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Few Childhood Cancer Survivors Get Recommended Screenings
Among childhood cancer survivors in Ontario, Canada, who faced an elevated risk due to chemotherapy or radiation treatments, 53% followed screening recommendations for cardiomyopathy, 13% met colorectal cancer screening guidelines, and 6% adhered to breast cancer screening guidelines.
“Although over 80% of children newly diagnosed with cancer will become long-term survivors, as many as four out of five of these survivors will develop a serious or life-threatening late effect of their cancer therapy by age 45,” lead author Jennifer Shuldiner, PhD, MPH, a scientist at Women’s College Hospital Institute for Health Systems Solutions and Virtual Care in Toronto, told this news organization.
For instance, the risk for colorectal cancer in childhood cancer survivors is two to three times higher than it is among the general population, and the risk for breast cancer is similar between those who underwent chest radiation and those with a BRCA mutation. As many as 50% of those who received anthracycline chemotherapy or radiation involving the heart later develop cardiotoxicity.
The North American Children’s Oncology Group has published long-term follow-up guidelines for survivors of childhood cancer, yet many survivors don’t follow them because of lack of awareness or other barriers, said Dr. Shuldiner.
“Prior research has shown that many survivors do not complete these recommended tests,” she said. “With better knowledge of this at-risk population, we can design, test, and implement appropriate interventions and supports to tackle the issues.”
The study was published online on March 11 in CMAJ.
Changes in Adherence
The researchers conducted a retrospective population-based cohort study analyzing Ontario healthcare administrative data for adult survivors of childhood cancer diagnosed between 1986 and 2014 who faced an elevated risk for therapy-related colorectal cancer, breast cancer, or cardiomyopathy. The research team then assessed long-term adherence to the North American Children’s Oncology Group guidelines and predictors of adherence.
Among 3241 survivors, 3205 (99%) were at elevated risk for cardiomyopathy, 327 (10%) were at elevated risk for colorectal cancer, and 234 (7%) were at elevated risk for breast cancer. In addition, 2806 (87%) were at risk for one late effect, 345 (11%) were at risk for two late effects, and 90 (3%) were at risk for three late effects.
Overall, 53%, 13%, and 6% were adherent to their recommended surveillance for cardiomyopathy, colorectal cancer, and breast cancer, respectively. Over time, adherence increased for colorectal cancer and cardiomyopathy but decreased for breast cancer.
In addition, patients who were older at diagnosis were more likely to follow screening guidelines for colorectal and breast cancers, whereas those who were younger at diagnosis were more likely to follow screening guidelines for cardiomyopathy.
During a median follow-up of 7.8 years, the proportion of time spent adherent was 43% for cardiomyopathy, 14% for colorectal cancer, and 10% for breast cancer.
Survivors who attended a long-term follow-up clinic in the previous year had low adherence rates as well, though they were higher than in the rest of the cohort. In this group, the proportion of time that was spent adherent was 71% for cardiomyopathy, 27% for colorectal cancer, and 15% for breast cancer.
Shuldiner and colleagues are launching a research trial to determine whether a provincial support system can help childhood cancer survivors receive the recommended surveillance. The support system provides information about screening recommendations to survivors as well as reminders and sends key information to their family doctors.
“We now understand that childhood cancer survivors need help to complete the recommended tests,” said Dr. Shuldiner. “If the trial is successful, we hope it will be implemented in Ontario.”
Survivorship Care Plans
Low screening rates may result from a lack of awareness about screening recommendations and the negative long-term effects of cancer treatments, the study authors wrote. Cancer survivors, caregivers, family physicians, specialists, and survivor support groups can share the responsibility of spreading awareness and adhering to guidelines, they noted. In some cases, a survivorship care plan (SCP) may help.
“SCPs are intended to improve adherence by providing follow-up information and facilitating the transition from cancer treatment to survivorship and from pediatric to adult care,” Adam Yan, MD, a staff oncologist and oncology informatics lead at the Hospital for Sick Children in Toronto, told this news organization.
Dr. Yan, who wasn’t involved with this study, has researched surveillance adherence for secondary cancers and cardiac dysfunction among childhood cancer survivors. He and his colleagues found that screening rates were typically low among survivors who faced high risks for cardiac dysfunction and breast, colorectal, or skin cancers.
However, having a survivorship care plan seemed to help, and survivors treated after 1990 were more likely to have an SCP.
“SCP possession by high-risk survivors was associated with increased breast, skin, and cardiac surveillance,” he said. “It is uncertain whether SCP possession leads to adherence or whether SCP possession is a marker of survivors who are focused on their health and thus likely to adhere to preventive health practices, including surveillance.”
The study was funded by the Canadian Institutes of Health Research and ICES, which receives support from the Ontario Ministry of Health and the Ministry of Long-Term Care. Dr. Shuldiner received a Canadian Institutes of Health Research Health System Impact Postdoctoral Fellowship in support of the work. Dr. Yan disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Among childhood cancer survivors in Ontario, Canada, who faced an elevated risk due to chemotherapy or radiation treatments, 53% followed screening recommendations for cardiomyopathy, 13% met colorectal cancer screening guidelines, and 6% adhered to breast cancer screening guidelines.
“Although over 80% of children newly diagnosed with cancer will become long-term survivors, as many as four out of five of these survivors will develop a serious or life-threatening late effect of their cancer therapy by age 45,” lead author Jennifer Shuldiner, PhD, MPH, a scientist at Women’s College Hospital Institute for Health Systems Solutions and Virtual Care in Toronto, told this news organization.
For instance, the risk for colorectal cancer in childhood cancer survivors is two to three times higher than it is among the general population, and the risk for breast cancer is similar between those who underwent chest radiation and those with a BRCA mutation. As many as 50% of those who received anthracycline chemotherapy or radiation involving the heart later develop cardiotoxicity.
The North American Children’s Oncology Group has published long-term follow-up guidelines for survivors of childhood cancer, yet many survivors don’t follow them because of lack of awareness or other barriers, said Dr. Shuldiner.
“Prior research has shown that many survivors do not complete these recommended tests,” she said. “With better knowledge of this at-risk population, we can design, test, and implement appropriate interventions and supports to tackle the issues.”
The study was published online on March 11 in CMAJ.
Changes in Adherence
The researchers conducted a retrospective population-based cohort study analyzing Ontario healthcare administrative data for adult survivors of childhood cancer diagnosed between 1986 and 2014 who faced an elevated risk for therapy-related colorectal cancer, breast cancer, or cardiomyopathy. The research team then assessed long-term adherence to the North American Children’s Oncology Group guidelines and predictors of adherence.
Among 3241 survivors, 3205 (99%) were at elevated risk for cardiomyopathy, 327 (10%) were at elevated risk for colorectal cancer, and 234 (7%) were at elevated risk for breast cancer. In addition, 2806 (87%) were at risk for one late effect, 345 (11%) were at risk for two late effects, and 90 (3%) were at risk for three late effects.
Overall, 53%, 13%, and 6% were adherent to their recommended surveillance for cardiomyopathy, colorectal cancer, and breast cancer, respectively. Over time, adherence increased for colorectal cancer and cardiomyopathy but decreased for breast cancer.
In addition, patients who were older at diagnosis were more likely to follow screening guidelines for colorectal and breast cancers, whereas those who were younger at diagnosis were more likely to follow screening guidelines for cardiomyopathy.
During a median follow-up of 7.8 years, the proportion of time spent adherent was 43% for cardiomyopathy, 14% for colorectal cancer, and 10% for breast cancer.
Survivors who attended a long-term follow-up clinic in the previous year had low adherence rates as well, though they were higher than in the rest of the cohort. In this group, the proportion of time that was spent adherent was 71% for cardiomyopathy, 27% for colorectal cancer, and 15% for breast cancer.
Shuldiner and colleagues are launching a research trial to determine whether a provincial support system can help childhood cancer survivors receive the recommended surveillance. The support system provides information about screening recommendations to survivors as well as reminders and sends key information to their family doctors.
“We now understand that childhood cancer survivors need help to complete the recommended tests,” said Dr. Shuldiner. “If the trial is successful, we hope it will be implemented in Ontario.”
Survivorship Care Plans
Low screening rates may result from a lack of awareness about screening recommendations and the negative long-term effects of cancer treatments, the study authors wrote. Cancer survivors, caregivers, family physicians, specialists, and survivor support groups can share the responsibility of spreading awareness and adhering to guidelines, they noted. In some cases, a survivorship care plan (SCP) may help.
“SCPs are intended to improve adherence by providing follow-up information and facilitating the transition from cancer treatment to survivorship and from pediatric to adult care,” Adam Yan, MD, a staff oncologist and oncology informatics lead at the Hospital for Sick Children in Toronto, told this news organization.
Dr. Yan, who wasn’t involved with this study, has researched surveillance adherence for secondary cancers and cardiac dysfunction among childhood cancer survivors. He and his colleagues found that screening rates were typically low among survivors who faced high risks for cardiac dysfunction and breast, colorectal, or skin cancers.
However, having a survivorship care plan seemed to help, and survivors treated after 1990 were more likely to have an SCP.
“SCP possession by high-risk survivors was associated with increased breast, skin, and cardiac surveillance,” he said. “It is uncertain whether SCP possession leads to adherence or whether SCP possession is a marker of survivors who are focused on their health and thus likely to adhere to preventive health practices, including surveillance.”
The study was funded by the Canadian Institutes of Health Research and ICES, which receives support from the Ontario Ministry of Health and the Ministry of Long-Term Care. Dr. Shuldiner received a Canadian Institutes of Health Research Health System Impact Postdoctoral Fellowship in support of the work. Dr. Yan disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Among childhood cancer survivors in Ontario, Canada, who faced an elevated risk due to chemotherapy or radiation treatments, 53% followed screening recommendations for cardiomyopathy, 13% met colorectal cancer screening guidelines, and 6% adhered to breast cancer screening guidelines.
“Although over 80% of children newly diagnosed with cancer will become long-term survivors, as many as four out of five of these survivors will develop a serious or life-threatening late effect of their cancer therapy by age 45,” lead author Jennifer Shuldiner, PhD, MPH, a scientist at Women’s College Hospital Institute for Health Systems Solutions and Virtual Care in Toronto, told this news organization.
For instance, the risk for colorectal cancer in childhood cancer survivors is two to three times higher than it is among the general population, and the risk for breast cancer is similar between those who underwent chest radiation and those with a BRCA mutation. As many as 50% of those who received anthracycline chemotherapy or radiation involving the heart later develop cardiotoxicity.
The North American Children’s Oncology Group has published long-term follow-up guidelines for survivors of childhood cancer, yet many survivors don’t follow them because of lack of awareness or other barriers, said Dr. Shuldiner.
“Prior research has shown that many survivors do not complete these recommended tests,” she said. “With better knowledge of this at-risk population, we can design, test, and implement appropriate interventions and supports to tackle the issues.”
The study was published online on March 11 in CMAJ.
Changes in Adherence
The researchers conducted a retrospective population-based cohort study analyzing Ontario healthcare administrative data for adult survivors of childhood cancer diagnosed between 1986 and 2014 who faced an elevated risk for therapy-related colorectal cancer, breast cancer, or cardiomyopathy. The research team then assessed long-term adherence to the North American Children’s Oncology Group guidelines and predictors of adherence.
Among 3241 survivors, 3205 (99%) were at elevated risk for cardiomyopathy, 327 (10%) were at elevated risk for colorectal cancer, and 234 (7%) were at elevated risk for breast cancer. In addition, 2806 (87%) were at risk for one late effect, 345 (11%) were at risk for two late effects, and 90 (3%) were at risk for three late effects.
Overall, 53%, 13%, and 6% were adherent to their recommended surveillance for cardiomyopathy, colorectal cancer, and breast cancer, respectively. Over time, adherence increased for colorectal cancer and cardiomyopathy but decreased for breast cancer.
In addition, patients who were older at diagnosis were more likely to follow screening guidelines for colorectal and breast cancers, whereas those who were younger at diagnosis were more likely to follow screening guidelines for cardiomyopathy.
During a median follow-up of 7.8 years, the proportion of time spent adherent was 43% for cardiomyopathy, 14% for colorectal cancer, and 10% for breast cancer.
Survivors who attended a long-term follow-up clinic in the previous year had low adherence rates as well, though they were higher than in the rest of the cohort. In this group, the proportion of time that was spent adherent was 71% for cardiomyopathy, 27% for colorectal cancer, and 15% for breast cancer.
Shuldiner and colleagues are launching a research trial to determine whether a provincial support system can help childhood cancer survivors receive the recommended surveillance. The support system provides information about screening recommendations to survivors as well as reminders and sends key information to their family doctors.
“We now understand that childhood cancer survivors need help to complete the recommended tests,” said Dr. Shuldiner. “If the trial is successful, we hope it will be implemented in Ontario.”
Survivorship Care Plans
Low screening rates may result from a lack of awareness about screening recommendations and the negative long-term effects of cancer treatments, the study authors wrote. Cancer survivors, caregivers, family physicians, specialists, and survivor support groups can share the responsibility of spreading awareness and adhering to guidelines, they noted. In some cases, a survivorship care plan (SCP) may help.
“SCPs are intended to improve adherence by providing follow-up information and facilitating the transition from cancer treatment to survivorship and from pediatric to adult care,” Adam Yan, MD, a staff oncologist and oncology informatics lead at the Hospital for Sick Children in Toronto, told this news organization.
Dr. Yan, who wasn’t involved with this study, has researched surveillance adherence for secondary cancers and cardiac dysfunction among childhood cancer survivors. He and his colleagues found that screening rates were typically low among survivors who faced high risks for cardiac dysfunction and breast, colorectal, or skin cancers.
However, having a survivorship care plan seemed to help, and survivors treated after 1990 were more likely to have an SCP.
“SCP possession by high-risk survivors was associated with increased breast, skin, and cardiac surveillance,” he said. “It is uncertain whether SCP possession leads to adherence or whether SCP possession is a marker of survivors who are focused on their health and thus likely to adhere to preventive health practices, including surveillance.”
The study was funded by the Canadian Institutes of Health Research and ICES, which receives support from the Ontario Ministry of Health and the Ministry of Long-Term Care. Dr. Shuldiner received a Canadian Institutes of Health Research Health System Impact Postdoctoral Fellowship in support of the work. Dr. Yan disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
EU Backs First Oral Monotherapy for Adults With PNH
The decision was hailed as a first step toward enabling patient access in European Union countries following a March 21 meeting of the Committee for Medicinal Products for Human Use (CHMP).
PNH is a rare, debilitating, and potentially life-threatening genetic disorder that causes hemolytic anemia. Symptoms of the disease include fatigue, body pain, blood clots, bleeding, and shortness of breath. The standard treatment is anti-C5 monoclonal antibodies (eculizumab or ravulizumab) via subcutaneous or intravenous infusion. However, a minority of patients with PNH who are treated with these complement inhibitors encounter residual hemolytic anemia and require red blood cell transfusions.
The active substance of Fabhalta is iptacopan, a proximal complement inhibitor. Iptacopan targets factor B to selectively inhibit the alternative complement pathway and control both C3-mediated extravascular hemolysis and terminal complement-mediated intravascular hemolysis.
Superior Results in Phase 3 Trials
The decision to grant a marketing authorization was taken following a review of two phase 3 trials. The main study was a randomized, open-label, active comparator trial involving 97 patients with PNH who had residual anemia despite receiving treatment with anti-C5 monoclonal antibodies for the previous 6 months. Of the trial participants, 62 received iptacopan monotherapy and 35 continued their anti-C5 regimen for 24 weeks.
Treatment with Fabhalta was found to be significantly superior to the anti-C5 regimen, with 51 of 60 patients who could be evaluated achieving hemoglobin improvement (≥ 2 g/dL) and 42 achieving sustained hemoglobin levels (≥ 12 g/dL) without transfusion, compared with no patients who continued treatment with anti-C5 monoclonal antibodies. Also, 59 of 62 patients treated with Fabhalta did not require blood transfusions between day 14 and day 168, compared with 14 of 35 patients in the anti-C5 group.
The second trial was a single-arm study involving 40 PNH patients who had not previously been treated with a complement inhibitor. Following treatment with Fabhalta, 31 of 33 patients who could be evaluated achieved hemoglobin improvement (≥ 2 g/dL) at week 24, whereas 19 achieved sustained hemoglobin levels (≥ 12 g/dL) without transfusion.
The most common side effects of Fabhalta are upper respiratory tract infection, headache, and diarrhea.
The CHMP stressed that Fabhalta should be prescribed by physicians who are experienced in the management of patients with hematologic disorders.
Fabhalta was supported through the EMA’s Priority Medicines (PRIME) scheme, which provides regulatory support for promising medicines with the potential to address unmet medical needs. The CHMP’s recommendation has been sent to the European Commission for a final decision.
Novartis said in a company statement on March 22 that, if approved, Fabhalta would be the first oral monotherapy available to PNH patients in Europe.
A version of this article appeared on Medscape.com.
The decision was hailed as a first step toward enabling patient access in European Union countries following a March 21 meeting of the Committee for Medicinal Products for Human Use (CHMP).
PNH is a rare, debilitating, and potentially life-threatening genetic disorder that causes hemolytic anemia. Symptoms of the disease include fatigue, body pain, blood clots, bleeding, and shortness of breath. The standard treatment is anti-C5 monoclonal antibodies (eculizumab or ravulizumab) via subcutaneous or intravenous infusion. However, a minority of patients with PNH who are treated with these complement inhibitors encounter residual hemolytic anemia and require red blood cell transfusions.
The active substance of Fabhalta is iptacopan, a proximal complement inhibitor. Iptacopan targets factor B to selectively inhibit the alternative complement pathway and control both C3-mediated extravascular hemolysis and terminal complement-mediated intravascular hemolysis.
Superior Results in Phase 3 Trials
The decision to grant a marketing authorization was taken following a review of two phase 3 trials. The main study was a randomized, open-label, active comparator trial involving 97 patients with PNH who had residual anemia despite receiving treatment with anti-C5 monoclonal antibodies for the previous 6 months. Of the trial participants, 62 received iptacopan monotherapy and 35 continued their anti-C5 regimen for 24 weeks.
Treatment with Fabhalta was found to be significantly superior to the anti-C5 regimen, with 51 of 60 patients who could be evaluated achieving hemoglobin improvement (≥ 2 g/dL) and 42 achieving sustained hemoglobin levels (≥ 12 g/dL) without transfusion, compared with no patients who continued treatment with anti-C5 monoclonal antibodies. Also, 59 of 62 patients treated with Fabhalta did not require blood transfusions between day 14 and day 168, compared with 14 of 35 patients in the anti-C5 group.
The second trial was a single-arm study involving 40 PNH patients who had not previously been treated with a complement inhibitor. Following treatment with Fabhalta, 31 of 33 patients who could be evaluated achieved hemoglobin improvement (≥ 2 g/dL) at week 24, whereas 19 achieved sustained hemoglobin levels (≥ 12 g/dL) without transfusion.
The most common side effects of Fabhalta are upper respiratory tract infection, headache, and diarrhea.
The CHMP stressed that Fabhalta should be prescribed by physicians who are experienced in the management of patients with hematologic disorders.
Fabhalta was supported through the EMA’s Priority Medicines (PRIME) scheme, which provides regulatory support for promising medicines with the potential to address unmet medical needs. The CHMP’s recommendation has been sent to the European Commission for a final decision.
Novartis said in a company statement on March 22 that, if approved, Fabhalta would be the first oral monotherapy available to PNH patients in Europe.
A version of this article appeared on Medscape.com.
The decision was hailed as a first step toward enabling patient access in European Union countries following a March 21 meeting of the Committee for Medicinal Products for Human Use (CHMP).
PNH is a rare, debilitating, and potentially life-threatening genetic disorder that causes hemolytic anemia. Symptoms of the disease include fatigue, body pain, blood clots, bleeding, and shortness of breath. The standard treatment is anti-C5 monoclonal antibodies (eculizumab or ravulizumab) via subcutaneous or intravenous infusion. However, a minority of patients with PNH who are treated with these complement inhibitors encounter residual hemolytic anemia and require red blood cell transfusions.
The active substance of Fabhalta is iptacopan, a proximal complement inhibitor. Iptacopan targets factor B to selectively inhibit the alternative complement pathway and control both C3-mediated extravascular hemolysis and terminal complement-mediated intravascular hemolysis.
Superior Results in Phase 3 Trials
The decision to grant a marketing authorization was taken following a review of two phase 3 trials. The main study was a randomized, open-label, active comparator trial involving 97 patients with PNH who had residual anemia despite receiving treatment with anti-C5 monoclonal antibodies for the previous 6 months. Of the trial participants, 62 received iptacopan monotherapy and 35 continued their anti-C5 regimen for 24 weeks.
Treatment with Fabhalta was found to be significantly superior to the anti-C5 regimen, with 51 of 60 patients who could be evaluated achieving hemoglobin improvement (≥ 2 g/dL) and 42 achieving sustained hemoglobin levels (≥ 12 g/dL) without transfusion, compared with no patients who continued treatment with anti-C5 monoclonal antibodies. Also, 59 of 62 patients treated with Fabhalta did not require blood transfusions between day 14 and day 168, compared with 14 of 35 patients in the anti-C5 group.
The second trial was a single-arm study involving 40 PNH patients who had not previously been treated with a complement inhibitor. Following treatment with Fabhalta, 31 of 33 patients who could be evaluated achieved hemoglobin improvement (≥ 2 g/dL) at week 24, whereas 19 achieved sustained hemoglobin levels (≥ 12 g/dL) without transfusion.
The most common side effects of Fabhalta are upper respiratory tract infection, headache, and diarrhea.
The CHMP stressed that Fabhalta should be prescribed by physicians who are experienced in the management of patients with hematologic disorders.
Fabhalta was supported through the EMA’s Priority Medicines (PRIME) scheme, which provides regulatory support for promising medicines with the potential to address unmet medical needs. The CHMP’s recommendation has been sent to the European Commission for a final decision.
Novartis said in a company statement on March 22 that, if approved, Fabhalta would be the first oral monotherapy available to PNH patients in Europe.
A version of this article appeared on Medscape.com.
CHIP: The Silent Threat Steps Into the Limelight
While it is increasingly apparent that , it has not been clear what to do about it.
Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.
“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
CHIP Defined
CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.
Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.
The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.
This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.
“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”
He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”
“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”
Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.
The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.
These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.
“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).
Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.
Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”
This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.
The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.
Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.
There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.
The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
No CHIP Test Yet
All of which has led for some to call for CHIP testing.
However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.
“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”
Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.
In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.
Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).
Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.
“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”
In low-risk individuals, the 10-year risk for MDS or AML is just 1%.
Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”
From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.
They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.
And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.
Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”
For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?
For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
Treat CHIP Like Lipoprotein(a)?
As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).
“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”
“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”
Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.
“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.
On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.
“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”
Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
While it is increasingly apparent that , it has not been clear what to do about it.
Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.
“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
CHIP Defined
CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.
Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.
The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.
This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.
“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”
He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”
“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”
Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.
The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.
These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.
“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).
Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.
Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”
This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.
The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.
Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.
There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.
The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
No CHIP Test Yet
All of which has led for some to call for CHIP testing.
However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.
“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”
Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.
In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.
Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).
Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.
“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”
In low-risk individuals, the 10-year risk for MDS or AML is just 1%.
Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”
From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.
They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.
And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.
Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”
For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?
For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
Treat CHIP Like Lipoprotein(a)?
As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).
“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”
“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”
Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.
“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.
On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.
“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”
Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
While it is increasingly apparent that , it has not been clear what to do about it.
Now, researchers at the cutting edge of both oncologic and cardiovascular research are not only defining the prognosis of CHIP with greater granularity but are also finding clues to mitigate the risks.
“It’s a very, very rapidly moving area,” said Christie M. Ballantyne, MD, Director, Center for Cardiometabolic Disease Prevention, Baylor College of Medicine, Houston, adding that, in many respects, “it’s a totally new area.”
CHIP Defined
CHIP was first recognized in the 1990s, when Martin F. Fey, MD, and colleagues from University and Inselspital, Bern, Switzerland, found X-linked inactivation in older women and suggested it was the result of acquired clonality later referred to as being of “indeterminate potential,” although that added syntax is currently a matter of debate.
Further work showed that, while somatic gene mutations occur spontaneously and are an unavoidable consequence of aging, their impact can vary widely.
The majority are “functionally silent,” while others may affect genes crucial to tissue self-renewal and differentiation, Lukasz Gondek, MD, PhD, assistant professor, Johns Hopkins Cellular and Molecular Medicine Program, Baltimore, and colleagues, noted in a recent review.
This results in the outgrowth of affected cells, known as clonal expansion, further dubbed clonal hematopoiesis when it occurs in hematopoietic tissue.
“Even though there’s clonal expansion, there’s no one CHIP,” Dr. Gondek said. “There are different flavors, and it depends on the genes that are mutated in the hematopoietic cells.”
He continued: “The older we get, the more mutations we acquire, and the probability that this mutation will hit the gene that’s responsible for expansion of the clone is higher.”
“That’s why CHIP is very uncommon in people under the age of 40, but it becomes more common in the fifth, sixth, and seventh decade of life and beyond.”
Indeed, it occurs in 10% to 15% of people aged 65 years or older, and in at least 30% of individuals by 80 years of age. In contrast, just 1% of those aged less than 50 years have the condition.
The most commonly affected genes, in around 80% of patients with CHIP, are the epigenetic regulators DNMT3A, TET2, and ASXL1; the DNA damage repair genes PPM1D and TP53; the regulatory tyrosine kinase JAK2; and the messenger RNA spliceosome components SF3B1 and SRSF2.
These mutations can have “two potential consequences,” explained Lachelle D. Weeks, MD, PhD, a hematologist at the Dana-Farber Cancer Institute, Boston.
“One is that there’s a risk of blood cancer development,” as several of the mutations are known drivers of leukemia or myelodysplastic syndromes (MDS).
Although the majority of individuals who acquire clonal hematopoiesis with age will never develop MDS, it nevertheless confers an 11- to 13-fold increased risk or an absolute risk of approximately 0.5%-1.0% per year.
Dr. Weeks continued that “the other side of it, though, is that those cells that have these mutations can also accelerate the risk of developing nonmalignant diseases like cardiovascular disease.”
This, Dr. Gondek explained, is because the mutations will be retained when the stem cells become monocytes or macrophages and, by either silencing or activating individual genes, they can make the cells more pro-inflammatory.
The result is that CHIP is associated with a marked increased risk for arteriosclerotic events such as stroke, myocardial infarction, decompensated heart failure, and cardiogenic shock, and worse outcomes after these events.
Researchers have shown that CHIP-related somatic mutations are associated with a twofold increased risk for coronary heart disease, a more than 2.5-fold increased risk for ischemic stroke, and a fourfold greater risk for myocardial infarction. A study from earlier this year found that CHIP also increases the risk for heart failure with preserved ejection fraction more than twofold.
There is even evidence to suggest that CHIP is associated with more severe acute kidney injury (AKI) and greater post-AKI kidney fibrosis.
The consequence is that individuals with CHIP face a 40% increased risk for all-cause mortality over 8 years.
No CHIP Test Yet
All of which has led for some to call for CHIP testing.
However, there are currently no screening programs for CHIP and no plans to introduce any. “So most CHIP is actually being diagnosed incidentally, when patients get genetic testing for some other indication,” said Dr. Weeks.
“The patients that we see in our CHIP clinic at Dana-Farber have genetic testing because they have low blood counts,” she continued, “and somebody’s trying to figure out: Do you have MDS?”
Other patients have genetic testing due to a family history of other cancers, “and so they’re getting hereditary cancer panels to determine if they have Lynch syndrome, or other hereditary syndromes,” which are picking up gene mutations associated with CHIP.
In other cases, study protocols are identifying CHIP “in various research contexts, and then as a follow-up, some of those patients end up with our clinic,” added Dr. Weeks.
Due to the associated risks for CHIP, “obviously everyone wants to know whether they are at risk for hematologic malignancy, or not,” said Dr. Gondek. To those ends, Dr. Weeks and colleagues developed the clonal hematopoiesis risk score (CHRS).
Published by NEJM Evidence in 2023, the score takes a range of predictive variables, such as age, number of mutations and their degree of associated risk, the variant allele fraction, and a series of blood indices to define patients as low-, intermediate-, or high-risk.
“A little over half” of high-risk individuals “will develop a blood cancer” such as MDS or acute myeloid leukemia (AML)” over the next 10 years, Weeks explained, while “for your intermediate risk folks, in that same time period, 7%-8% of them will develop a blood cancer.”
In low-risk individuals, the 10-year risk for MDS or AML is just 1%.
Dr. Weeks noted the “caveat that there are environmental factors or patient-specific issues that might increase your risk that are not considered in the calculator,” such the presence of hereditary cancer syndromes, “or if you’re getting chemotherapy for other cancers.”
From a cardiology point of view, Dr. Ballantyne said that, above all, “cardiologists need to be aware that some of these people are at increased risk for cardiovascular events.” This prompted a team including Dr. Weeks and Dr. Ballantyne to study whether the CHRS can also predict cardiovascular risk.
They found that people designated low-risk on the score faced an 8% increased risk for all-cause mortality vs individuals without CHIP during a median follow-up of 7 years. This rose to a 12% increase in intermediate-risk individuals.
And those deemed high-risk had a 2.5-fold increased risk for early mortality and a threefold higher risk for cardiovascular death.
Dr. Weeks noted: “We have not done a dedicated study to define a cardiovascular disease-specific calculator for CHIP,” but in the meantime, the CHRS is a “very reasonable way to estimate what someone’s risk of progression or adverse events is for cardiovascular disease.”
For clinicians, however, the key question becomes: What can be done to mitigate the risks, particularly in high-risk individuals?
For malignant conditions, the approach is to monitor patients, although “we and other centers are in the process of developing various interventional clinical trials to test various agents on their ability to improve blood counts, as well as to mitigate the risk of progression to overt blood cancer,” said Dr. Weeks.
Treat CHIP Like Lipoprotein(a)?
As for cardiovascular risk, Dr. Ballantyne believes that, because CHIP is an unmodifiable risk factor, an example to follow could be lipoprotein(a) (LP[a]).
“We don’t have a therapy specifically to target LP(a) yet, but we do know that the things that benefit in general,” he said, such as “taking a statin, lowering blood pressure into the optimal zone, diet ,and exercise.”
“What we do in our clinic, and what others have been doing,” Dr. Weeks added, “is for every patient who comes in and is diagnosed with CHIP, we are referring them to preventative cardiology for very aggressive preventative management.”
Finally, both Dr. Ballantyne and Dr. Weeks agree that there are many potential innovations on the horizon.
“It’s pretty exciting in terms of beginning to understand some of the links between aging, cardiovascular disease, and cancer that we had not been thinking about,” Dr. Ballantyne said.
On the malignant side, Dr. Weeks is already working on a prospective study to determine how the risks associated with CHIP evolve when patients undergo chemotherapy and radiation for other cancers.
“That will be really exciting and will help us to develop a specific calculator in that context,” she said, adding that a cardiovascular-specific calculator “is also coming down the line.”
Dr. Weeks declared relationships with Abbvie, Vertex, and Sobi. Dr. Ballantyne declared a relationship with Ten Sixteen Bio, and funding from the National Heart, Lung, and Blood Institute. No other relevant financial relationships were declared.
A version of this article appeared on Medscape.com.
Most Cancer Trial Centers Located Closer to White, Affluent Populations
This inequity may be potentiating the underrepresentation of racially minoritized and socioeconomically disadvantaged populations in clinical trials, suggesting that employment of satellite hospitals is needed to expand access to investigational therapies, reported lead author Hassal Lee, MD, PhD, of Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, and colleagues.
“Minoritized and socioeconomically disadvantaged populations are underrepresented in clinical trials,” the investigators wrote in JAMA Oncology. “This may reduce the generalizability of trial results and propagate health disparities. Contributors to inequitable trial participation include individual-level factors and structural factors.”
Specifically, travel time to trial centers, as well as socioeconomic deprivation, can reduce likelihood of trial participation.
“Data on these parameters and population data on self-identified race exist, but their interrelation with clinical research facilities has not been systematically analyzed,” they wrote.
To try to draw comparisons between the distribution of patients of different races and socioeconomic statuses and the locations of clinical research facilities, Dr. Lee and colleagues aggregated data from the US Census, National Trial registry, Nature Index of Cancer Research Health Institutions, OpenStreetMap, National Cancer Institute–designated Cancer Centers list, and National Homeland Infrastructure Foundation. They then characterized catchment population demographics within 30-, 60-, and 120-minute driving commute times of all US hospitals, along with a more focused look at centers capable of conducting phase 1, phase 2, and phase 3 trials.
These efforts revealed broad geographic inequity.The 78 major centers that conduct 94% of all US cancer trials are located within 30 minutes of populations that have a 10.1% higher proportion of self-identified White individuals than the average US county, and a median income $18,900 higher than average (unpaired mean differences).
The publication also includes several maps characterizing racial and socioeconomic demographics within various catchment areas. For example, centers in New York City, Houston, and Chicago have the most diverse catchment populations within a 30-minute commute. Maps of all cities in the United States with populations greater than 500,000 are available in a supplementary index.
“This study indicates that geographical population distributions may present barriers to equitable clinical trial access and that data are available to proactively strategize about reduction of such barriers,” Dr. Lee and colleagues wrote.
The findings call attention to modifiable socioeconomic factors associated with trial participation, they added, like financial toxicity and affordable transportation, noting that ethnic and racial groups consent to trials at similar rates after controlling for income.
In addition, Dr. Lee and colleagues advised clinical trial designers to enlist satellite hospitals to increase participant diversity, since long commutes exacerbate “socioeconomic burdens associated with clinical trial participation,” with trial participation decreasing as commute time increases.
“Existing clinical trial centers may build collaborative efforts with nearby hospitals closer to underrepresented populations or set up community centers to support new collaborative networks to improve geographical access equity,” they wrote. “Methodologically, our approach is transferable to any country, region, or global effort with sufficient source data and can inform decision-making along the continuum of cancer care, from screening to implementing specialist care.”
A coauthor disclosed relationships with Flagship Therapeutics, Leidos Holding Ltd, Pershing Square Foundation, and others.
This inequity may be potentiating the underrepresentation of racially minoritized and socioeconomically disadvantaged populations in clinical trials, suggesting that employment of satellite hospitals is needed to expand access to investigational therapies, reported lead author Hassal Lee, MD, PhD, of Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, and colleagues.
“Minoritized and socioeconomically disadvantaged populations are underrepresented in clinical trials,” the investigators wrote in JAMA Oncology. “This may reduce the generalizability of trial results and propagate health disparities. Contributors to inequitable trial participation include individual-level factors and structural factors.”
Specifically, travel time to trial centers, as well as socioeconomic deprivation, can reduce likelihood of trial participation.
“Data on these parameters and population data on self-identified race exist, but their interrelation with clinical research facilities has not been systematically analyzed,” they wrote.
To try to draw comparisons between the distribution of patients of different races and socioeconomic statuses and the locations of clinical research facilities, Dr. Lee and colleagues aggregated data from the US Census, National Trial registry, Nature Index of Cancer Research Health Institutions, OpenStreetMap, National Cancer Institute–designated Cancer Centers list, and National Homeland Infrastructure Foundation. They then characterized catchment population demographics within 30-, 60-, and 120-minute driving commute times of all US hospitals, along with a more focused look at centers capable of conducting phase 1, phase 2, and phase 3 trials.
These efforts revealed broad geographic inequity.The 78 major centers that conduct 94% of all US cancer trials are located within 30 minutes of populations that have a 10.1% higher proportion of self-identified White individuals than the average US county, and a median income $18,900 higher than average (unpaired mean differences).
The publication also includes several maps characterizing racial and socioeconomic demographics within various catchment areas. For example, centers in New York City, Houston, and Chicago have the most diverse catchment populations within a 30-minute commute. Maps of all cities in the United States with populations greater than 500,000 are available in a supplementary index.
“This study indicates that geographical population distributions may present barriers to equitable clinical trial access and that data are available to proactively strategize about reduction of such barriers,” Dr. Lee and colleagues wrote.
The findings call attention to modifiable socioeconomic factors associated with trial participation, they added, like financial toxicity and affordable transportation, noting that ethnic and racial groups consent to trials at similar rates after controlling for income.
In addition, Dr. Lee and colleagues advised clinical trial designers to enlist satellite hospitals to increase participant diversity, since long commutes exacerbate “socioeconomic burdens associated with clinical trial participation,” with trial participation decreasing as commute time increases.
“Existing clinical trial centers may build collaborative efforts with nearby hospitals closer to underrepresented populations or set up community centers to support new collaborative networks to improve geographical access equity,” they wrote. “Methodologically, our approach is transferable to any country, region, or global effort with sufficient source data and can inform decision-making along the continuum of cancer care, from screening to implementing specialist care.”
A coauthor disclosed relationships with Flagship Therapeutics, Leidos Holding Ltd, Pershing Square Foundation, and others.
This inequity may be potentiating the underrepresentation of racially minoritized and socioeconomically disadvantaged populations in clinical trials, suggesting that employment of satellite hospitals is needed to expand access to investigational therapies, reported lead author Hassal Lee, MD, PhD, of Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, and colleagues.
“Minoritized and socioeconomically disadvantaged populations are underrepresented in clinical trials,” the investigators wrote in JAMA Oncology. “This may reduce the generalizability of trial results and propagate health disparities. Contributors to inequitable trial participation include individual-level factors and structural factors.”
Specifically, travel time to trial centers, as well as socioeconomic deprivation, can reduce likelihood of trial participation.
“Data on these parameters and population data on self-identified race exist, but their interrelation with clinical research facilities has not been systematically analyzed,” they wrote.
To try to draw comparisons between the distribution of patients of different races and socioeconomic statuses and the locations of clinical research facilities, Dr. Lee and colleagues aggregated data from the US Census, National Trial registry, Nature Index of Cancer Research Health Institutions, OpenStreetMap, National Cancer Institute–designated Cancer Centers list, and National Homeland Infrastructure Foundation. They then characterized catchment population demographics within 30-, 60-, and 120-minute driving commute times of all US hospitals, along with a more focused look at centers capable of conducting phase 1, phase 2, and phase 3 trials.
These efforts revealed broad geographic inequity.The 78 major centers that conduct 94% of all US cancer trials are located within 30 minutes of populations that have a 10.1% higher proportion of self-identified White individuals than the average US county, and a median income $18,900 higher than average (unpaired mean differences).
The publication also includes several maps characterizing racial and socioeconomic demographics within various catchment areas. For example, centers in New York City, Houston, and Chicago have the most diverse catchment populations within a 30-minute commute. Maps of all cities in the United States with populations greater than 500,000 are available in a supplementary index.
“This study indicates that geographical population distributions may present barriers to equitable clinical trial access and that data are available to proactively strategize about reduction of such barriers,” Dr. Lee and colleagues wrote.
The findings call attention to modifiable socioeconomic factors associated with trial participation, they added, like financial toxicity and affordable transportation, noting that ethnic and racial groups consent to trials at similar rates after controlling for income.
In addition, Dr. Lee and colleagues advised clinical trial designers to enlist satellite hospitals to increase participant diversity, since long commutes exacerbate “socioeconomic burdens associated with clinical trial participation,” with trial participation decreasing as commute time increases.
“Existing clinical trial centers may build collaborative efforts with nearby hospitals closer to underrepresented populations or set up community centers to support new collaborative networks to improve geographical access equity,” they wrote. “Methodologically, our approach is transferable to any country, region, or global effort with sufficient source data and can inform decision-making along the continuum of cancer care, from screening to implementing specialist care.”
A coauthor disclosed relationships with Flagship Therapeutics, Leidos Holding Ltd, Pershing Square Foundation, and others.
FROM JAMA ONCOLOGY
Secondary Cancers Post CAR T Therapy: A Concern?
TOPLINE:
METHODOLOGY:
- In November 2023, the FDA announced its investigation into whether chimeric antigen receptor (CAR) T-cell immunotherapies can cause secondary blood cancers, specifically T-cell malignancies. At the time, the agency said: “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes.”
- In January 2024, the FDA issued boxed warnings on the six approved CART cell therapies, citing the possibility of second primary malignancies, including CAR-positive lymphomas, in patients who had received a CAR T agent.
- To evaluate the extent of these secondary cancers, researchers analyzed the FDA Adverse Event Reporting System database for CAR T-cell reports citing second primary malignancies.
TAKEAWAY:
- Overall, the authors identified 12,394 unique adverse events associated with CAR T therapy; of these, 536 adverse events (4.3%) were second primary malignancies.
- Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) accounted for most of the second primary malignancies reports — 51.7% (277 of 536 patients) for axi-cel and 33% (177 of 536 patients) for tis-cel.
- The researchers identified 19 cases of T-cell malignancies, representing only 0.15% of all unique adverse events and 3.54% of all second primary malignancies (19 of 536 patients); 17 of these cases were T-cell non-Hodgkin lymphomas, and two were T-cell large granular lymphocytic leukemia.
- Among the reported 536 second primary malignancies, the most frequent cancers were leukemias (333 reports, or 62%), followed by skin neoplasms (54 reports, or 10.1%), hematopoietic neoplasms excluding leukemias and lymphomas (26 reports, 4.85%), nervous system tumors (21 reports, 3.92%), and respiratory neoplasms (20 reports, 3.73%).
IN PRACTICE:
“We will continue to monitor the data released by the FDA to learn more about CAR T-associated risks. However, it’s crucial to stress that the benefits of CAR T-cell therapies still outweigh the risks for the approved indications,” Magdi Elsallab, MD, the study’s co-lead author, said in a news release.
SOURCE:
This work, led by Dr. Elsallab from Harvard Medical School in Boston, was published online on March 14 in Blood.
LIMITATIONS:
The limitations of the analysis include the presence of duplicate report submissions, incomplete data, difficulty establishing causal relationships, and the potential for both underreporting and overreporting based on the severity of adverse events. Furthermore, without the total number of prescribed products, it was difficult to determine the adverse event frequency.
DISCLOSURES:
The study funding source was not disclosed. Some of the authors reported financial ties with various organizations outside this work, including Bristol Myers Squibb, Janssen Biotech, Johnson & Johnson, Kite Pharma, and Novartis.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- In November 2023, the FDA announced its investigation into whether chimeric antigen receptor (CAR) T-cell immunotherapies can cause secondary blood cancers, specifically T-cell malignancies. At the time, the agency said: “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes.”
- In January 2024, the FDA issued boxed warnings on the six approved CART cell therapies, citing the possibility of second primary malignancies, including CAR-positive lymphomas, in patients who had received a CAR T agent.
- To evaluate the extent of these secondary cancers, researchers analyzed the FDA Adverse Event Reporting System database for CAR T-cell reports citing second primary malignancies.
TAKEAWAY:
- Overall, the authors identified 12,394 unique adverse events associated with CAR T therapy; of these, 536 adverse events (4.3%) were second primary malignancies.
- Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) accounted for most of the second primary malignancies reports — 51.7% (277 of 536 patients) for axi-cel and 33% (177 of 536 patients) for tis-cel.
- The researchers identified 19 cases of T-cell malignancies, representing only 0.15% of all unique adverse events and 3.54% of all second primary malignancies (19 of 536 patients); 17 of these cases were T-cell non-Hodgkin lymphomas, and two were T-cell large granular lymphocytic leukemia.
- Among the reported 536 second primary malignancies, the most frequent cancers were leukemias (333 reports, or 62%), followed by skin neoplasms (54 reports, or 10.1%), hematopoietic neoplasms excluding leukemias and lymphomas (26 reports, 4.85%), nervous system tumors (21 reports, 3.92%), and respiratory neoplasms (20 reports, 3.73%).
IN PRACTICE:
“We will continue to monitor the data released by the FDA to learn more about CAR T-associated risks. However, it’s crucial to stress that the benefits of CAR T-cell therapies still outweigh the risks for the approved indications,” Magdi Elsallab, MD, the study’s co-lead author, said in a news release.
SOURCE:
This work, led by Dr. Elsallab from Harvard Medical School in Boston, was published online on March 14 in Blood.
LIMITATIONS:
The limitations of the analysis include the presence of duplicate report submissions, incomplete data, difficulty establishing causal relationships, and the potential for both underreporting and overreporting based on the severity of adverse events. Furthermore, without the total number of prescribed products, it was difficult to determine the adverse event frequency.
DISCLOSURES:
The study funding source was not disclosed. Some of the authors reported financial ties with various organizations outside this work, including Bristol Myers Squibb, Janssen Biotech, Johnson & Johnson, Kite Pharma, and Novartis.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- In November 2023, the FDA announced its investigation into whether chimeric antigen receptor (CAR) T-cell immunotherapies can cause secondary blood cancers, specifically T-cell malignancies. At the time, the agency said: “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes.”
- In January 2024, the FDA issued boxed warnings on the six approved CART cell therapies, citing the possibility of second primary malignancies, including CAR-positive lymphomas, in patients who had received a CAR T agent.
- To evaluate the extent of these secondary cancers, researchers analyzed the FDA Adverse Event Reporting System database for CAR T-cell reports citing second primary malignancies.
TAKEAWAY:
- Overall, the authors identified 12,394 unique adverse events associated with CAR T therapy; of these, 536 adverse events (4.3%) were second primary malignancies.
- Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) accounted for most of the second primary malignancies reports — 51.7% (277 of 536 patients) for axi-cel and 33% (177 of 536 patients) for tis-cel.
- The researchers identified 19 cases of T-cell malignancies, representing only 0.15% of all unique adverse events and 3.54% of all second primary malignancies (19 of 536 patients); 17 of these cases were T-cell non-Hodgkin lymphomas, and two were T-cell large granular lymphocytic leukemia.
- Among the reported 536 second primary malignancies, the most frequent cancers were leukemias (333 reports, or 62%), followed by skin neoplasms (54 reports, or 10.1%), hematopoietic neoplasms excluding leukemias and lymphomas (26 reports, 4.85%), nervous system tumors (21 reports, 3.92%), and respiratory neoplasms (20 reports, 3.73%).
IN PRACTICE:
“We will continue to monitor the data released by the FDA to learn more about CAR T-associated risks. However, it’s crucial to stress that the benefits of CAR T-cell therapies still outweigh the risks for the approved indications,” Magdi Elsallab, MD, the study’s co-lead author, said in a news release.
SOURCE:
This work, led by Dr. Elsallab from Harvard Medical School in Boston, was published online on March 14 in Blood.
LIMITATIONS:
The limitations of the analysis include the presence of duplicate report submissions, incomplete data, difficulty establishing causal relationships, and the potential for both underreporting and overreporting based on the severity of adverse events. Furthermore, without the total number of prescribed products, it was difficult to determine the adverse event frequency.
DISCLOSURES:
The study funding source was not disclosed. Some of the authors reported financial ties with various organizations outside this work, including Bristol Myers Squibb, Janssen Biotech, Johnson & Johnson, Kite Pharma, and Novartis.
A version of this article appeared on Medscape.com.
FDA Approves Ponatinib for Upfront Ph+ ALL
The approval makes the third-generation tyrosine kinase inhibitor (TKI) the first targeted treatment approved for upfront use in adults with Ph+ ALL, Takeda said in a press release.
Ponatinib was previously approved as monotherapy for Ph+ ALL when no other kinase inhibitors are indicated or for T315I-positive Ph+ ALL, as well as for chronic myeloid leukemia.
Approval for the new indication was based on the PhALLCON trial. In the trial, 245 patients were randomized 2:1 to either ponatinib 30 mg once daily or the first-generation TKI imatinib (Gleevec, Novartis) 600 mg once daily on a chemotherapy background consisting of three cycles of vincristine/dexamethasone induction, six cycles methotrexate/cytarabine consolidation, and 11 cycles of vincristine/prednisone maintenance.
At the end of induction, 12% of patients in the imatinib arm vs 30% in the ponatinib group were in complete remission with no minimal residual disease. Event-free survival data are not yet mature.
At the 2023 American Society of Clinical Oncology annual meeting, an investigator on the trial said that ponatinib plus low-intensity chemotherapy has the potential to become the new standard of care for upfront Ph+ All. However, continued approval for the new indication may depend on trials confirming clinical benefit, Takeda said.
Ponatinib carries a boxed warning of arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.
The most common adverse reactions reported in the PhALLCON trial were hepatic dysfunction, arthralgia, rash, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.
The recommended ponatinib dose is 30 mg orally once daily until the end of induction, dropping down to 15 mg once daily in patients who go into remission with no minimal residual disease after induction, for up to 20 cycles or until loss of response or unacceptable toxicity.
Thirty tablets of 30 mg or 15 mg cost $21,944.54, according to Drugs.com.
A version of this article appeared on Medscape.com.
The approval makes the third-generation tyrosine kinase inhibitor (TKI) the first targeted treatment approved for upfront use in adults with Ph+ ALL, Takeda said in a press release.
Ponatinib was previously approved as monotherapy for Ph+ ALL when no other kinase inhibitors are indicated or for T315I-positive Ph+ ALL, as well as for chronic myeloid leukemia.
Approval for the new indication was based on the PhALLCON trial. In the trial, 245 patients were randomized 2:1 to either ponatinib 30 mg once daily or the first-generation TKI imatinib (Gleevec, Novartis) 600 mg once daily on a chemotherapy background consisting of three cycles of vincristine/dexamethasone induction, six cycles methotrexate/cytarabine consolidation, and 11 cycles of vincristine/prednisone maintenance.
At the end of induction, 12% of patients in the imatinib arm vs 30% in the ponatinib group were in complete remission with no minimal residual disease. Event-free survival data are not yet mature.
At the 2023 American Society of Clinical Oncology annual meeting, an investigator on the trial said that ponatinib plus low-intensity chemotherapy has the potential to become the new standard of care for upfront Ph+ All. However, continued approval for the new indication may depend on trials confirming clinical benefit, Takeda said.
Ponatinib carries a boxed warning of arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.
The most common adverse reactions reported in the PhALLCON trial were hepatic dysfunction, arthralgia, rash, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.
The recommended ponatinib dose is 30 mg orally once daily until the end of induction, dropping down to 15 mg once daily in patients who go into remission with no minimal residual disease after induction, for up to 20 cycles or until loss of response or unacceptable toxicity.
Thirty tablets of 30 mg or 15 mg cost $21,944.54, according to Drugs.com.
A version of this article appeared on Medscape.com.
The approval makes the third-generation tyrosine kinase inhibitor (TKI) the first targeted treatment approved for upfront use in adults with Ph+ ALL, Takeda said in a press release.
Ponatinib was previously approved as monotherapy for Ph+ ALL when no other kinase inhibitors are indicated or for T315I-positive Ph+ ALL, as well as for chronic myeloid leukemia.
Approval for the new indication was based on the PhALLCON trial. In the trial, 245 patients were randomized 2:1 to either ponatinib 30 mg once daily or the first-generation TKI imatinib (Gleevec, Novartis) 600 mg once daily on a chemotherapy background consisting of three cycles of vincristine/dexamethasone induction, six cycles methotrexate/cytarabine consolidation, and 11 cycles of vincristine/prednisone maintenance.
At the end of induction, 12% of patients in the imatinib arm vs 30% in the ponatinib group were in complete remission with no minimal residual disease. Event-free survival data are not yet mature.
At the 2023 American Society of Clinical Oncology annual meeting, an investigator on the trial said that ponatinib plus low-intensity chemotherapy has the potential to become the new standard of care for upfront Ph+ All. However, continued approval for the new indication may depend on trials confirming clinical benefit, Takeda said.
Ponatinib carries a boxed warning of arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.
The most common adverse reactions reported in the PhALLCON trial were hepatic dysfunction, arthralgia, rash, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.
The recommended ponatinib dose is 30 mg orally once daily until the end of induction, dropping down to 15 mg once daily in patients who go into remission with no minimal residual disease after induction, for up to 20 cycles or until loss of response or unacceptable toxicity.
Thirty tablets of 30 mg or 15 mg cost $21,944.54, according to Drugs.com.
A version of this article appeared on Medscape.com.
New Drug Approvals Are the Wrong Metric for Cancer Policy
How should we define success in cancer policy — what should the endpoint be?
It’s debatable. Is it fewer cancer deaths? Perhaps improved access to therapies or a reduction in disparities?
One thing I know with certainty: The number of new cancer drugs approved by the US Food and Drug Administration (FDA) is not and should not be our primary endpoint in and of itself.
I’ll go a step further: It is not even a surrogate marker for success.
Unfortunately, a new drug approval does not necessarily mean improved patient outcomes. In fact, the majority of cancer drugs approved these days improve neither survival nor quality of life. Our previous work has shown better mortality outcomes in other high-income countries that have not approved or do not fund several cancer drugs that the FDA has approved.
Even if a drug has a meaningful benefit, at an average cost of more than $250,000 per year, if a new drug cannot reach patients because of access or cost issues, it’s meaningless.
However, regulators and media celebrate the number (and speed) of drug approvals every year as if it were a marker of success in and of itself. But approving more drugs should not be the goal; improving outcomes should. The FDA’s current approach is akin to a university celebrating its graduation rate by lowering the requirements to pass.
When US patients lack access to cisplatin and carboplatin, any talk of a Moonshot or precision medicine ‘ending cancer as we know it’ is premature and even embarrassing.
This is exactly what the FDA has been doing with our regulatory standards for drug approval. They have gradually lowered the requirements for approval from two randomized trials to one randomized trial, then further to one randomized trial with a surrogate endpoint. In many instances, they have gone even further, demanding merely single-arm trials. They’ve also gone from requiring overall survival benefits to celebrating nondetrimental effects on overall survival. It’s no wonder that we approve more drugs today than we did in the past — the bar for approval is pretty low nowadays.
In 2019, our lab found an interesting phenomenon: The number of approvals based on surrogate endpoints has been increasing while the number of accelerated approvals has been decreasing. This made no sense at first, because you’d think surrogate-based approvals and accelerated approvals would be collinear. However, we realized that the recent approvals based on surrogate endpoints were regular approvals instead of accelerated approvals, which explained the phenomenon. Not only is the FDA approving more drugs on the basis of lower levels of evidence, but the agency is also offering regular instead of accelerated approval, thereby removing the safety net of a confirmatory trial.
Nearly everybody sees this as a cause for celebration. Pharma celebrates record profits, regulators celebrate record numbers of drug approvals, insurance companies celebrate because they can pass these costs on as insurance premiums and make even more money, and physicians and patients celebrate access to the shiniest, sexiest new cancer drug.
Everybody is happy in this system. The only problem is that patient outcomes don’t improve, resources are taken away from other priorities, and society suffers a net harm.
When you contrast this celebration with the reality on the ground, the difference is stark and sobering. In our clinics, patients lack access to even old chemotherapeutic drugs that are already generic and cheap but make a meaningful difference in patient outcomes. Citing a current lack of incentives, several generic cancer drug manufacturers have stopped making these drugs; the US supply now relies heavily on importing them from emerging economies such as India. When US patients lack access to cisplatin and carboplatin, any talk of a Moonshot or precision medicine “ending cancer as we know it” is premature and even embarrassing.
5-Fluorouracil, methotrexate, and the platinums are backbones of cancer treatment. Cisplatin and carboplatin are not drugs we use with the hope of improving survival by a couple of months; these drugs are the difference between life and death for patients with testicular and ovarian cancers. In a survey of 948 global oncologists, these were considered among the most essential cancer drugs by oncologists in high-income and low- and middle-income countries alike. Although oncologists in low- and middle-income countries sometimes argue that even these cheap generic drugs may be unaffordable to their patients, they usually remain available; access is a function of both availability and affordability. However, the shortage situation in the US is unique in that availability — rather than affordability — is impacting access.
Our profit-over-patients policy has landed us in a terrible paradox.
Generic drugs are cheap, and any industrialized country can manufacture them. This is why so few companies actually do so; the profit margins are low and companies have little incentive to produce them, despite their benefit. Meanwhile, the FDA is approving and offering access to new shiny molecules that cost more than $15,000 per month yet offer less than a month of progression-free survival benefit and no overall survival benefit (see margetuximab in breast cancer). We have a literal fatal attraction to everything new and shiny.
This is a clear misalignment of priorities in US cancer drug policy. Our profit-over-patients policy has landed us in a terrible paradox: If a drug is cheap and meaningful, it won’t be available, but if it is marginal and expensive, we will do everything to ensure patients can get it. It’s no wonder that patients on Medicaid are disproportionately affected by these drug shortages. Unless all patients have easy access to cisplatin, carboplatin, and 5-fluorouracil, it is frankly embarrassing to celebrate the number of new cancer drugs approved each year.
We all have a responsibility in this — policymakers and lawmakers, regulators and payers, manufacturers and distributors, the American Society of Clinical Oncology and other oncology societies, and physicians and patients. This is where our advocacy work should focus. The primary endpoint of our cancer policy should not be how many new treatments we can approve or how many expensive drugs a rich person with the best insurance can get at a leading cancer center. The true measure of our civilization is how it treats its most vulnerable members.
Dr. Gyawali has disclosed the following relevant financial relationship: Received consulting fees from Vivio Health.
Dr. Gyawali is an associate professor in the Departments of Oncology and Public Health Sciences and a scientist in the Division of Cancer Care and Epidemiology at Queen’s University in Kingston, Ontario, Canada, and is also affiliated faculty at the Program on Regulation, Therapeutics, and Law in the Department of Medicine at Brigham and Women’s Hospital in Boston. His clinical and research interests revolve around cancer policy, global oncology, evidence-based oncology, financial toxicities of cancer treatment, clinical trial methods, and supportive care. He tweets at @oncology_bg.
A version of this article appeared on Medscape.com.
How should we define success in cancer policy — what should the endpoint be?
It’s debatable. Is it fewer cancer deaths? Perhaps improved access to therapies or a reduction in disparities?
One thing I know with certainty: The number of new cancer drugs approved by the US Food and Drug Administration (FDA) is not and should not be our primary endpoint in and of itself.
I’ll go a step further: It is not even a surrogate marker for success.
Unfortunately, a new drug approval does not necessarily mean improved patient outcomes. In fact, the majority of cancer drugs approved these days improve neither survival nor quality of life. Our previous work has shown better mortality outcomes in other high-income countries that have not approved or do not fund several cancer drugs that the FDA has approved.
Even if a drug has a meaningful benefit, at an average cost of more than $250,000 per year, if a new drug cannot reach patients because of access or cost issues, it’s meaningless.
However, regulators and media celebrate the number (and speed) of drug approvals every year as if it were a marker of success in and of itself. But approving more drugs should not be the goal; improving outcomes should. The FDA’s current approach is akin to a university celebrating its graduation rate by lowering the requirements to pass.
When US patients lack access to cisplatin and carboplatin, any talk of a Moonshot or precision medicine ‘ending cancer as we know it’ is premature and even embarrassing.
This is exactly what the FDA has been doing with our regulatory standards for drug approval. They have gradually lowered the requirements for approval from two randomized trials to one randomized trial, then further to one randomized trial with a surrogate endpoint. In many instances, they have gone even further, demanding merely single-arm trials. They’ve also gone from requiring overall survival benefits to celebrating nondetrimental effects on overall survival. It’s no wonder that we approve more drugs today than we did in the past — the bar for approval is pretty low nowadays.
In 2019, our lab found an interesting phenomenon: The number of approvals based on surrogate endpoints has been increasing while the number of accelerated approvals has been decreasing. This made no sense at first, because you’d think surrogate-based approvals and accelerated approvals would be collinear. However, we realized that the recent approvals based on surrogate endpoints were regular approvals instead of accelerated approvals, which explained the phenomenon. Not only is the FDA approving more drugs on the basis of lower levels of evidence, but the agency is also offering regular instead of accelerated approval, thereby removing the safety net of a confirmatory trial.
Nearly everybody sees this as a cause for celebration. Pharma celebrates record profits, regulators celebrate record numbers of drug approvals, insurance companies celebrate because they can pass these costs on as insurance premiums and make even more money, and physicians and patients celebrate access to the shiniest, sexiest new cancer drug.
Everybody is happy in this system. The only problem is that patient outcomes don’t improve, resources are taken away from other priorities, and society suffers a net harm.
When you contrast this celebration with the reality on the ground, the difference is stark and sobering. In our clinics, patients lack access to even old chemotherapeutic drugs that are already generic and cheap but make a meaningful difference in patient outcomes. Citing a current lack of incentives, several generic cancer drug manufacturers have stopped making these drugs; the US supply now relies heavily on importing them from emerging economies such as India. When US patients lack access to cisplatin and carboplatin, any talk of a Moonshot or precision medicine “ending cancer as we know it” is premature and even embarrassing.
5-Fluorouracil, methotrexate, and the platinums are backbones of cancer treatment. Cisplatin and carboplatin are not drugs we use with the hope of improving survival by a couple of months; these drugs are the difference between life and death for patients with testicular and ovarian cancers. In a survey of 948 global oncologists, these were considered among the most essential cancer drugs by oncologists in high-income and low- and middle-income countries alike. Although oncologists in low- and middle-income countries sometimes argue that even these cheap generic drugs may be unaffordable to their patients, they usually remain available; access is a function of both availability and affordability. However, the shortage situation in the US is unique in that availability — rather than affordability — is impacting access.
Our profit-over-patients policy has landed us in a terrible paradox.
Generic drugs are cheap, and any industrialized country can manufacture them. This is why so few companies actually do so; the profit margins are low and companies have little incentive to produce them, despite their benefit. Meanwhile, the FDA is approving and offering access to new shiny molecules that cost more than $15,000 per month yet offer less than a month of progression-free survival benefit and no overall survival benefit (see margetuximab in breast cancer). We have a literal fatal attraction to everything new and shiny.
This is a clear misalignment of priorities in US cancer drug policy. Our profit-over-patients policy has landed us in a terrible paradox: If a drug is cheap and meaningful, it won’t be available, but if it is marginal and expensive, we will do everything to ensure patients can get it. It’s no wonder that patients on Medicaid are disproportionately affected by these drug shortages. Unless all patients have easy access to cisplatin, carboplatin, and 5-fluorouracil, it is frankly embarrassing to celebrate the number of new cancer drugs approved each year.
We all have a responsibility in this — policymakers and lawmakers, regulators and payers, manufacturers and distributors, the American Society of Clinical Oncology and other oncology societies, and physicians and patients. This is where our advocacy work should focus. The primary endpoint of our cancer policy should not be how many new treatments we can approve or how many expensive drugs a rich person with the best insurance can get at a leading cancer center. The true measure of our civilization is how it treats its most vulnerable members.
Dr. Gyawali has disclosed the following relevant financial relationship: Received consulting fees from Vivio Health.
Dr. Gyawali is an associate professor in the Departments of Oncology and Public Health Sciences and a scientist in the Division of Cancer Care and Epidemiology at Queen’s University in Kingston, Ontario, Canada, and is also affiliated faculty at the Program on Regulation, Therapeutics, and Law in the Department of Medicine at Brigham and Women’s Hospital in Boston. His clinical and research interests revolve around cancer policy, global oncology, evidence-based oncology, financial toxicities of cancer treatment, clinical trial methods, and supportive care. He tweets at @oncology_bg.
A version of this article appeared on Medscape.com.
How should we define success in cancer policy — what should the endpoint be?
It’s debatable. Is it fewer cancer deaths? Perhaps improved access to therapies or a reduction in disparities?
One thing I know with certainty: The number of new cancer drugs approved by the US Food and Drug Administration (FDA) is not and should not be our primary endpoint in and of itself.
I’ll go a step further: It is not even a surrogate marker for success.
Unfortunately, a new drug approval does not necessarily mean improved patient outcomes. In fact, the majority of cancer drugs approved these days improve neither survival nor quality of life. Our previous work has shown better mortality outcomes in other high-income countries that have not approved or do not fund several cancer drugs that the FDA has approved.
Even if a drug has a meaningful benefit, at an average cost of more than $250,000 per year, if a new drug cannot reach patients because of access or cost issues, it’s meaningless.
However, regulators and media celebrate the number (and speed) of drug approvals every year as if it were a marker of success in and of itself. But approving more drugs should not be the goal; improving outcomes should. The FDA’s current approach is akin to a university celebrating its graduation rate by lowering the requirements to pass.
When US patients lack access to cisplatin and carboplatin, any talk of a Moonshot or precision medicine ‘ending cancer as we know it’ is premature and even embarrassing.
This is exactly what the FDA has been doing with our regulatory standards for drug approval. They have gradually lowered the requirements for approval from two randomized trials to one randomized trial, then further to one randomized trial with a surrogate endpoint. In many instances, they have gone even further, demanding merely single-arm trials. They’ve also gone from requiring overall survival benefits to celebrating nondetrimental effects on overall survival. It’s no wonder that we approve more drugs today than we did in the past — the bar for approval is pretty low nowadays.
In 2019, our lab found an interesting phenomenon: The number of approvals based on surrogate endpoints has been increasing while the number of accelerated approvals has been decreasing. This made no sense at first, because you’d think surrogate-based approvals and accelerated approvals would be collinear. However, we realized that the recent approvals based on surrogate endpoints were regular approvals instead of accelerated approvals, which explained the phenomenon. Not only is the FDA approving more drugs on the basis of lower levels of evidence, but the agency is also offering regular instead of accelerated approval, thereby removing the safety net of a confirmatory trial.
Nearly everybody sees this as a cause for celebration. Pharma celebrates record profits, regulators celebrate record numbers of drug approvals, insurance companies celebrate because they can pass these costs on as insurance premiums and make even more money, and physicians and patients celebrate access to the shiniest, sexiest new cancer drug.
Everybody is happy in this system. The only problem is that patient outcomes don’t improve, resources are taken away from other priorities, and society suffers a net harm.
When you contrast this celebration with the reality on the ground, the difference is stark and sobering. In our clinics, patients lack access to even old chemotherapeutic drugs that are already generic and cheap but make a meaningful difference in patient outcomes. Citing a current lack of incentives, several generic cancer drug manufacturers have stopped making these drugs; the US supply now relies heavily on importing them from emerging economies such as India. When US patients lack access to cisplatin and carboplatin, any talk of a Moonshot or precision medicine “ending cancer as we know it” is premature and even embarrassing.
5-Fluorouracil, methotrexate, and the platinums are backbones of cancer treatment. Cisplatin and carboplatin are not drugs we use with the hope of improving survival by a couple of months; these drugs are the difference between life and death for patients with testicular and ovarian cancers. In a survey of 948 global oncologists, these were considered among the most essential cancer drugs by oncologists in high-income and low- and middle-income countries alike. Although oncologists in low- and middle-income countries sometimes argue that even these cheap generic drugs may be unaffordable to their patients, they usually remain available; access is a function of both availability and affordability. However, the shortage situation in the US is unique in that availability — rather than affordability — is impacting access.
Our profit-over-patients policy has landed us in a terrible paradox.
Generic drugs are cheap, and any industrialized country can manufacture them. This is why so few companies actually do so; the profit margins are low and companies have little incentive to produce them, despite their benefit. Meanwhile, the FDA is approving and offering access to new shiny molecules that cost more than $15,000 per month yet offer less than a month of progression-free survival benefit and no overall survival benefit (see margetuximab in breast cancer). We have a literal fatal attraction to everything new and shiny.
This is a clear misalignment of priorities in US cancer drug policy. Our profit-over-patients policy has landed us in a terrible paradox: If a drug is cheap and meaningful, it won’t be available, but if it is marginal and expensive, we will do everything to ensure patients can get it. It’s no wonder that patients on Medicaid are disproportionately affected by these drug shortages. Unless all patients have easy access to cisplatin, carboplatin, and 5-fluorouracil, it is frankly embarrassing to celebrate the number of new cancer drugs approved each year.
We all have a responsibility in this — policymakers and lawmakers, regulators and payers, manufacturers and distributors, the American Society of Clinical Oncology and other oncology societies, and physicians and patients. This is where our advocacy work should focus. The primary endpoint of our cancer policy should not be how many new treatments we can approve or how many expensive drugs a rich person with the best insurance can get at a leading cancer center. The true measure of our civilization is how it treats its most vulnerable members.
Dr. Gyawali has disclosed the following relevant financial relationship: Received consulting fees from Vivio Health.
Dr. Gyawali is an associate professor in the Departments of Oncology and Public Health Sciences and a scientist in the Division of Cancer Care and Epidemiology at Queen’s University in Kingston, Ontario, Canada, and is also affiliated faculty at the Program on Regulation, Therapeutics, and Law in the Department of Medicine at Brigham and Women’s Hospital in Boston. His clinical and research interests revolve around cancer policy, global oncology, evidence-based oncology, financial toxicities of cancer treatment, clinical trial methods, and supportive care. He tweets at @oncology_bg.
A version of this article appeared on Medscape.com.
Extraordinary Patients Inspired Father of Cancer Immunotherapy
His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.
To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.
Dr. Rosenberg, a senior investigator for the Center for Cancer Research at the National Cancer Institute (NCI), and chief of the NCI Surgery Branch, shared the history behind his novel research and the patient stories that inspired his discoveries, during an interview.
Tell us a little about yourself and where you grew up.
Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.
As a young boy, did you always want to become a doctor?
Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.
How did that experience impact your aspirations?
Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.
What led to your interest in cancer treatment?
Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.
Were there patients who inspired your research?
Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
Was the second patient’s case as impressive?
Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.
From there, how did your work evolve?
Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.
Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?
Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.
How did this finding impact your future discoveries?
Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.
What guidance would you have for other physician-investigators or young doctors who want to follow in your path?
Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.
His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.
To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.
Dr. Rosenberg, a senior investigator for the Center for Cancer Research at the National Cancer Institute (NCI), and chief of the NCI Surgery Branch, shared the history behind his novel research and the patient stories that inspired his discoveries, during an interview.
Tell us a little about yourself and where you grew up.
Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.
As a young boy, did you always want to become a doctor?
Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.
How did that experience impact your aspirations?
Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.
What led to your interest in cancer treatment?
Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.
Were there patients who inspired your research?
Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
Was the second patient’s case as impressive?
Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.
From there, how did your work evolve?
Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.
Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?
Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.
How did this finding impact your future discoveries?
Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.
What guidance would you have for other physician-investigators or young doctors who want to follow in your path?
Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.
His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.
To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.
Dr. Rosenberg, a senior investigator for the Center for Cancer Research at the National Cancer Institute (NCI), and chief of the NCI Surgery Branch, shared the history behind his novel research and the patient stories that inspired his discoveries, during an interview.
Tell us a little about yourself and where you grew up.
Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.
As a young boy, did you always want to become a doctor?
Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.
How did that experience impact your aspirations?
Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.
What led to your interest in cancer treatment?
Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.
Were there patients who inspired your research?
Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
Was the second patient’s case as impressive?
Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.
From there, how did your work evolve?
Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.
Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?
Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.
How did this finding impact your future discoveries?
Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.
What guidance would you have for other physician-investigators or young doctors who want to follow in your path?
Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.
Myeloma: FDA Advisers Greenlight Early CAR-T
The FDA asked its Oncologic Drugs Advisory Committee (ODAC) to vote on two separate but similar questions at the March 15 meeting. Much of their discussion centered on higher rates of deaths for patients on the CAR-T therapies during early stages of key studies.
ODAC voted 11-0 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for ciltacabtagene autoleucel (cilta-cel, Carvykti, Johnson & Johnson’s Janssen). J&J is seeking approval for use of the drug for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide.
ODAC voted 8-3 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb). The company is seeking approval of the drug for people with relapsed or refractory multiple myeloma (RRMM) who have received an IMiD, a PI, and an anti-CD38 antibody.
The FDA staff will consider ODAC’s votes and recommendations, but is not bound by them. Janssen’s parent company, J&J, said the FDA’s deadline for deciding on the request to change the cilta-cel label is April 5. Bristol Myers Squibb (BMS) said there is not a PDUFA deadline at this time for its application.
Both CAR-T treatments currently are approved for RRMM after 4 or more prior lines of therapy, including an IMiD, PI and an anti-CD38 monoclonal antibody. Last year BMS and Janssen filed their separate applications, both seeking to have their drugs used earlier in the course of RRMM.
Data provided in support of both requests for expanded use raised alarms at the FDA, with more deaths seen in the early stage of testing among patients given the CAR-T drugs compared to those given standard-of-care regimens, the agency staff said.
The application for cilta-cel rests heavily on the data from the CARTITUDE-4 trial. As reported in The New England Journal of Medicine last year, progression-free survival (PFS) at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group.
But the FDA staff review focused on worrying signs in the early months of this study. For example, the rate of death in the first 10 months post randomization was higher in the cilta-cel arm (29 of 208; 14%) than in the standard therapy arm (25 of 211; 12%) based on an analysis of the intent-to-treat (ITT) population, the FDA said.
In its review of the ide-cel application, the FDA staff said the median PFS was 13.3 months in the ide-cel arm (95% CI: 11.8, 16.1), and 4.4 months (95% CI: 3.4, 5.9) in the standard of care (SOC) arm.
However, the rate of deaths in the first 9 months post randomization was higher in the ide-cel arm (45/254; 18%) than in the comparator standard-of-care group (15/132; 11%) in the ITT population, the FDA staff said. In the safety analysis population, the rate of deaths from adverse events that occurred within 90 days from starting treatment was 2.7% in the ide-cel arm and 1.6 % in the standard-regimen group.
ODAC ultimately appeared more impressed by data indicating the potential benefit, measured as progression-free survival (PFS), of the two drugs under review, than they were concerned about the issues about early deaths raised by FDA staff.
Panelist Jorge J. Nieva, MD, of the University of Southern California said the CAR-T drugs may present another case of “front-loaded risk” as has been noted for other treatments for serious medical procedures, such as allogeneic transplantations and thoracic surgeries.
In response, Robert Sokolic, MD, the branch chief for malignant hematology at FDA, replied that the data raised concerns that did in fact remind him of these procedures.
“I’m a bone marrow transplant physician. And that’s exactly what I said when I saw these curves. This looks like an allogeneic transplant curve,” Dr. Sokolic said.
But there’s a major difference between that procedure and CAR-T in the context being considered at the ODAC meeting, he said.
With allogeneic transplant, physicians “counsel patients. We ask them to accept an upfront burden of increased mortality, because we know that down the line, overall, there’s a benefit in survival,” Dr. Sokolic said.
In contrast, the primary endpoint in the key studies for expansion of CAR-T drugs was progression-free survival (PFS), with overall survival as a second endpoint. The FDA staff in briefing documents noted how overall survival, the gold standard in research, delivers far more reliable answers for patients and doctors in assessing treatments.
In the exchange with Dr. Nieva, Dr. Sokolic noted that there’s far less certainty of benefit at this time when asking patients to consider CAR-T earlier in the progression of MM, especially given the safety concerns.
“We know there’s benefit in PFS. We know there’s a safety concern,” Dr. Sokolic said.“That’s not balanced by an overall survival balance on the tail end. It may be when the data are more mature, but it’s not there yet.”
Describing Risks to Patients
ODAC panelists also stressed a need to help patients understand what’s known — and not yet known — about these CAR-T therapies. It will be very challenging for patients to understand and interpret the data from key studies on these medicines, said ODAC panelist Susan Lattimore, RN, of Oregon Health & Science University. She suggested the FDA seek labeling that would be “overtly transparent” and use lay terms to describe the potential risks and benefits.
In its presentations to the FDA and ODAC, J&J noted that the COVID pandemic has affected testing and that the rate of deaths flips in time to be higher in the comparator group.
In its briefing document for the meeting, BMS emphasized that most of the patients in the ide-cel arm who died in the first 6 months of its trial did not get the study drug. There were 9 deaths in the standard-regimen arm, or 6.8% of the group, compared with 30, or 11.8% in the ide-cel group.
In the ide-cel arm, the majority of early deaths (17/30; 56.7%) occurred in patients who never received ide-cel treatment, with 13 of those 17 dying from disease progression, the company said in its briefing document. The early death rate among patients who received the allocated study treatment was similar between arms (5.1% in the ide-cel arm vs 6.8% in the standard regimen arm),the company said.
In the staff briefing, the FDA said the median PFS was 13.3 months in the ide-cel arm, compared with 4.4 months in the standard of care (SOC) arm. But there was a “clear and persistent increased mortality” for the ide-cel group, compared with the standard regimen arm, with increased rates of death up to 9 months. In addition, the overall survival disadvantage persisted to 15 months after randomization, when the survival curves finally crossed, the FDA staff said in its March 15 presentation.
ODAC Chairman Ravi A. Madan, MD, of the National Cancer Institute, was among the panelists who voted “no” in the ide-cel question. He said the risk-benefit profile of the drug does not appear favorable at this time for expanded use.
“There’s a lot of optimism about moving these therapies earlier in the disease states of multiple myeloma,” Dr. Madan said, calling the PFS data “quite remarkable.
“But for me this data at this level of maturity really didn’t provide convincing evidence that ide-cel earlier had a favorable risk benefit assessment in a proposed indication.”
ODAC panelist Christopher H. Lieu, MD, of the University of Colorado, said he struggled to decide how to vote on the ide-cel question and in the end voted yes.
He said the response to the treatment doesn’t appear to be as durable as hoped, considering the significant burden that CAR-T therapy imposes on patients. However, the PFS data suggest that ide-cel could offer patients with RRMM a chance for significant times off therapy with associated quality of life improvement.
“I do believe that the risk-benefit profile is favorable for this population as a whole,” he said. “But it’s a closer margin than I think we would like and patients will need to have in-depth discussions about the risks and benefits and balance that with the possible benefits with their provider.”
The FDA asked its Oncologic Drugs Advisory Committee (ODAC) to vote on two separate but similar questions at the March 15 meeting. Much of their discussion centered on higher rates of deaths for patients on the CAR-T therapies during early stages of key studies.
ODAC voted 11-0 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for ciltacabtagene autoleucel (cilta-cel, Carvykti, Johnson & Johnson’s Janssen). J&J is seeking approval for use of the drug for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide.
ODAC voted 8-3 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb). The company is seeking approval of the drug for people with relapsed or refractory multiple myeloma (RRMM) who have received an IMiD, a PI, and an anti-CD38 antibody.
The FDA staff will consider ODAC’s votes and recommendations, but is not bound by them. Janssen’s parent company, J&J, said the FDA’s deadline for deciding on the request to change the cilta-cel label is April 5. Bristol Myers Squibb (BMS) said there is not a PDUFA deadline at this time for its application.
Both CAR-T treatments currently are approved for RRMM after 4 or more prior lines of therapy, including an IMiD, PI and an anti-CD38 monoclonal antibody. Last year BMS and Janssen filed their separate applications, both seeking to have their drugs used earlier in the course of RRMM.
Data provided in support of both requests for expanded use raised alarms at the FDA, with more deaths seen in the early stage of testing among patients given the CAR-T drugs compared to those given standard-of-care regimens, the agency staff said.
The application for cilta-cel rests heavily on the data from the CARTITUDE-4 trial. As reported in The New England Journal of Medicine last year, progression-free survival (PFS) at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group.
But the FDA staff review focused on worrying signs in the early months of this study. For example, the rate of death in the first 10 months post randomization was higher in the cilta-cel arm (29 of 208; 14%) than in the standard therapy arm (25 of 211; 12%) based on an analysis of the intent-to-treat (ITT) population, the FDA said.
In its review of the ide-cel application, the FDA staff said the median PFS was 13.3 months in the ide-cel arm (95% CI: 11.8, 16.1), and 4.4 months (95% CI: 3.4, 5.9) in the standard of care (SOC) arm.
However, the rate of deaths in the first 9 months post randomization was higher in the ide-cel arm (45/254; 18%) than in the comparator standard-of-care group (15/132; 11%) in the ITT population, the FDA staff said. In the safety analysis population, the rate of deaths from adverse events that occurred within 90 days from starting treatment was 2.7% in the ide-cel arm and 1.6 % in the standard-regimen group.
ODAC ultimately appeared more impressed by data indicating the potential benefit, measured as progression-free survival (PFS), of the two drugs under review, than they were concerned about the issues about early deaths raised by FDA staff.
Panelist Jorge J. Nieva, MD, of the University of Southern California said the CAR-T drugs may present another case of “front-loaded risk” as has been noted for other treatments for serious medical procedures, such as allogeneic transplantations and thoracic surgeries.
In response, Robert Sokolic, MD, the branch chief for malignant hematology at FDA, replied that the data raised concerns that did in fact remind him of these procedures.
“I’m a bone marrow transplant physician. And that’s exactly what I said when I saw these curves. This looks like an allogeneic transplant curve,” Dr. Sokolic said.
But there’s a major difference between that procedure and CAR-T in the context being considered at the ODAC meeting, he said.
With allogeneic transplant, physicians “counsel patients. We ask them to accept an upfront burden of increased mortality, because we know that down the line, overall, there’s a benefit in survival,” Dr. Sokolic said.
In contrast, the primary endpoint in the key studies for expansion of CAR-T drugs was progression-free survival (PFS), with overall survival as a second endpoint. The FDA staff in briefing documents noted how overall survival, the gold standard in research, delivers far more reliable answers for patients and doctors in assessing treatments.
In the exchange with Dr. Nieva, Dr. Sokolic noted that there’s far less certainty of benefit at this time when asking patients to consider CAR-T earlier in the progression of MM, especially given the safety concerns.
“We know there’s benefit in PFS. We know there’s a safety concern,” Dr. Sokolic said.“That’s not balanced by an overall survival balance on the tail end. It may be when the data are more mature, but it’s not there yet.”
Describing Risks to Patients
ODAC panelists also stressed a need to help patients understand what’s known — and not yet known — about these CAR-T therapies. It will be very challenging for patients to understand and interpret the data from key studies on these medicines, said ODAC panelist Susan Lattimore, RN, of Oregon Health & Science University. She suggested the FDA seek labeling that would be “overtly transparent” and use lay terms to describe the potential risks and benefits.
In its presentations to the FDA and ODAC, J&J noted that the COVID pandemic has affected testing and that the rate of deaths flips in time to be higher in the comparator group.
In its briefing document for the meeting, BMS emphasized that most of the patients in the ide-cel arm who died in the first 6 months of its trial did not get the study drug. There were 9 deaths in the standard-regimen arm, or 6.8% of the group, compared with 30, or 11.8% in the ide-cel group.
In the ide-cel arm, the majority of early deaths (17/30; 56.7%) occurred in patients who never received ide-cel treatment, with 13 of those 17 dying from disease progression, the company said in its briefing document. The early death rate among patients who received the allocated study treatment was similar between arms (5.1% in the ide-cel arm vs 6.8% in the standard regimen arm),the company said.
In the staff briefing, the FDA said the median PFS was 13.3 months in the ide-cel arm, compared with 4.4 months in the standard of care (SOC) arm. But there was a “clear and persistent increased mortality” for the ide-cel group, compared with the standard regimen arm, with increased rates of death up to 9 months. In addition, the overall survival disadvantage persisted to 15 months after randomization, when the survival curves finally crossed, the FDA staff said in its March 15 presentation.
ODAC Chairman Ravi A. Madan, MD, of the National Cancer Institute, was among the panelists who voted “no” in the ide-cel question. He said the risk-benefit profile of the drug does not appear favorable at this time for expanded use.
“There’s a lot of optimism about moving these therapies earlier in the disease states of multiple myeloma,” Dr. Madan said, calling the PFS data “quite remarkable.
“But for me this data at this level of maturity really didn’t provide convincing evidence that ide-cel earlier had a favorable risk benefit assessment in a proposed indication.”
ODAC panelist Christopher H. Lieu, MD, of the University of Colorado, said he struggled to decide how to vote on the ide-cel question and in the end voted yes.
He said the response to the treatment doesn’t appear to be as durable as hoped, considering the significant burden that CAR-T therapy imposes on patients. However, the PFS data suggest that ide-cel could offer patients with RRMM a chance for significant times off therapy with associated quality of life improvement.
“I do believe that the risk-benefit profile is favorable for this population as a whole,” he said. “But it’s a closer margin than I think we would like and patients will need to have in-depth discussions about the risks and benefits and balance that with the possible benefits with their provider.”
The FDA asked its Oncologic Drugs Advisory Committee (ODAC) to vote on two separate but similar questions at the March 15 meeting. Much of their discussion centered on higher rates of deaths for patients on the CAR-T therapies during early stages of key studies.
ODAC voted 11-0 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for ciltacabtagene autoleucel (cilta-cel, Carvykti, Johnson & Johnson’s Janssen). J&J is seeking approval for use of the drug for adults with relapsed or refractory multiple myeloma (RRMM) who have received at least one prior line of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide.
ODAC voted 8-3 to say the risk-benefit assessment appeared favorable for a requested broadening of the patient pool for idecabtagene vicleucel (ide-cel, Abecma, Bristol Myers Squibb). The company is seeking approval of the drug for people with relapsed or refractory multiple myeloma (RRMM) who have received an IMiD, a PI, and an anti-CD38 antibody.
The FDA staff will consider ODAC’s votes and recommendations, but is not bound by them. Janssen’s parent company, J&J, said the FDA’s deadline for deciding on the request to change the cilta-cel label is April 5. Bristol Myers Squibb (BMS) said there is not a PDUFA deadline at this time for its application.
Both CAR-T treatments currently are approved for RRMM after 4 or more prior lines of therapy, including an IMiD, PI and an anti-CD38 monoclonal antibody. Last year BMS and Janssen filed their separate applications, both seeking to have their drugs used earlier in the course of RRMM.
Data provided in support of both requests for expanded use raised alarms at the FDA, with more deaths seen in the early stage of testing among patients given the CAR-T drugs compared to those given standard-of-care regimens, the agency staff said.
The application for cilta-cel rests heavily on the data from the CARTITUDE-4 trial. As reported in The New England Journal of Medicine last year, progression-free survival (PFS) at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group.
But the FDA staff review focused on worrying signs in the early months of this study. For example, the rate of death in the first 10 months post randomization was higher in the cilta-cel arm (29 of 208; 14%) than in the standard therapy arm (25 of 211; 12%) based on an analysis of the intent-to-treat (ITT) population, the FDA said.
In its review of the ide-cel application, the FDA staff said the median PFS was 13.3 months in the ide-cel arm (95% CI: 11.8, 16.1), and 4.4 months (95% CI: 3.4, 5.9) in the standard of care (SOC) arm.
However, the rate of deaths in the first 9 months post randomization was higher in the ide-cel arm (45/254; 18%) than in the comparator standard-of-care group (15/132; 11%) in the ITT population, the FDA staff said. In the safety analysis population, the rate of deaths from adverse events that occurred within 90 days from starting treatment was 2.7% in the ide-cel arm and 1.6 % in the standard-regimen group.
ODAC ultimately appeared more impressed by data indicating the potential benefit, measured as progression-free survival (PFS), of the two drugs under review, than they were concerned about the issues about early deaths raised by FDA staff.
Panelist Jorge J. Nieva, MD, of the University of Southern California said the CAR-T drugs may present another case of “front-loaded risk” as has been noted for other treatments for serious medical procedures, such as allogeneic transplantations and thoracic surgeries.
In response, Robert Sokolic, MD, the branch chief for malignant hematology at FDA, replied that the data raised concerns that did in fact remind him of these procedures.
“I’m a bone marrow transplant physician. And that’s exactly what I said when I saw these curves. This looks like an allogeneic transplant curve,” Dr. Sokolic said.
But there’s a major difference between that procedure and CAR-T in the context being considered at the ODAC meeting, he said.
With allogeneic transplant, physicians “counsel patients. We ask them to accept an upfront burden of increased mortality, because we know that down the line, overall, there’s a benefit in survival,” Dr. Sokolic said.
In contrast, the primary endpoint in the key studies for expansion of CAR-T drugs was progression-free survival (PFS), with overall survival as a second endpoint. The FDA staff in briefing documents noted how overall survival, the gold standard in research, delivers far more reliable answers for patients and doctors in assessing treatments.
In the exchange with Dr. Nieva, Dr. Sokolic noted that there’s far less certainty of benefit at this time when asking patients to consider CAR-T earlier in the progression of MM, especially given the safety concerns.
“We know there’s benefit in PFS. We know there’s a safety concern,” Dr. Sokolic said.“That’s not balanced by an overall survival balance on the tail end. It may be when the data are more mature, but it’s not there yet.”
Describing Risks to Patients
ODAC panelists also stressed a need to help patients understand what’s known — and not yet known — about these CAR-T therapies. It will be very challenging for patients to understand and interpret the data from key studies on these medicines, said ODAC panelist Susan Lattimore, RN, of Oregon Health & Science University. She suggested the FDA seek labeling that would be “overtly transparent” and use lay terms to describe the potential risks and benefits.
In its presentations to the FDA and ODAC, J&J noted that the COVID pandemic has affected testing and that the rate of deaths flips in time to be higher in the comparator group.
In its briefing document for the meeting, BMS emphasized that most of the patients in the ide-cel arm who died in the first 6 months of its trial did not get the study drug. There were 9 deaths in the standard-regimen arm, or 6.8% of the group, compared with 30, or 11.8% in the ide-cel group.
In the ide-cel arm, the majority of early deaths (17/30; 56.7%) occurred in patients who never received ide-cel treatment, with 13 of those 17 dying from disease progression, the company said in its briefing document. The early death rate among patients who received the allocated study treatment was similar between arms (5.1% in the ide-cel arm vs 6.8% in the standard regimen arm),the company said.
In the staff briefing, the FDA said the median PFS was 13.3 months in the ide-cel arm, compared with 4.4 months in the standard of care (SOC) arm. But there was a “clear and persistent increased mortality” for the ide-cel group, compared with the standard regimen arm, with increased rates of death up to 9 months. In addition, the overall survival disadvantage persisted to 15 months after randomization, when the survival curves finally crossed, the FDA staff said in its March 15 presentation.
ODAC Chairman Ravi A. Madan, MD, of the National Cancer Institute, was among the panelists who voted “no” in the ide-cel question. He said the risk-benefit profile of the drug does not appear favorable at this time for expanded use.
“There’s a lot of optimism about moving these therapies earlier in the disease states of multiple myeloma,” Dr. Madan said, calling the PFS data “quite remarkable.
“But for me this data at this level of maturity really didn’t provide convincing evidence that ide-cel earlier had a favorable risk benefit assessment in a proposed indication.”
ODAC panelist Christopher H. Lieu, MD, of the University of Colorado, said he struggled to decide how to vote on the ide-cel question and in the end voted yes.
He said the response to the treatment doesn’t appear to be as durable as hoped, considering the significant burden that CAR-T therapy imposes on patients. However, the PFS data suggest that ide-cel could offer patients with RRMM a chance for significant times off therapy with associated quality of life improvement.
“I do believe that the risk-benefit profile is favorable for this population as a whole,” he said. “But it’s a closer margin than I think we would like and patients will need to have in-depth discussions about the risks and benefits and balance that with the possible benefits with their provider.”
FDA Approves First CAR T-Cell Therapy for rrCLL, rrSLL
Specifically, the CD19-directed chimeric antigen receptor (CAR) T-cell product (Breyanzi) from Juno Therapeutics, a Bristol-Myers Squib company, is approved for adults with CLL or SLL who have received at least two prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. It is the first CAR T-cell therapy approved in this setting.
“CLL and SLL are currently considered incurable diseases with few treatment options in the relapsed setting that can confer complete responses,” lead trial investigator Tanya Siddiqi, MD, of City of Hope in Duarte, California, said in the press release.
The FDA’s approval of liso-cel in this setting “is a remarkable breakthrough, shifting the treatment paradigm from continuous therapy with sequential regimens to overcome drug resistance, to a one-time personalized T-cell based approach that has the potential to offer patients complete and lasting remission,” Dr. Siddiqi added.
Liso-cel was first approved in 2021 for relapsed or refractory large B-cell lymphoma, as reported at the time by this news organization.
Approval for the new CLL and SLL indication followed Priority Review and was based on findings from the pivotal TRANSCEND CLL 004 study, in which 20% of patients with CLL or SLL achieved a complete response after a one-time liso-cel infusion, according to a Bristol-Myers Squibb press release.
The 89 participants in the open-label, phase 1/2 study received a single dose of liso-cel containing 90-110 x 106CAR-positive viable T cells. The overall response rate was 45%, and median duration of response was 35.3 months. Among the 20% of patients achieving a complete response, the median duration of that response was not reached at the time of data cutoff.
Liso-cel had a tolerable safety profile. Cytokine release syndrome and neurologic events were mostly low grade. Cytokine release syndrome of any grade occurred in 83% of patients; 9% were grade 3, and none were grade 4 or 5.
Neurologic events of any grade occurred in 46% of patients, with grade 3 events occurring in 20% of patients; one grade 4 event and no grade 5 events occurred.
A version of this article appeared on Medscape.com.
Specifically, the CD19-directed chimeric antigen receptor (CAR) T-cell product (Breyanzi) from Juno Therapeutics, a Bristol-Myers Squib company, is approved for adults with CLL or SLL who have received at least two prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. It is the first CAR T-cell therapy approved in this setting.
“CLL and SLL are currently considered incurable diseases with few treatment options in the relapsed setting that can confer complete responses,” lead trial investigator Tanya Siddiqi, MD, of City of Hope in Duarte, California, said in the press release.
The FDA’s approval of liso-cel in this setting “is a remarkable breakthrough, shifting the treatment paradigm from continuous therapy with sequential regimens to overcome drug resistance, to a one-time personalized T-cell based approach that has the potential to offer patients complete and lasting remission,” Dr. Siddiqi added.
Liso-cel was first approved in 2021 for relapsed or refractory large B-cell lymphoma, as reported at the time by this news organization.
Approval for the new CLL and SLL indication followed Priority Review and was based on findings from the pivotal TRANSCEND CLL 004 study, in which 20% of patients with CLL or SLL achieved a complete response after a one-time liso-cel infusion, according to a Bristol-Myers Squibb press release.
The 89 participants in the open-label, phase 1/2 study received a single dose of liso-cel containing 90-110 x 106CAR-positive viable T cells. The overall response rate was 45%, and median duration of response was 35.3 months. Among the 20% of patients achieving a complete response, the median duration of that response was not reached at the time of data cutoff.
Liso-cel had a tolerable safety profile. Cytokine release syndrome and neurologic events were mostly low grade. Cytokine release syndrome of any grade occurred in 83% of patients; 9% were grade 3, and none were grade 4 or 5.
Neurologic events of any grade occurred in 46% of patients, with grade 3 events occurring in 20% of patients; one grade 4 event and no grade 5 events occurred.
A version of this article appeared on Medscape.com.
Specifically, the CD19-directed chimeric antigen receptor (CAR) T-cell product (Breyanzi) from Juno Therapeutics, a Bristol-Myers Squib company, is approved for adults with CLL or SLL who have received at least two prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. It is the first CAR T-cell therapy approved in this setting.
“CLL and SLL are currently considered incurable diseases with few treatment options in the relapsed setting that can confer complete responses,” lead trial investigator Tanya Siddiqi, MD, of City of Hope in Duarte, California, said in the press release.
The FDA’s approval of liso-cel in this setting “is a remarkable breakthrough, shifting the treatment paradigm from continuous therapy with sequential regimens to overcome drug resistance, to a one-time personalized T-cell based approach that has the potential to offer patients complete and lasting remission,” Dr. Siddiqi added.
Liso-cel was first approved in 2021 for relapsed or refractory large B-cell lymphoma, as reported at the time by this news organization.
Approval for the new CLL and SLL indication followed Priority Review and was based on findings from the pivotal TRANSCEND CLL 004 study, in which 20% of patients with CLL or SLL achieved a complete response after a one-time liso-cel infusion, according to a Bristol-Myers Squibb press release.
The 89 participants in the open-label, phase 1/2 study received a single dose of liso-cel containing 90-110 x 106CAR-positive viable T cells. The overall response rate was 45%, and median duration of response was 35.3 months. Among the 20% of patients achieving a complete response, the median duration of that response was not reached at the time of data cutoff.
Liso-cel had a tolerable safety profile. Cytokine release syndrome and neurologic events were mostly low grade. Cytokine release syndrome of any grade occurred in 83% of patients; 9% were grade 3, and none were grade 4 or 5.
Neurologic events of any grade occurred in 46% of patients, with grade 3 events occurring in 20% of patients; one grade 4 event and no grade 5 events occurred.
A version of this article appeared on Medscape.com.