctDNA clearance were predictive of later recurrence.
Dr West moves on to a large global study that demonstrated a clear link between air pollution and lung cancer. Pollution was shown to be a tumor promoter of rare driver mutations in normal lung tissue.
After discussing disappointing data from CANOPY-A indicating that adjuvant canakinumab does not improve survival outcomes, he closes with an examination of the PATHFINDER study. This involved more than 6600 patients who were screened for cancer after a single blood test. Although the study identified cancer in 1.4% of participants, the low positive predictive value raises questions over the wider application of this test.
--
Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, California; Medical Director, AccessHope, Los Angeles, California
Howard (Jack) West, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: Amgen; AstraZeneca; Eli Lilly; EQRx; Genentech/Roche; Merck; Mirati; Pfizer; Regeneron; Takeda
Serve(d) as a speaker or a member of a speakers bureau for: AstraZeneca; Merck
Had my patient come in today, we may have had other options
Decades ago I saw a patient with non–small cell lung cancer (NSCLC) whose tumor was sent out for next-generation sequencing only to find a HER2 mutation. What to do? Had my patient come in today, we may have had other options.
Multiple studies have shown that trastuzumab (Herceptin, Genentech), as assessed by HER2 overexpression or amplification, has been shown to have essentially no efficacy benefit in NSCLC alone or in combination with chemotherapy. In fact, a randomized, phase 2 study of gemcitabine-cisplatin with or without trastuzumab in HER2 mutation–positive NSCLC essentially showed no difference between gemcitabine-cisplatin or gemcitabine-cisplatin with trastuzumab.
NSCLC has become the poster child for targeted therapies. After all, NSCLC makes up about 85% of all lung cancer cases, some of which are driven by gene mutations or other genetic abnormalities like translocation, fusion, or amplification. Seven of these genetic alterations have Food and Drug Administration–approved targeted drugs: EGFR, ALK, ROS1, BRAF V6006, RET, KRAS, MET, and NTRK fusions. And, now we have a new one: HER2.
In August, the FDA granted accelerated approval of trastuzumab deruxtecan (T-DXd) (Enhertu, Daiichi Sankyo) for the second-line treatment of NSCLC patients with HER alterations. T-DXd is a humanized anti-HER antibody linked to a topoisomerase 1 inhibitor. When given intravenously, the antibody portion of the molecule binds to cells with a mutated HER2 on the surface. The molecule is taken up by the cancer cell and the linker between the antibody and the chemotherapy drug is broken, so the drug will be delivered very specifically only to cancer cells that have a mutated HER2. In theory, they will only target cells with HER alterations and thus should have less toxicity.
Unlike other driver mutations, HER mutations are relatively rare. Roughly 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis. Accelerated approved by the FDA was based on data from the DESTINY-Lung 02 phase 2 trial. An interim efficacy analysis of this trial reported an overall response rate to trastuzumab deruxtecan (at 5.4 mg/kg every 3 weeks) of 57.7% in 52 patients. Median duration of response was 8.7 months. Data are also available from the DESTINY-Lung-01 clinical trial, published in the New England Journal of Medicine, in which 91 patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment were treated with T-DXd (at 6.4 mg/kg every 3 weeks). The investigators reported a 55% objective response rate, a median duration of response of 9.3 months, a median progression-free survival (PFS) of 8.2 months, and a median overall survival of almost 18 months.
Companion tests
Biomarker testing is obviously a must in these cases. The FDA-approved companion diagnostic tests to detect HER2 mutations: Life Companion tests, Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue, and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that, if no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Other approvals
T-DXd is also approved for advanced breast and gastric patients who are HER-2 positive. Of note, the majority of HER2-positive NSCLC have HER2 mutations, whereas the majority of HER2-positive breast and gastric cancers have HER2 amplification (increased copy number) or overexpression (increased protein expression).
T-DXd is approved for unresectable or metastatic HER2-positive breast cancer patients who have received a prior anti-HER2–based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. DESTINY-Breast01 enrolled breast cancer patients who had received two or more prior anti-HER2 therapies in the metastatic setting, and reported a response rate of 60.3% with a median duration of response of 14.8 months.
For patients with locally advanced or metastatic HER2-positive gastric cancer who have received two or more prior therapies, including a trastuzumab-based regimen, approval was based on a randomized, phase 3 study comparing 6.4 mg/kg of T-DXd with physician’s choice – either irinotecan or paclitaxel. Overall survival was 12.5 months in the T-DXd arm, compared with 8.4 months in the irinotecan or paclitaxel arm (hazard ratio, 0.59). Response rates were 40.5% and 11.3%, respectively. Median PFS was 5.6 months in the T-DXd arm, compared with a median PFS of 3.5 months in the chemotherapy arm.
Trastuzumab emtansine vs. trastuzumab deruxtecan
Trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, Kadcyla) is another antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the antimicrotubule agent DM1. It is also approved for advanced breast cancer patients with HER2-positive disease. Although no studies comparing T-DXd with trastuzumab emtansine have been conducted in lung cancer patients, a randomized, phase 3 trial in patients with HER2-positive advanced breast cancer comparing the two reported an overall response rate of 79.7% of the patients who received trastuzumab deruxtecan and 34.2% of those who received trastuzumab emtansine. Drug-related interstitial lung disease (ILD) occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; at 12 months, 75.8% of the patients in the trastuzumab deruxtecan were alive without progression, compared with 34.1% of those receiving trastuzumab emtansine.
ILDs
In DESTINY-Lung01, ILD occurred in 26% of patients and resulted in death in two patients. Increased rates of ILD were more commonly observed at higher dose levels. Of 491 patients with unresectable or metastatic HER2-positive breast cancer treated with 5.4 mg/kg of T-TDx, ILD occurred in 13% of patients. Fatal outcomes caused by ILD and/or pneumonitis occurred in 1.4% of patients. Median time to first onset was 5.5 months (range, 1.1-20.8 months). In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with 6.4 mg/kg, T-DXd ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range, 1.2-21.0 months).
Chemotherapy-like adverse effects
Other adverse events are more typically seen with cytotoxic agents and are presumably related to the release of the topoisomerase inhibitor into the blood stream. Although common (occurring in 97% of patients), these adverse events are generally mild (grade 1 or 2). Nausea was reported in about two-thirds of patients. Other side effects occurring in 20% or more of patients included vomiting, decreased appetite, alopecia, and constipation and diarrhea, musculoskeletal pain, and respiratory infections. Laboratory abnormalities occurred in 20% or more of patients included myelosuppression, increased AST, ALT, alkaline phosphatase, and hypokalemia (28%). Grade 3 or higher drug-related adverse events were observed in 46% of patients, with the most common being neutropenia and anemia which was observed in 19% and 10% of patients in the DESTINY-LUNG-01 trial.
Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.
Decades ago I saw a patient with non–small cell lung cancer (NSCLC) whose tumor was sent out for next-generation sequencing only to find a HER2 mutation. What to do? Had my patient come in today, we may have had other options.
Multiple studies have shown that trastuzumab (Herceptin, Genentech), as assessed by HER2 overexpression or amplification, has been shown to have essentially no efficacy benefit in NSCLC alone or in combination with chemotherapy. In fact, a randomized, phase 2 study of gemcitabine-cisplatin with or without trastuzumab in HER2 mutation–positive NSCLC essentially showed no difference between gemcitabine-cisplatin or gemcitabine-cisplatin with trastuzumab.
NSCLC has become the poster child for targeted therapies. After all, NSCLC makes up about 85% of all lung cancer cases, some of which are driven by gene mutations or other genetic abnormalities like translocation, fusion, or amplification. Seven of these genetic alterations have Food and Drug Administration–approved targeted drugs: EGFR, ALK, ROS1, BRAF V6006, RET, KRAS, MET, and NTRK fusions. And, now we have a new one: HER2.
In August, the FDA granted accelerated approval of trastuzumab deruxtecan (T-DXd) (Enhertu, Daiichi Sankyo) for the second-line treatment of NSCLC patients with HER alterations. T-DXd is a humanized anti-HER antibody linked to a topoisomerase 1 inhibitor. When given intravenously, the antibody portion of the molecule binds to cells with a mutated HER2 on the surface. The molecule is taken up by the cancer cell and the linker between the antibody and the chemotherapy drug is broken, so the drug will be delivered very specifically only to cancer cells that have a mutated HER2. In theory, they will only target cells with HER alterations and thus should have less toxicity.
Unlike other driver mutations, HER mutations are relatively rare. Roughly 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis. Accelerated approved by the FDA was based on data from the DESTINY-Lung 02 phase 2 trial. An interim efficacy analysis of this trial reported an overall response rate to trastuzumab deruxtecan (at 5.4 mg/kg every 3 weeks) of 57.7% in 52 patients. Median duration of response was 8.7 months. Data are also available from the DESTINY-Lung-01 clinical trial, published in the New England Journal of Medicine, in which 91 patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment were treated with T-DXd (at 6.4 mg/kg every 3 weeks). The investigators reported a 55% objective response rate, a median duration of response of 9.3 months, a median progression-free survival (PFS) of 8.2 months, and a median overall survival of almost 18 months.
Companion tests
Biomarker testing is obviously a must in these cases. The FDA-approved companion diagnostic tests to detect HER2 mutations: Life Companion tests, Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue, and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that, if no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Other approvals
T-DXd is also approved for advanced breast and gastric patients who are HER-2 positive. Of note, the majority of HER2-positive NSCLC have HER2 mutations, whereas the majority of HER2-positive breast and gastric cancers have HER2 amplification (increased copy number) or overexpression (increased protein expression).
T-DXd is approved for unresectable or metastatic HER2-positive breast cancer patients who have received a prior anti-HER2–based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. DESTINY-Breast01 enrolled breast cancer patients who had received two or more prior anti-HER2 therapies in the metastatic setting, and reported a response rate of 60.3% with a median duration of response of 14.8 months.
For patients with locally advanced or metastatic HER2-positive gastric cancer who have received two or more prior therapies, including a trastuzumab-based regimen, approval was based on a randomized, phase 3 study comparing 6.4 mg/kg of T-DXd with physician’s choice – either irinotecan or paclitaxel. Overall survival was 12.5 months in the T-DXd arm, compared with 8.4 months in the irinotecan or paclitaxel arm (hazard ratio, 0.59). Response rates were 40.5% and 11.3%, respectively. Median PFS was 5.6 months in the T-DXd arm, compared with a median PFS of 3.5 months in the chemotherapy arm.
Trastuzumab emtansine vs. trastuzumab deruxtecan
Trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, Kadcyla) is another antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the antimicrotubule agent DM1. It is also approved for advanced breast cancer patients with HER2-positive disease. Although no studies comparing T-DXd with trastuzumab emtansine have been conducted in lung cancer patients, a randomized, phase 3 trial in patients with HER2-positive advanced breast cancer comparing the two reported an overall response rate of 79.7% of the patients who received trastuzumab deruxtecan and 34.2% of those who received trastuzumab emtansine. Drug-related interstitial lung disease (ILD) occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; at 12 months, 75.8% of the patients in the trastuzumab deruxtecan were alive without progression, compared with 34.1% of those receiving trastuzumab emtansine.
ILDs
In DESTINY-Lung01, ILD occurred in 26% of patients and resulted in death in two patients. Increased rates of ILD were more commonly observed at higher dose levels. Of 491 patients with unresectable or metastatic HER2-positive breast cancer treated with 5.4 mg/kg of T-TDx, ILD occurred in 13% of patients. Fatal outcomes caused by ILD and/or pneumonitis occurred in 1.4% of patients. Median time to first onset was 5.5 months (range, 1.1-20.8 months). In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with 6.4 mg/kg, T-DXd ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range, 1.2-21.0 months).
Chemotherapy-like adverse effects
Other adverse events are more typically seen with cytotoxic agents and are presumably related to the release of the topoisomerase inhibitor into the blood stream. Although common (occurring in 97% of patients), these adverse events are generally mild (grade 1 or 2). Nausea was reported in about two-thirds of patients. Other side effects occurring in 20% or more of patients included vomiting, decreased appetite, alopecia, and constipation and diarrhea, musculoskeletal pain, and respiratory infections. Laboratory abnormalities occurred in 20% or more of patients included myelosuppression, increased AST, ALT, alkaline phosphatase, and hypokalemia (28%). Grade 3 or higher drug-related adverse events were observed in 46% of patients, with the most common being neutropenia and anemia which was observed in 19% and 10% of patients in the DESTINY-LUNG-01 trial.
Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.
Decades ago I saw a patient with non–small cell lung cancer (NSCLC) whose tumor was sent out for next-generation sequencing only to find a HER2 mutation. What to do? Had my patient come in today, we may have had other options.
Multiple studies have shown that trastuzumab (Herceptin, Genentech), as assessed by HER2 overexpression or amplification, has been shown to have essentially no efficacy benefit in NSCLC alone or in combination with chemotherapy. In fact, a randomized, phase 2 study of gemcitabine-cisplatin with or without trastuzumab in HER2 mutation–positive NSCLC essentially showed no difference between gemcitabine-cisplatin or gemcitabine-cisplatin with trastuzumab.
NSCLC has become the poster child for targeted therapies. After all, NSCLC makes up about 85% of all lung cancer cases, some of which are driven by gene mutations or other genetic abnormalities like translocation, fusion, or amplification. Seven of these genetic alterations have Food and Drug Administration–approved targeted drugs: EGFR, ALK, ROS1, BRAF V6006, RET, KRAS, MET, and NTRK fusions. And, now we have a new one: HER2.
In August, the FDA granted accelerated approval of trastuzumab deruxtecan (T-DXd) (Enhertu, Daiichi Sankyo) for the second-line treatment of NSCLC patients with HER alterations. T-DXd is a humanized anti-HER antibody linked to a topoisomerase 1 inhibitor. When given intravenously, the antibody portion of the molecule binds to cells with a mutated HER2 on the surface. The molecule is taken up by the cancer cell and the linker between the antibody and the chemotherapy drug is broken, so the drug will be delivered very specifically only to cancer cells that have a mutated HER2. In theory, they will only target cells with HER alterations and thus should have less toxicity.
Unlike other driver mutations, HER mutations are relatively rare. Roughly 3% of nonsquamous NSCLC tumors carry mutations in the HER2 gene, and they are associated with female sex, never-smokers, and a poor prognosis. Accelerated approved by the FDA was based on data from the DESTINY-Lung 02 phase 2 trial. An interim efficacy analysis of this trial reported an overall response rate to trastuzumab deruxtecan (at 5.4 mg/kg every 3 weeks) of 57.7% in 52 patients. Median duration of response was 8.7 months. Data are also available from the DESTINY-Lung-01 clinical trial, published in the New England Journal of Medicine, in which 91 patients with metastatic HER2-mutant NSCLC that was refractory to standard treatment were treated with T-DXd (at 6.4 mg/kg every 3 weeks). The investigators reported a 55% objective response rate, a median duration of response of 9.3 months, a median progression-free survival (PFS) of 8.2 months, and a median overall survival of almost 18 months.
Companion tests
Biomarker testing is obviously a must in these cases. The FDA-approved companion diagnostic tests to detect HER2 mutations: Life Companion tests, Technologies Corporation’s Oncomine Dx Target Test for use in lung tissue, and Guardant Health’s Guardant360 CDx for use on plasma samples. The agency notes that, if no mutation is detected in a plasma specimen, the tumor tissue should be tested.
Other approvals
T-DXd is also approved for advanced breast and gastric patients who are HER-2 positive. Of note, the majority of HER2-positive NSCLC have HER2 mutations, whereas the majority of HER2-positive breast and gastric cancers have HER2 amplification (increased copy number) or overexpression (increased protein expression).
T-DXd is approved for unresectable or metastatic HER2-positive breast cancer patients who have received a prior anti-HER2–based regimen in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. DESTINY-Breast01 enrolled breast cancer patients who had received two or more prior anti-HER2 therapies in the metastatic setting, and reported a response rate of 60.3% with a median duration of response of 14.8 months.
For patients with locally advanced or metastatic HER2-positive gastric cancer who have received two or more prior therapies, including a trastuzumab-based regimen, approval was based on a randomized, phase 3 study comparing 6.4 mg/kg of T-DXd with physician’s choice – either irinotecan or paclitaxel. Overall survival was 12.5 months in the T-DXd arm, compared with 8.4 months in the irinotecan or paclitaxel arm (hazard ratio, 0.59). Response rates were 40.5% and 11.3%, respectively. Median PFS was 5.6 months in the T-DXd arm, compared with a median PFS of 3.5 months in the chemotherapy arm.
Trastuzumab emtansine vs. trastuzumab deruxtecan
Trastuzumab emtansine (T-DM1, ado-trastuzumab emtansine, Kadcyla) is another antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the antimicrotubule agent DM1. It is also approved for advanced breast cancer patients with HER2-positive disease. Although no studies comparing T-DXd with trastuzumab emtansine have been conducted in lung cancer patients, a randomized, phase 3 trial in patients with HER2-positive advanced breast cancer comparing the two reported an overall response rate of 79.7% of the patients who received trastuzumab deruxtecan and 34.2% of those who received trastuzumab emtansine. Drug-related interstitial lung disease (ILD) occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; at 12 months, 75.8% of the patients in the trastuzumab deruxtecan were alive without progression, compared with 34.1% of those receiving trastuzumab emtansine.
ILDs
In DESTINY-Lung01, ILD occurred in 26% of patients and resulted in death in two patients. Increased rates of ILD were more commonly observed at higher dose levels. Of 491 patients with unresectable or metastatic HER2-positive breast cancer treated with 5.4 mg/kg of T-TDx, ILD occurred in 13% of patients. Fatal outcomes caused by ILD and/or pneumonitis occurred in 1.4% of patients. Median time to first onset was 5.5 months (range, 1.1-20.8 months). In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma treated with 6.4 mg/kg, T-DXd ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range, 1.2-21.0 months).
Chemotherapy-like adverse effects
Other adverse events are more typically seen with cytotoxic agents and are presumably related to the release of the topoisomerase inhibitor into the blood stream. Although common (occurring in 97% of patients), these adverse events are generally mild (grade 1 or 2). Nausea was reported in about two-thirds of patients. Other side effects occurring in 20% or more of patients included vomiting, decreased appetite, alopecia, and constipation and diarrhea, musculoskeletal pain, and respiratory infections. Laboratory abnormalities occurred in 20% or more of patients included myelosuppression, increased AST, ALT, alkaline phosphatase, and hypokalemia (28%). Grade 3 or higher drug-related adverse events were observed in 46% of patients, with the most common being neutropenia and anemia which was observed in 19% and 10% of patients in the DESTINY-LUNG-01 trial.
Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.
Cancer as a full contact sport
John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.
John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?
Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.
He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.
And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
Interprofessional teamwork is fundamental to treat ‘total pain’
None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?
Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.
But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.
You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
Teamwork improves quality of life
My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.
The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.
Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.
John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.
John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?
Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.
He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.
And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
Interprofessional teamwork is fundamental to treat ‘total pain’
None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?
Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.
But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.
You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
Teamwork improves quality of life
My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.
The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.
Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.
John worked as a handyman and lived on a small sailboat in a marina. When he was diagnosed with metastatic kidney cancer at age 48, he quickly fell through the cracks. He failed to show to appointments and took oral anticancer treatments, but just sporadically. He had Medicaid, so insurance wasn’t the issue. It was everything else.
John was behind on his slip fees; he hadn’t been able to work for some time because of his progressive weakness and pain. He was chronically in danger of getting kicked out of his makeshift home aboard the boat. He had no reliable transportation to the clinic and so he didn’t come to appointments regularly. The specialty pharmacy refused to deliver his expensive oral chemotherapy to his address at the marina. He went days without eating full meals because he was too weak to cook for himself. Plus, he was estranged from his family who were unaware of his illness. His oncologist was overwhelmed trying to take care of him. He had a reasonable chance of achieving disease control on first-line oral therapy, but his problems seemed to hinder these chances at every turn. She was distraught – what could she do?
Enter the team approach. John’s oncologist reached out to our palliative care program for help. We recognized that this was a job too big for us alone so we connected John with the Extensivist Medicine program at UCLA Health, a high-intensity primary care program led by a physician specializing in primary care for high-risk individuals. The program provides wraparound outpatient services for chronically and seriously ill patients, like John, who are at risk for falling through the cracks. John went from receiving very little support to now having an entire team of caring professionals focused on helping him achieve his best possible outcome despite the seriousness of his disease.
He now had the support of a high-functioning team with clearly defined roles. Social work connected him with housing, food, and transportation resources. A nurse called him every day to check in and make sure he was taking medications and reminded him about his upcoming appointments. Case management helped him get needed equipment, such as grab bars and a walker. As his palliative care nurse practitioner, I counseled him on understanding his prognosis and planning ahead for medical emergencies. Our psycho-oncology clinicians helped John reconcile with his family, who were more than willing to take him in once they realized how ill he was. Once these social factors were addressed, John could more easily stay current with his oral chemotherapy, giving him the best chance possible to achieve a robust treatment response that could buy him more time.
And, John did get that time – he got 6 months of improved quality of life, during which he reconnected with his family, including his children, and rebuilt these important relationships. Eventually treatment failed him. His disease, already widely metastatic, became more active and painful. He accepted hospice care at his sister’s house and we transitioned him from our team to the hospice team. He died peacefully surrounded by family.
Interprofessional teamwork is fundamental to treat ‘total pain’
None of this would have been possible without the work of high-functioning teams. It is a commonly held belief that interprofessional teamwork is fundamental to the care of patients and families living with serious illness. But why? How did this idea come about? And what evidence is there to support teamwork?
Dame Cicely Saunders, who founded the modern hospice movement in mid-20th century England, embodied the interdisciplinary team by working first as a nurse, then a social worker, and finally as a physician. She wrote about patients’ “total pain,” the crisis of physical, spiritual, social, and emotional distress that many people have at the end of life. She understood that no single health care discipline was adequate to the task of addressing each of these domains equally well. Thus, hospice became synonymous with care provided by a quartet of specialists – physicians, nurses, social workers, and chaplains. Nowadays, there are other specialists that are added to the mix – home health aides, pharmacists, physical and occupational therapists, music and pet therapists, and so on.
But in medicine, like all areas of science, convention and tradition only go so far. What evidence is there to support the work of an interdisciplinary team in managing the distress of patients and families living with advanced illnesses? It turns out that there is good evidence to support the use of high-functioning interdisciplinary teams in the care of the seriously ill. Palliative care is associated with improved patient outcomes, including improvements in symptom control, quality of life, and end of life care, when it is delivered by an interdisciplinary team rather than by a solo practitioner.
You may think that teamwork is most useful for patients like John who have seemingly intractable social barriers. But it is also true that for even patients with many more social advantages teamwork improves quality of life. I got to see this up close recently in my own life.
Teamwork improves quality of life
My father recently passed away after a 9-month battle with advanced cancer. He had every advantage possible – financial stability, high health literacy, an incredibly devoted spouse who happens to be an RN, good insurance, and access to top-notch medical care. Yet, even he benefited from a team approach. It started small, with the oncologist and oncology NP providing excellent, patient-centered care. Then it grew to include myself as the daughter/palliative care nurse practitioner who made recommendations for treating his nausea and ensured that his advance directive was completed and uploaded to his chart. When my dad needed physical therapy, the home health agency sent a wonderful physical therapist, who brought all sorts of equipment that kept him more functional than he would have been otherwise. Other family members helped out – my sisters helped connect my dad with a priest who came to the home to provide spiritual care, which was crucial to ensuring that he was at peace. And, in his final days, my dad had the hospice team to help manage his symptoms and his family members to provide hands-on care.
The complexity of cancer care has long necessitated a team approach to planning cancer treatment – known as a tumor board – with medical oncology, radiation oncology, surgery, and pathology all weighing in. It makes sense that patients and their families would also need a team of clinicians representing different specialty areas to assist with the wide array of physical, psychosocial, practical, and spiritual concerns that arise throughout the cancer disease trajectory.
Ms. D’Ambruoso is a hospice and palliative care nurse practitioner for UCLA Health Cancer Care, Santa Monica, Calif.
In progressive lung cancer second biopsies may be the norm now
Shortly after osimertinib was approved for patients with non–small cell lung cancer in 2020 by the Food and Drug Administration, a patient came to me with increasing shortness of breath. He had been on erlotinib (Tarceva) for about 2 years and had done well. Nearly all of his pulmonary lesions had resolved and he was feeling well. He enjoyed boating in the summer and visiting grandkids in California in the winter. However, on this day, it was different. He was losing weight; he was tired and didn’t feel strong enough to put his boat in the water that spring. Long story short: We ordered a CT scan and all of his lesions were progressing. Since osimertinib had just been approved, we got a second biopsy, hoping that his insurance would pay for it. It did and sure enough, a new T790M mutation was present. He was on osimertinib for another 2 years before progressing and starting chemotherapy.
Second biopsies increasingly routine
The practice of ordering a second biopsy for patients with non–small cell lung carcinoma (NSCLC) was not common practice until after 2015 when the Food and Drug Administration approved gefitinib, a tyrosine kinase inhibitor (TKI) for patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.
Up until then, second biopsies were not routinely done for lung cancers. But with the advent of targeted therapy and new drugs designed specifically to tackle first- and second-line treatment resistance mutations, rebiopsies have become a necessity for patients with progressive disease.
Epidermal growth factors, including HER2, ErbB2, and MET, are receptors of tyrosine kinases that control cell growth, but when in overdrive, they can lead to the development of cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, colon adenocarcinoma, and NSCLC.
EGFRs date back to 1962 with their discovery by Stanley Cohen. The discovery was so important that in 1986, Mr. Cohen was awarded the Nobel Prize in physiology or medicine for the discovery along with Rita Levi-Montalcini.
Now, many years later, we finally have a string of new approvals for mutations in the EGF family of receptors and several under study.
Sensitizing mutations
The more commonly used strategy for blocking EGFR signaling in lung cancer is the use of tyrosine kinase inhibitors, which compete with adenosine triphosphate (ATP) for binding to the tyrosine kinase portion of the receptor. They are located at chromosome 7p11.2. The most frequent mutations that sensitize patients to EGFR inhibitors include exon 19 deletions and L858R point mutation in exon 21, although multiple other driver mutations also exist.
The first-generation of EGFR TKIs include gefitinib and erlotinib, which bind reversibly to the EGF receptor. Second-generation inhibitors afatinib and dacomitinib bind irreversibly. Osimertinib, a third-generation EGFR TKI, which also binds irreversibly, was approved in 2020 for adjuvant therapy, and first- and second-line treatment in patients with NSCLC who have EGFR mutation–positive disease.
First-generation EGFR tyrosine kinase inhibitors
Four randomized, first-line, placebo-controlled phase 3 trials conducted with EGFR TKIs in combination with platinum-based doublet chemotherapy in an EGFR nonselected patient population failed to show a survival benefit with erlotinib or gefitinib (TRIBUTE, Tarceva Lung Cancer Investigation Trial, INTACT 1, INTACT 2).
However, a first-line study randomized patients to gefitinib or chemotherapy with carboplatin-paclitaxel, and included patients with or without an EGFR mutations. In the subgroup of patients with an EGFR mutation, progression-free survival (PFS) was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48), whereas in the subgroup of patients who were negative for the mutation, PFS was significantly longer among those who received chemotherapy (HR for progression or death with gefitinib, 2.85).
Numerous studies have shown that EGFR TKIs used in the first-line setting improved progression free survival, response rates, and quality of life while reducing toxicity. A recent meta-analysis of randomized clinical trials involving EGFR TKIs showed that EGFR TKI improved PFS with a HR of 0.40, compared with standard chemotherapy with fewer serious adverse events, although no benefit on overall survival was observed (HR, 0.96; 95% confidence interval, 0.83-1.10; P = .556).
T790M: The most common resistance mutation
T790M is the most common resistance mechanism to develop in patients with EGFR mutations being treated with EGFR TKIs. A randomized phase 3 trial of osimertinib vs. chemotherapy in patients with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy, reported a median duration of progression-free survival that was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; HR, 0.30). In addition, among 144 patients with metastases to the central nervous system, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; HR, 0.32). However, now that osimertinib has moved into the front-line setting, it has left a void for the treatment of patients with advanced disease who have failed osimertinib.
New resistance mechanisms continue to be identified
One of the most common sets of resistance mutations are insertions in exon 20 of the EGF receptor gene. These are a heterogenous group of mutations, many of which do not respond to first-, second-, or third-generation TKIs. Some, such as EGFR-A763_Y764insFQEA, may be sensitive to first- and third-generation EGFR TKIs. Other drugs targeting exon 20 insertion mutations are under development.
Newly approved by the FDA within the last year are mobocertinib and CLN-081 for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.
Savolitinib is a receptor tyrosine kinase (MET) inhibitor currently under development for NSCLC and other cancers. Amivantamab-vmjw was approved by the FDA last year for metastatic NSCLC. It targets EGF and MET receptors in patients with EGFR exon 20 insertion mutations.
We finally have approved drugs for exon 20 insertions and c-Met amplification, even though their approvals are based on small, single arm studies with no definitive claims of improved efficacy over older therapies. as in my patient described in this article.
Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.
Shortly after osimertinib was approved for patients with non–small cell lung cancer in 2020 by the Food and Drug Administration, a patient came to me with increasing shortness of breath. He had been on erlotinib (Tarceva) for about 2 years and had done well. Nearly all of his pulmonary lesions had resolved and he was feeling well. He enjoyed boating in the summer and visiting grandkids in California in the winter. However, on this day, it was different. He was losing weight; he was tired and didn’t feel strong enough to put his boat in the water that spring. Long story short: We ordered a CT scan and all of his lesions were progressing. Since osimertinib had just been approved, we got a second biopsy, hoping that his insurance would pay for it. It did and sure enough, a new T790M mutation was present. He was on osimertinib for another 2 years before progressing and starting chemotherapy.
Second biopsies increasingly routine
The practice of ordering a second biopsy for patients with non–small cell lung carcinoma (NSCLC) was not common practice until after 2015 when the Food and Drug Administration approved gefitinib, a tyrosine kinase inhibitor (TKI) for patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.
Up until then, second biopsies were not routinely done for lung cancers. But with the advent of targeted therapy and new drugs designed specifically to tackle first- and second-line treatment resistance mutations, rebiopsies have become a necessity for patients with progressive disease.
Epidermal growth factors, including HER2, ErbB2, and MET, are receptors of tyrosine kinases that control cell growth, but when in overdrive, they can lead to the development of cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, colon adenocarcinoma, and NSCLC.
EGFRs date back to 1962 with their discovery by Stanley Cohen. The discovery was so important that in 1986, Mr. Cohen was awarded the Nobel Prize in physiology or medicine for the discovery along with Rita Levi-Montalcini.
Now, many years later, we finally have a string of new approvals for mutations in the EGF family of receptors and several under study.
Sensitizing mutations
The more commonly used strategy for blocking EGFR signaling in lung cancer is the use of tyrosine kinase inhibitors, which compete with adenosine triphosphate (ATP) for binding to the tyrosine kinase portion of the receptor. They are located at chromosome 7p11.2. The most frequent mutations that sensitize patients to EGFR inhibitors include exon 19 deletions and L858R point mutation in exon 21, although multiple other driver mutations also exist.
The first-generation of EGFR TKIs include gefitinib and erlotinib, which bind reversibly to the EGF receptor. Second-generation inhibitors afatinib and dacomitinib bind irreversibly. Osimertinib, a third-generation EGFR TKI, which also binds irreversibly, was approved in 2020 for adjuvant therapy, and first- and second-line treatment in patients with NSCLC who have EGFR mutation–positive disease.
First-generation EGFR tyrosine kinase inhibitors
Four randomized, first-line, placebo-controlled phase 3 trials conducted with EGFR TKIs in combination with platinum-based doublet chemotherapy in an EGFR nonselected patient population failed to show a survival benefit with erlotinib or gefitinib (TRIBUTE, Tarceva Lung Cancer Investigation Trial, INTACT 1, INTACT 2).
However, a first-line study randomized patients to gefitinib or chemotherapy with carboplatin-paclitaxel, and included patients with or without an EGFR mutations. In the subgroup of patients with an EGFR mutation, progression-free survival (PFS) was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48), whereas in the subgroup of patients who were negative for the mutation, PFS was significantly longer among those who received chemotherapy (HR for progression or death with gefitinib, 2.85).
Numerous studies have shown that EGFR TKIs used in the first-line setting improved progression free survival, response rates, and quality of life while reducing toxicity. A recent meta-analysis of randomized clinical trials involving EGFR TKIs showed that EGFR TKI improved PFS with a HR of 0.40, compared with standard chemotherapy with fewer serious adverse events, although no benefit on overall survival was observed (HR, 0.96; 95% confidence interval, 0.83-1.10; P = .556).
T790M: The most common resistance mutation
T790M is the most common resistance mechanism to develop in patients with EGFR mutations being treated with EGFR TKIs. A randomized phase 3 trial of osimertinib vs. chemotherapy in patients with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy, reported a median duration of progression-free survival that was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; HR, 0.30). In addition, among 144 patients with metastases to the central nervous system, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; HR, 0.32). However, now that osimertinib has moved into the front-line setting, it has left a void for the treatment of patients with advanced disease who have failed osimertinib.
New resistance mechanisms continue to be identified
One of the most common sets of resistance mutations are insertions in exon 20 of the EGF receptor gene. These are a heterogenous group of mutations, many of which do not respond to first-, second-, or third-generation TKIs. Some, such as EGFR-A763_Y764insFQEA, may be sensitive to first- and third-generation EGFR TKIs. Other drugs targeting exon 20 insertion mutations are under development.
Newly approved by the FDA within the last year are mobocertinib and CLN-081 for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.
Savolitinib is a receptor tyrosine kinase (MET) inhibitor currently under development for NSCLC and other cancers. Amivantamab-vmjw was approved by the FDA last year for metastatic NSCLC. It targets EGF and MET receptors in patients with EGFR exon 20 insertion mutations.
We finally have approved drugs for exon 20 insertions and c-Met amplification, even though their approvals are based on small, single arm studies with no definitive claims of improved efficacy over older therapies. as in my patient described in this article.
Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.
Shortly after osimertinib was approved for patients with non–small cell lung cancer in 2020 by the Food and Drug Administration, a patient came to me with increasing shortness of breath. He had been on erlotinib (Tarceva) for about 2 years and had done well. Nearly all of his pulmonary lesions had resolved and he was feeling well. He enjoyed boating in the summer and visiting grandkids in California in the winter. However, on this day, it was different. He was losing weight; he was tired and didn’t feel strong enough to put his boat in the water that spring. Long story short: We ordered a CT scan and all of his lesions were progressing. Since osimertinib had just been approved, we got a second biopsy, hoping that his insurance would pay for it. It did and sure enough, a new T790M mutation was present. He was on osimertinib for another 2 years before progressing and starting chemotherapy.
Second biopsies increasingly routine
The practice of ordering a second biopsy for patients with non–small cell lung carcinoma (NSCLC) was not common practice until after 2015 when the Food and Drug Administration approved gefitinib, a tyrosine kinase inhibitor (TKI) for patients whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.
Up until then, second biopsies were not routinely done for lung cancers. But with the advent of targeted therapy and new drugs designed specifically to tackle first- and second-line treatment resistance mutations, rebiopsies have become a necessity for patients with progressive disease.
Epidermal growth factors, including HER2, ErbB2, and MET, are receptors of tyrosine kinases that control cell growth, but when in overdrive, they can lead to the development of cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, colon adenocarcinoma, and NSCLC.
EGFRs date back to 1962 with their discovery by Stanley Cohen. The discovery was so important that in 1986, Mr. Cohen was awarded the Nobel Prize in physiology or medicine for the discovery along with Rita Levi-Montalcini.
Now, many years later, we finally have a string of new approvals for mutations in the EGF family of receptors and several under study.
Sensitizing mutations
The more commonly used strategy for blocking EGFR signaling in lung cancer is the use of tyrosine kinase inhibitors, which compete with adenosine triphosphate (ATP) for binding to the tyrosine kinase portion of the receptor. They are located at chromosome 7p11.2. The most frequent mutations that sensitize patients to EGFR inhibitors include exon 19 deletions and L858R point mutation in exon 21, although multiple other driver mutations also exist.
The first-generation of EGFR TKIs include gefitinib and erlotinib, which bind reversibly to the EGF receptor. Second-generation inhibitors afatinib and dacomitinib bind irreversibly. Osimertinib, a third-generation EGFR TKI, which also binds irreversibly, was approved in 2020 for adjuvant therapy, and first- and second-line treatment in patients with NSCLC who have EGFR mutation–positive disease.
First-generation EGFR tyrosine kinase inhibitors
Four randomized, first-line, placebo-controlled phase 3 trials conducted with EGFR TKIs in combination with platinum-based doublet chemotherapy in an EGFR nonselected patient population failed to show a survival benefit with erlotinib or gefitinib (TRIBUTE, Tarceva Lung Cancer Investigation Trial, INTACT 1, INTACT 2).
However, a first-line study randomized patients to gefitinib or chemotherapy with carboplatin-paclitaxel, and included patients with or without an EGFR mutations. In the subgroup of patients with an EGFR mutation, progression-free survival (PFS) was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48), whereas in the subgroup of patients who were negative for the mutation, PFS was significantly longer among those who received chemotherapy (HR for progression or death with gefitinib, 2.85).
Numerous studies have shown that EGFR TKIs used in the first-line setting improved progression free survival, response rates, and quality of life while reducing toxicity. A recent meta-analysis of randomized clinical trials involving EGFR TKIs showed that EGFR TKI improved PFS with a HR of 0.40, compared with standard chemotherapy with fewer serious adverse events, although no benefit on overall survival was observed (HR, 0.96; 95% confidence interval, 0.83-1.10; P = .556).
T790M: The most common resistance mutation
T790M is the most common resistance mechanism to develop in patients with EGFR mutations being treated with EGFR TKIs. A randomized phase 3 trial of osimertinib vs. chemotherapy in patients with T790M-positive advanced NSCLC who had disease progression after first-line EGFR-TKI therapy, reported a median duration of progression-free survival that was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; HR, 0.30). In addition, among 144 patients with metastases to the central nervous system, the median duration of PFS was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; HR, 0.32). However, now that osimertinib has moved into the front-line setting, it has left a void for the treatment of patients with advanced disease who have failed osimertinib.
New resistance mechanisms continue to be identified
One of the most common sets of resistance mutations are insertions in exon 20 of the EGF receptor gene. These are a heterogenous group of mutations, many of which do not respond to first-, second-, or third-generation TKIs. Some, such as EGFR-A763_Y764insFQEA, may be sensitive to first- and third-generation EGFR TKIs. Other drugs targeting exon 20 insertion mutations are under development.
Newly approved by the FDA within the last year are mobocertinib and CLN-081 for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.
Savolitinib is a receptor tyrosine kinase (MET) inhibitor currently under development for NSCLC and other cancers. Amivantamab-vmjw was approved by the FDA last year for metastatic NSCLC. It targets EGF and MET receptors in patients with EGFR exon 20 insertion mutations.
We finally have approved drugs for exon 20 insertions and c-Met amplification, even though their approvals are based on small, single arm studies with no definitive claims of improved efficacy over older therapies. as in my patient described in this article.
Dr. Schiller is a medical oncologist and founding member of Oncologists United for Climate and Health. She is a former board member of the International Association for the Study of Lung Cancer and a current board member of the Lung Cancer Research Foundation.
Despite benefits, extended-interval pembro uptake remains low
In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.
The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.
Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.
However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.
Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.
Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.
Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.
And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.
The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.
Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.
“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.
“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.
In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.
It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.
If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.
“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.
To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”
Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.
Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”
Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.
The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.
A version of this article first appeared on Medscape.com.
In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.
The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.
Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.
However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.
Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.
Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.
Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.
And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.
The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.
Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.
“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.
“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.
In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.
It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.
If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.
“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.
To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”
Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.
Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”
Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.
The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.
A version of this article first appeared on Medscape.com.
In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.
The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.
Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.
However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.
Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.
Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.
Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.
And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.
The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.
Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.
“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.
“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.
In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.
It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.
If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.
“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.
To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”
Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.
Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”
Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.
The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.
A version of this article first appeared on Medscape.com.
FROM JAMA ONCOLOGY
Weight gain linked to cancer survival in men and women
Cancer cachexia is a syndrome of weight loss that frequently occurs during cancer treatment. Consequences can include skeletal muscle loss, fatigue, functional impairment, worse quality of life, and worse survival. On the other hand, weight gain during cancer treatment has been tied to better survival.
Few studies have examined the relationship between weight gain and outcomes by sex.
“The finding that weight gain occurred in subsets of males and females is a new observation. The fact that weight gain occurs in cancer patients during anticancer treatment could confound results of clinical [trials] evaluating novel anticachexia treatments. Simultaneously studying longitudinal body weights and serum and cellular biomarkers in cancer patients might provide insights into mechanisms involved in cachexia. Increased understanding of mechanisms driving cachexia could lead to new therapeutic strategies,” said study coauthor Philip Bonomi, MD, who is an oncologist at Rush Medical College, Chicago.
“This data, although it appears to be very basic, is critically important, especially as we consider our novel interventions in the treatment of cancer cachexia,” said Eric Roeland, MD, during his presentation of the study at the annual meeting of European Society for Medical Oncology. Dr. Roeland is a medical oncologist at Oregon Health & Science University, Portland.
Dr. Roeland is also the lead author of cancer cachexia guidelines published by the American Society of Clinical Oncology in 2020. The guidelines suggest that dietary counseling can be offered to patients, but warns against routine use of enteral feeding tubes and parenteral nutrition. Although no specific drug can be recommended for cancer cachexia, progesterone analogs and corticosteroids used over the short term (weeks) can be used on a trial base to improve appetite and weight gain. While not approved in the United States, anamorelin was approved in 2020 in Japan for cancer cachexia in NSCLC, gastric cancer, pancreatic cancer, and colorectal cancer.
The new study should raise awareness of the importance of adverse effects of cancer treatments, said Karin Jordan, MD, University Hospital Heidelberg (Germany). She served as a discussant following the presentation. “As a medical oncologist, we focus a bit too much on the benefits of antineoplastic therapy, both on cure and on the survival benefit. But what is also very, very important to do is a balanced oncology treatment to focus on the risks of oncology therapies,” she said.
The study is limited by its retrospective nature and potential for bias. “The hypothesis that weight gain leads to improved survival is not really proven as it likewise may be the other way around,” Dr. Jordan said.
However, in oncology research, a phenomenon called the “obesity paradox” is increasingly catching the interest of investigators. Observational studies have shown that overweight patients with certain cancers (specifically, colorectal, endometrial and lung cancer). actually have improved overall survival as compared with normal-weight patients.
Details from the new study
The researchers pooled data 1,030 patients who participated in three phase 3 clinical trials conducted between 2005 and 2011. The patients all received platinum-based chemotherapy as part of control arms. 304 were female and 726 were male. The median age was 62. 16.7% were Asian, the mean body mass index was 24.6 kg/m2, 88.5% had stage 4 disease, 36.9% had adenocarcinoma, and 86.3% were current or former smokers.
Males and females had similar magnitudes and rate of weight gain over the course of treatment. Any weight gain was associated with improved overall survival in both males (12.7 vs. 8.0 months; hazard ratio, 0.60; P < .001) and females (16.2 vs. 10.1 months; HR, 0.65; P = .0028). Patients who had a weight gain of 2.5% of body weight or more saw an improvement in overall survival in both males (14.0 vs. 8.2 months; HR, 0.57; P < .001) and females (16.7 vs. 11.3 months; HR, 0.61; P = .0041).
Patients with a weight gain of 5% or more was associated with improved survival in males (13.6 vs. 8.9 months; HR, 0.62; P = .0001), but there was no statistically significant association in females (16.7 vs. 12.6 months; HR, 0.69; P = .1107).
Regardless of weight-gain status, males had lower survival rates than females. All of the associations were independent of smoking status.
The study was funded by Pfizer. Dr. Bonomi has received honoraria from Pfizer and Helsinn for participation in scientific advisory boards. Dr. Jordan has consulted for Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, and BD Solution. She has received research funding from Deutsche Krebshilfe. She has received honoraria from MSD, Merck, Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, Pomme-med, PharmaMar, arttemoi, OnkoUpdate, Stemline, and Roche.
Cancer cachexia is a syndrome of weight loss that frequently occurs during cancer treatment. Consequences can include skeletal muscle loss, fatigue, functional impairment, worse quality of life, and worse survival. On the other hand, weight gain during cancer treatment has been tied to better survival.
Few studies have examined the relationship between weight gain and outcomes by sex.
“The finding that weight gain occurred in subsets of males and females is a new observation. The fact that weight gain occurs in cancer patients during anticancer treatment could confound results of clinical [trials] evaluating novel anticachexia treatments. Simultaneously studying longitudinal body weights and serum and cellular biomarkers in cancer patients might provide insights into mechanisms involved in cachexia. Increased understanding of mechanisms driving cachexia could lead to new therapeutic strategies,” said study coauthor Philip Bonomi, MD, who is an oncologist at Rush Medical College, Chicago.
“This data, although it appears to be very basic, is critically important, especially as we consider our novel interventions in the treatment of cancer cachexia,” said Eric Roeland, MD, during his presentation of the study at the annual meeting of European Society for Medical Oncology. Dr. Roeland is a medical oncologist at Oregon Health & Science University, Portland.
Dr. Roeland is also the lead author of cancer cachexia guidelines published by the American Society of Clinical Oncology in 2020. The guidelines suggest that dietary counseling can be offered to patients, but warns against routine use of enteral feeding tubes and parenteral nutrition. Although no specific drug can be recommended for cancer cachexia, progesterone analogs and corticosteroids used over the short term (weeks) can be used on a trial base to improve appetite and weight gain. While not approved in the United States, anamorelin was approved in 2020 in Japan for cancer cachexia in NSCLC, gastric cancer, pancreatic cancer, and colorectal cancer.
The new study should raise awareness of the importance of adverse effects of cancer treatments, said Karin Jordan, MD, University Hospital Heidelberg (Germany). She served as a discussant following the presentation. “As a medical oncologist, we focus a bit too much on the benefits of antineoplastic therapy, both on cure and on the survival benefit. But what is also very, very important to do is a balanced oncology treatment to focus on the risks of oncology therapies,” she said.
The study is limited by its retrospective nature and potential for bias. “The hypothesis that weight gain leads to improved survival is not really proven as it likewise may be the other way around,” Dr. Jordan said.
However, in oncology research, a phenomenon called the “obesity paradox” is increasingly catching the interest of investigators. Observational studies have shown that overweight patients with certain cancers (specifically, colorectal, endometrial and lung cancer). actually have improved overall survival as compared with normal-weight patients.
Details from the new study
The researchers pooled data 1,030 patients who participated in three phase 3 clinical trials conducted between 2005 and 2011. The patients all received platinum-based chemotherapy as part of control arms. 304 were female and 726 were male. The median age was 62. 16.7% were Asian, the mean body mass index was 24.6 kg/m2, 88.5% had stage 4 disease, 36.9% had adenocarcinoma, and 86.3% were current or former smokers.
Males and females had similar magnitudes and rate of weight gain over the course of treatment. Any weight gain was associated with improved overall survival in both males (12.7 vs. 8.0 months; hazard ratio, 0.60; P < .001) and females (16.2 vs. 10.1 months; HR, 0.65; P = .0028). Patients who had a weight gain of 2.5% of body weight or more saw an improvement in overall survival in both males (14.0 vs. 8.2 months; HR, 0.57; P < .001) and females (16.7 vs. 11.3 months; HR, 0.61; P = .0041).
Patients with a weight gain of 5% or more was associated with improved survival in males (13.6 vs. 8.9 months; HR, 0.62; P = .0001), but there was no statistically significant association in females (16.7 vs. 12.6 months; HR, 0.69; P = .1107).
Regardless of weight-gain status, males had lower survival rates than females. All of the associations were independent of smoking status.
The study was funded by Pfizer. Dr. Bonomi has received honoraria from Pfizer and Helsinn for participation in scientific advisory boards. Dr. Jordan has consulted for Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, and BD Solution. She has received research funding from Deutsche Krebshilfe. She has received honoraria from MSD, Merck, Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, Pomme-med, PharmaMar, arttemoi, OnkoUpdate, Stemline, and Roche.
Cancer cachexia is a syndrome of weight loss that frequently occurs during cancer treatment. Consequences can include skeletal muscle loss, fatigue, functional impairment, worse quality of life, and worse survival. On the other hand, weight gain during cancer treatment has been tied to better survival.
Few studies have examined the relationship between weight gain and outcomes by sex.
“The finding that weight gain occurred in subsets of males and females is a new observation. The fact that weight gain occurs in cancer patients during anticancer treatment could confound results of clinical [trials] evaluating novel anticachexia treatments. Simultaneously studying longitudinal body weights and serum and cellular biomarkers in cancer patients might provide insights into mechanisms involved in cachexia. Increased understanding of mechanisms driving cachexia could lead to new therapeutic strategies,” said study coauthor Philip Bonomi, MD, who is an oncologist at Rush Medical College, Chicago.
“This data, although it appears to be very basic, is critically important, especially as we consider our novel interventions in the treatment of cancer cachexia,” said Eric Roeland, MD, during his presentation of the study at the annual meeting of European Society for Medical Oncology. Dr. Roeland is a medical oncologist at Oregon Health & Science University, Portland.
Dr. Roeland is also the lead author of cancer cachexia guidelines published by the American Society of Clinical Oncology in 2020. The guidelines suggest that dietary counseling can be offered to patients, but warns against routine use of enteral feeding tubes and parenteral nutrition. Although no specific drug can be recommended for cancer cachexia, progesterone analogs and corticosteroids used over the short term (weeks) can be used on a trial base to improve appetite and weight gain. While not approved in the United States, anamorelin was approved in 2020 in Japan for cancer cachexia in NSCLC, gastric cancer, pancreatic cancer, and colorectal cancer.
The new study should raise awareness of the importance of adverse effects of cancer treatments, said Karin Jordan, MD, University Hospital Heidelberg (Germany). She served as a discussant following the presentation. “As a medical oncologist, we focus a bit too much on the benefits of antineoplastic therapy, both on cure and on the survival benefit. But what is also very, very important to do is a balanced oncology treatment to focus on the risks of oncology therapies,” she said.
The study is limited by its retrospective nature and potential for bias. “The hypothesis that weight gain leads to improved survival is not really proven as it likewise may be the other way around,” Dr. Jordan said.
However, in oncology research, a phenomenon called the “obesity paradox” is increasingly catching the interest of investigators. Observational studies have shown that overweight patients with certain cancers (specifically, colorectal, endometrial and lung cancer). actually have improved overall survival as compared with normal-weight patients.
Details from the new study
The researchers pooled data 1,030 patients who participated in three phase 3 clinical trials conducted between 2005 and 2011. The patients all received platinum-based chemotherapy as part of control arms. 304 were female and 726 were male. The median age was 62. 16.7% were Asian, the mean body mass index was 24.6 kg/m2, 88.5% had stage 4 disease, 36.9% had adenocarcinoma, and 86.3% were current or former smokers.
Males and females had similar magnitudes and rate of weight gain over the course of treatment. Any weight gain was associated with improved overall survival in both males (12.7 vs. 8.0 months; hazard ratio, 0.60; P < .001) and females (16.2 vs. 10.1 months; HR, 0.65; P = .0028). Patients who had a weight gain of 2.5% of body weight or more saw an improvement in overall survival in both males (14.0 vs. 8.2 months; HR, 0.57; P < .001) and females (16.7 vs. 11.3 months; HR, 0.61; P = .0041).
Patients with a weight gain of 5% or more was associated with improved survival in males (13.6 vs. 8.9 months; HR, 0.62; P = .0001), but there was no statistically significant association in females (16.7 vs. 12.6 months; HR, 0.69; P = .1107).
Regardless of weight-gain status, males had lower survival rates than females. All of the associations were independent of smoking status.
The study was funded by Pfizer. Dr. Bonomi has received honoraria from Pfizer and Helsinn for participation in scientific advisory boards. Dr. Jordan has consulted for Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, and BD Solution. She has received research funding from Deutsche Krebshilfe. She has received honoraria from MSD, Merck, Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, Pomme-med, PharmaMar, arttemoi, OnkoUpdate, Stemline, and Roche.
FROM ESMO CONGRESS 2022