Lung Cancer

Cancer drug approvals between 2000 and 2016 were associated with a significant reduction in deaths from the most common cancers in the United States, according to a new study.

Reductions in mortality were most notable for tumor types with relatively more approvals, including lung and breast cancer, melanoma, lymphoma, and leukemia.

A report from the American Cancer Society (ACS) estimated that, from 1991 to 2017, there were 2,902,200 total cancer deaths avoided from improvements in mortality from all potential sources.

The new findings, reported in the Journal of Medical Economics, suggest that drugs approved between 2000 and 2016 to treat the 15 most common cancer types helped to reduce mortality by 24% per 100,000 people.

“This study provides evidence that a significant share of that reduction from 2000 to 2016 was associated with the introduction of new therapies. The ACS report and other studies demonstrate that the improvements in lung cancer specifically are likely due to new treatments,” said lead study author Joanna P. MacEwan, MD, of PRECISIONheor in Los Angeles.

The findings contribute to a better understanding of whether increased spending on cancer drugs are worth the investment, according to the study authors.

“We provide evidence that the gains in survival measured in clinical trials are translating into health benefits for patients in the real world and confirm previous research that has also shown that new pharmaceutical treatments are associated with improved real-world survival outcomes for patients,” Dr. MacEwan said.
 

Full effect not yet observed

The researchers used a series of national data sets from sources including the Centers for Disease Control and Prevention; the U.S. Mortality Files by the National Center of Health Statistics; Survival, Epidemiology and End Results program; and United States Cancer Statistics.

The team calculated age-adjusted cancer mortality rates per year for the 15 most common tumor types and also looked at incident cases of cancer by tumor type, represented as per 100,000 people, for all ages, races, and genders.

The researchers then translated the change in cancer mortality in the U.S. from 2000 to 2016 associated with treatment stocks in each year into deaths averted per year.

Across the 16 years, mortality was down by 1,291,769 deaths. The following cancers had significant reductions in mortality: breast (n = 127,874), colorectal (n = 46,705), lung (n = 375,256), prostate (n = 476,210), gastric (n = 758), and renal (n = 739) cancers, as well as non-Hodgkin lymphoma (n = 48,836) and leukemia (n = 4,011).

Estimated mortality increased by 825 deaths in patients with thyroid cancer and 7,768 deaths for those with bladder cancer. These rises are likely due to the result of sparse drug approvals during this period – five for thyroid cancer and three for bladder cancer – Dr. MacEwan said. There were no approvals in liver or uterine cancer and few approvals in pancreatic and oral cancer.

The full effect of new drug introductions may not have been observed yet, Dr. MacEwan noted.

“There are fewer patients using the treatments for drugs approved in the later years of our study and less follow-up time to measure outcomes,” she said. “Over time, utilization of the newer therapies will likely increase and the full effect on mortality will be observed.”
 

Other factors at play

Multiple factors have led to the declines in mortality, said William G. Cance, MD, chief medical and scientific officer for the ACS, who was not involved in this study. “We are slowly sorting out the explanations in greater granularity.”  

Dr. MacEwan said improved cancer screening may partially explain the decline in mortality in some tumor types.

“If screening in a particular tumor type improved during the study period and tumors were diagnosed earlier, then mortality for that tumor type may decline,” she said. “However, we did not find strong evidence to suggest that there were significant changes in screening during our study period. Breast cancer screening rates, for example, were stable over our study period.”  

Cancer screening is not as strong an influence as it should be, Dr. Cance said.

“The lung cancer screening rate is low. In breast and colorectal cancers, we need to double down on earlier screening,” he said, noting that less than one-quarter of adults between ages 45 and 50 years are currently screened for colorectal cancer. The ACS recommends that people at average risk of colorectal cancer start regular screening at age 45.

More research is necessary to evaluate the relationship between drug approvals and cancer mortality, Dr. MacEwan said.

“Research directly linking utilization of new therapies to improved survival or reduced mortality in the real-world setting would more definitively demonstrate the impact of new treatments,” she said. “New therapies have improved outcomes for many patients and should continue to be considered as key elements of cancer treatment.”

“We need to continue to reduce tobacco smoking and improve on modifiable behaviors at the same time as we work on getting new drugs to cancer patients,” Dr. Cance said. “We are coming into an era of multiple new therapeutics, including targeted therapies, immunotherapies, and cellular therapies. Clinicians need to look closely at the trial data of new drugs and pay close attention to those that have the most mortality impact.”

“We also need equitable distribution of newer drugs,” Dr. Cance added. “They should be distributed to everybody who deserves them. Mortality is often impacted by social determinants of health.”

Funding for this research was provided by Pfizer. Study authors disclosed relationships, including employment, with Pfizer. Dr. Cance had no disclosures.

SOURCE: MacEwan JP et al. J Med Econ. 2020 Nov 9;1-12.

Cancer drug approvals between 2000 and 2016 were associated with a significant reduction in deaths from the most common cancers in the United States, according to a new study.

Reductions in mortality were most notable for tumor types with relatively more approvals, including lung and breast cancer, melanoma, lymphoma, and leukemia.

A report from the American Cancer Society (ACS) estimated that, from 1991 to 2017, there were 2,902,200 total cancer deaths avoided from improvements in mortality from all potential sources.

The new findings, reported in the Journal of Medical Economics, suggest that drugs approved between 2000 and 2016 to treat the 15 most common cancer types helped to reduce mortality by 24% per 100,000 people.

“This study provides evidence that a significant share of that reduction from 2000 to 2016 was associated with the introduction of new therapies. The ACS report and other studies demonstrate that the improvements in lung cancer specifically are likely due to new treatments,” said lead study author Joanna P. MacEwan, MD, of PRECISIONheor in Los Angeles.

The findings contribute to a better understanding of whether increased spending on cancer drugs are worth the investment, according to the study authors.

“We provide evidence that the gains in survival measured in clinical trials are translating into health benefits for patients in the real world and confirm previous research that has also shown that new pharmaceutical treatments are associated with improved real-world survival outcomes for patients,” Dr. MacEwan said.
 

Full effect not yet observed

The researchers used a series of national data sets from sources including the Centers for Disease Control and Prevention; the U.S. Mortality Files by the National Center of Health Statistics; Survival, Epidemiology and End Results program; and United States Cancer Statistics.

The team calculated age-adjusted cancer mortality rates per year for the 15 most common tumor types and also looked at incident cases of cancer by tumor type, represented as per 100,000 people, for all ages, races, and genders.

The researchers then translated the change in cancer mortality in the U.S. from 2000 to 2016 associated with treatment stocks in each year into deaths averted per year.

Across the 16 years, mortality was down by 1,291,769 deaths. The following cancers had significant reductions in mortality: breast (n = 127,874), colorectal (n = 46,705), lung (n = 375,256), prostate (n = 476,210), gastric (n = 758), and renal (n = 739) cancers, as well as non-Hodgkin lymphoma (n = 48,836) and leukemia (n = 4,011).

Estimated mortality increased by 825 deaths in patients with thyroid cancer and 7,768 deaths for those with bladder cancer. These rises are likely due to the result of sparse drug approvals during this period – five for thyroid cancer and three for bladder cancer – Dr. MacEwan said. There were no approvals in liver or uterine cancer and few approvals in pancreatic and oral cancer.

The full effect of new drug introductions may not have been observed yet, Dr. MacEwan noted.

“There are fewer patients using the treatments for drugs approved in the later years of our study and less follow-up time to measure outcomes,” she said. “Over time, utilization of the newer therapies will likely increase and the full effect on mortality will be observed.”
 

Other factors at play

Multiple factors have led to the declines in mortality, said William G. Cance, MD, chief medical and scientific officer for the ACS, who was not involved in this study. “We are slowly sorting out the explanations in greater granularity.”  

Dr. MacEwan said improved cancer screening may partially explain the decline in mortality in some tumor types.

“If screening in a particular tumor type improved during the study period and tumors were diagnosed earlier, then mortality for that tumor type may decline,” she said. “However, we did not find strong evidence to suggest that there were significant changes in screening during our study period. Breast cancer screening rates, for example, were stable over our study period.”  

Cancer screening is not as strong an influence as it should be, Dr. Cance said.

“The lung cancer screening rate is low. In breast and colorectal cancers, we need to double down on earlier screening,” he said, noting that less than one-quarter of adults between ages 45 and 50 years are currently screened for colorectal cancer. The ACS recommends that people at average risk of colorectal cancer start regular screening at age 45.

More research is necessary to evaluate the relationship between drug approvals and cancer mortality, Dr. MacEwan said.

“Research directly linking utilization of new therapies to improved survival or reduced mortality in the real-world setting would more definitively demonstrate the impact of new treatments,” she said. “New therapies have improved outcomes for many patients and should continue to be considered as key elements of cancer treatment.”

“We need to continue to reduce tobacco smoking and improve on modifiable behaviors at the same time as we work on getting new drugs to cancer patients,” Dr. Cance said. “We are coming into an era of multiple new therapeutics, including targeted therapies, immunotherapies, and cellular therapies. Clinicians need to look closely at the trial data of new drugs and pay close attention to those that have the most mortality impact.”

“We also need equitable distribution of newer drugs,” Dr. Cance added. “They should be distributed to everybody who deserves them. Mortality is often impacted by social determinants of health.”

Funding for this research was provided by Pfizer. Study authors disclosed relationships, including employment, with Pfizer. Dr. Cance had no disclosures.

SOURCE: MacEwan JP et al. J Med Econ. 2020 Nov 9;1-12.

Cancer drug approvals between 2000 and 2016 were associated with a significant reduction in deaths from the most common cancers in the United States, according to a new study.

Reductions in mortality were most notable for tumor types with relatively more approvals, including lung and breast cancer, melanoma, lymphoma, and leukemia.

A report from the American Cancer Society (ACS) estimated that, from 1991 to 2017, there were 2,902,200 total cancer deaths avoided from improvements in mortality from all potential sources.

The new findings, reported in the Journal of Medical Economics, suggest that drugs approved between 2000 and 2016 to treat the 15 most common cancer types helped to reduce mortality by 24% per 100,000 people.

“This study provides evidence that a significant share of that reduction from 2000 to 2016 was associated with the introduction of new therapies. The ACS report and other studies demonstrate that the improvements in lung cancer specifically are likely due to new treatments,” said lead study author Joanna P. MacEwan, MD, of PRECISIONheor in Los Angeles.

The findings contribute to a better understanding of whether increased spending on cancer drugs are worth the investment, according to the study authors.

“We provide evidence that the gains in survival measured in clinical trials are translating into health benefits for patients in the real world and confirm previous research that has also shown that new pharmaceutical treatments are associated with improved real-world survival outcomes for patients,” Dr. MacEwan said.
 

Full effect not yet observed

The researchers used a series of national data sets from sources including the Centers for Disease Control and Prevention; the U.S. Mortality Files by the National Center of Health Statistics; Survival, Epidemiology and End Results program; and United States Cancer Statistics.

The team calculated age-adjusted cancer mortality rates per year for the 15 most common tumor types and also looked at incident cases of cancer by tumor type, represented as per 100,000 people, for all ages, races, and genders.

The researchers then translated the change in cancer mortality in the U.S. from 2000 to 2016 associated with treatment stocks in each year into deaths averted per year.

Across the 16 years, mortality was down by 1,291,769 deaths. The following cancers had significant reductions in mortality: breast (n = 127,874), colorectal (n = 46,705), lung (n = 375,256), prostate (n = 476,210), gastric (n = 758), and renal (n = 739) cancers, as well as non-Hodgkin lymphoma (n = 48,836) and leukemia (n = 4,011).

Estimated mortality increased by 825 deaths in patients with thyroid cancer and 7,768 deaths for those with bladder cancer. These rises are likely due to the result of sparse drug approvals during this period – five for thyroid cancer and three for bladder cancer – Dr. MacEwan said. There were no approvals in liver or uterine cancer and few approvals in pancreatic and oral cancer.

The full effect of new drug introductions may not have been observed yet, Dr. MacEwan noted.

“There are fewer patients using the treatments for drugs approved in the later years of our study and less follow-up time to measure outcomes,” she said. “Over time, utilization of the newer therapies will likely increase and the full effect on mortality will be observed.”
 

Other factors at play

Multiple factors have led to the declines in mortality, said William G. Cance, MD, chief medical and scientific officer for the ACS, who was not involved in this study. “We are slowly sorting out the explanations in greater granularity.”  

Dr. MacEwan said improved cancer screening may partially explain the decline in mortality in some tumor types.

“If screening in a particular tumor type improved during the study period and tumors were diagnosed earlier, then mortality for that tumor type may decline,” she said. “However, we did not find strong evidence to suggest that there were significant changes in screening during our study period. Breast cancer screening rates, for example, were stable over our study period.”  

Cancer screening is not as strong an influence as it should be, Dr. Cance said.

“The lung cancer screening rate is low. In breast and colorectal cancers, we need to double down on earlier screening,” he said, noting that less than one-quarter of adults between ages 45 and 50 years are currently screened for colorectal cancer. The ACS recommends that people at average risk of colorectal cancer start regular screening at age 45.

More research is necessary to evaluate the relationship between drug approvals and cancer mortality, Dr. MacEwan said.

“Research directly linking utilization of new therapies to improved survival or reduced mortality in the real-world setting would more definitively demonstrate the impact of new treatments,” she said. “New therapies have improved outcomes for many patients and should continue to be considered as key elements of cancer treatment.”

“We need to continue to reduce tobacco smoking and improve on modifiable behaviors at the same time as we work on getting new drugs to cancer patients,” Dr. Cance said. “We are coming into an era of multiple new therapeutics, including targeted therapies, immunotherapies, and cellular therapies. Clinicians need to look closely at the trial data of new drugs and pay close attention to those that have the most mortality impact.”

“We also need equitable distribution of newer drugs,” Dr. Cance added. “They should be distributed to everybody who deserves them. Mortality is often impacted by social determinants of health.”

Funding for this research was provided by Pfizer. Study authors disclosed relationships, including employment, with Pfizer. Dr. Cance had no disclosures.

SOURCE: MacEwan JP et al. J Med Econ. 2020 Nov 9;1-12.

About one in eight patients with cancer have inherited genetic mutations that may have contributed to the development of their cancers, but nearly half of these mutations would have been missed using current clinical guidelines.

These findings come from the largest study of its kind so far, conducted in nearly 3,000 patients with a wide range of cancer stages and types, including breast, colorectal, lung, ovarian, pancreatic, bladder, prostate, and endometrial cancers.

“This study tells us that the clinical practice guidelines are not very sensitive for identifying who does or doesn’t have a genetic mutation that is predisposing them to cancer,” commented first author Niloy Jewell Samadder, MD, director of the high-risk cancer clinic at the Mayo Clinic in Phoenix.

Finding a genetic mutation can alter clinical management of the cancer.

“This really does open up treatment and management options that might not have been accessible to these patients,” Dr. Samadder emphasized.

The results were published online on Oct. 30 in JAMA Oncology and were presented simultaneously at the American Society of Human Genetics. Dr. Samadder discussed details of the study in a video posted on YouTube.

A clinician not involved in the study said the new results should lead to changes in practice.

“For cancer patients, I think the debate is over. We should test everybody,” Peter Beitsch, MD, surgical oncologist at the Dallas Surgical Group, said in an interview.

The Mayo Clinic is changing its daily practice at all four of its cancer centers. The changes will begin in the first quarter of 2021 at its Arizona campus.

“Every cancer patient who comes to Mayo Clinic will be offered genomic evaluation that includes genetic testing to identify if they have an underlying genetic mutation that predisposes to their cancer and [helps physicians decide] how to incorporate that knowledge into designing the best surgical and treatment options for that patient and their family,” Dr. Samadder said.
 

Study details

The study included 2,984 patients with cancer who were receiving care for a variety of solid tumor cancers at Mayo Clinic cancer centers in Arizona, Florida, Minnesota, and a community cancer center in Wisconsin.

Patients were tested for about 84 genes using next-generation sequencing provided by Invitae.

Among participants, 13.3% (n = 397) tested positive for pathogenic mutations. Of these, about 70% (282 of 397 patients) carried moderate- and high-penetrance genes that increased their risk for cancer. For almost 28.2% (n = 42) of patients with high-penetrance mutations, changes were made in treatment as a result of genetic testing. These included changes in surgical management, immunotherapy, chemotherapy, or enrollment in a clinical trial for which they may otherwise have not been eligible.

Researchers also compared their universal testing approach with targeted testing recommended in guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, and the American College of Medical Genetics.

They identified pathogenic mutations in 192 patients whose mutations would have been missed using guideline-recommended criteria, such as tumor pathology or family history. This represents 6.4% of all participants in the study (192 of 2,984 patients) and 48.4% of patients who tested positive for pathogenic mutations (397 of 2,984 patients).

“Genetic testing is underutilized in cancer care, both for patients and for their families, often due to outdated guidelines that restrict testing to a narrow group of high-risk patients. All cancer patients should have access to complete genetic information that can guide their care and inform their families’ health,” coauthor Robert Nussbaum, MD, chief medical officer of Invitae, said in a statement.

Some clinicians have been pushing for genetic testing of all patients with cancer, including Dr. Beitsch, who was lead author of a similar study in breast cancer patients published last year in the Journal of Oncology. That article made waves when the authors concluded that all breast cancer patients should have expanded panel genetic testing.

This new Mayo Clinic study extends the findings in breast cancer to “all cancer patients, not just breast cancer patients,” Dr. Beitsch said in an interview.
 

Long-running debate

The new findings and opinions add to a long-running debate in oncology over the role of genetic testing and screening for pathogenic mutations.

Part of the debate about genetic testing has hinged on the question of costs, said Dr. Beitsch. When genetic testing first became available, it was conducted by hand, and costs were often prohibitive. Since then, genetic testing has been automated using next-generation sequencing, and the cost has decreased considerably.

“The Invitae cash price for an 80-plus gene panel is $250. That’s [the cost of] a mani-pedi in Dallas. I don’t discount that it’s a lot of money for a lot of people. Yes, it’s expensive, but it’s a lot less expensive than it used to be,” Dr. Beitsch said.

Another issue is that doctors are not entirely sure how to manage variants of uncertain significance (VUSs) when they are found. In the Mayo Clinic study, about half (47.4%; n = 1415) of participants had VUSs. The authors noted that these results are consistent with past studies.

Dr. Beitsch said that VUSs are a matter of education. To date, only about 2% of VUSs have been associated with cancer. The remainder, about 98%, do not affect treatment for patients who have already been diagnosed with cancer.

“We all have VUSs. They’re just minor variations in a gene. The vast majority of them have no consequence and don’t alter the function of the gene,” he said. “I tell everybody to ignore the VUSs [when found in patients with cancer]. Do not act on them at all. We just need to educate everybody to make sure they don’t get stressed about it.”

These comments echo guidance from the American Society of Breast Surgeons, which says that VUSs are DNA sequences that are not clinically actionable. This type of result needs to be considered as inconclusive, and patient management should not be influenced by such results.

However, VUSs are more significant if they are found in individuals who do not have cancer but who have a strong family history of cancer. In such cases, clinicians should be more aware, Dr. Beitsch emphasized.

“Patients who have a VUS and don’t have a cancer should absolutely pay more attention to their health. They got tested for a reason, and that reason is usually strong family history,” Dr. Beitsch said.

He added that a major advantage of genetic testing is that it can enable cascade genetic testing of family members. Identifying pathogenic mutations in family members can lead them to undergo screening to detect early cancers, and preventive measures can be taken that may be lifesaving.

In the Mayo Clinic study, researchers offered genetic testing to family members of patients who tested positive for a pathogenic mutation. Testing was available free of charge for up to 90 days after a participant tested positive. In addition, family members were shown an educational video.

Nevertheless, only 17.6% (n = 70) of patients with pathogenic mutations had family members who underwent testing. Among these, 45% (79 of 176) of family members who were tested were found to carry pathogenic mutations.

“This really told us that financial barriers are not the only barrier to families understanding and undergoing preventive testing,” Dr. Samadder said. “There are probably a number of other barriers – socioeconomic or emotional – that we have to deal with.”

Genetic testing was provided by Invitae. The study was supported by several grants, including a Mayo Transform the Practice Grant, and by Mayo Clinic’s Center for Individualized Medicine. Two coauthors are employees of Invitae. Dr. Beitsch reported participating in a study 2 years ago that was funded by Invitae. He currently receives no financial support from Invitae. Several authors report receiving fees from one or more of the following companies: Pfizer, Maze Therapeutics, Genome Medical, Astellas, and Merck.

This article first appeared on Medscape.com.

About one in eight patients with cancer have inherited genetic mutations that may have contributed to the development of their cancers, but nearly half of these mutations would have been missed using current clinical guidelines.

These findings come from the largest study of its kind so far, conducted in nearly 3,000 patients with a wide range of cancer stages and types, including breast, colorectal, lung, ovarian, pancreatic, bladder, prostate, and endometrial cancers.

“This study tells us that the clinical practice guidelines are not very sensitive for identifying who does or doesn’t have a genetic mutation that is predisposing them to cancer,” commented first author Niloy Jewell Samadder, MD, director of the high-risk cancer clinic at the Mayo Clinic in Phoenix.

Finding a genetic mutation can alter clinical management of the cancer.

“This really does open up treatment and management options that might not have been accessible to these patients,” Dr. Samadder emphasized.

The results were published online on Oct. 30 in JAMA Oncology and were presented simultaneously at the American Society of Human Genetics. Dr. Samadder discussed details of the study in a video posted on YouTube.

A clinician not involved in the study said the new results should lead to changes in practice.

“For cancer patients, I think the debate is over. We should test everybody,” Peter Beitsch, MD, surgical oncologist at the Dallas Surgical Group, said in an interview.

The Mayo Clinic is changing its daily practice at all four of its cancer centers. The changes will begin in the first quarter of 2021 at its Arizona campus.

“Every cancer patient who comes to Mayo Clinic will be offered genomic evaluation that includes genetic testing to identify if they have an underlying genetic mutation that predisposes to their cancer and [helps physicians decide] how to incorporate that knowledge into designing the best surgical and treatment options for that patient and their family,” Dr. Samadder said.
 

Study details

The study included 2,984 patients with cancer who were receiving care for a variety of solid tumor cancers at Mayo Clinic cancer centers in Arizona, Florida, Minnesota, and a community cancer center in Wisconsin.

Patients were tested for about 84 genes using next-generation sequencing provided by Invitae.

Among participants, 13.3% (n = 397) tested positive for pathogenic mutations. Of these, about 70% (282 of 397 patients) carried moderate- and high-penetrance genes that increased their risk for cancer. For almost 28.2% (n = 42) of patients with high-penetrance mutations, changes were made in treatment as a result of genetic testing. These included changes in surgical management, immunotherapy, chemotherapy, or enrollment in a clinical trial for which they may otherwise have not been eligible.

Researchers also compared their universal testing approach with targeted testing recommended in guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, and the American College of Medical Genetics.

They identified pathogenic mutations in 192 patients whose mutations would have been missed using guideline-recommended criteria, such as tumor pathology or family history. This represents 6.4% of all participants in the study (192 of 2,984 patients) and 48.4% of patients who tested positive for pathogenic mutations (397 of 2,984 patients).

“Genetic testing is underutilized in cancer care, both for patients and for their families, often due to outdated guidelines that restrict testing to a narrow group of high-risk patients. All cancer patients should have access to complete genetic information that can guide their care and inform their families’ health,” coauthor Robert Nussbaum, MD, chief medical officer of Invitae, said in a statement.

Some clinicians have been pushing for genetic testing of all patients with cancer, including Dr. Beitsch, who was lead author of a similar study in breast cancer patients published last year in the Journal of Oncology. That article made waves when the authors concluded that all breast cancer patients should have expanded panel genetic testing.

This new Mayo Clinic study extends the findings in breast cancer to “all cancer patients, not just breast cancer patients,” Dr. Beitsch said in an interview.
 

Long-running debate

The new findings and opinions add to a long-running debate in oncology over the role of genetic testing and screening for pathogenic mutations.

Part of the debate about genetic testing has hinged on the question of costs, said Dr. Beitsch. When genetic testing first became available, it was conducted by hand, and costs were often prohibitive. Since then, genetic testing has been automated using next-generation sequencing, and the cost has decreased considerably.

“The Invitae cash price for an 80-plus gene panel is $250. That’s [the cost of] a mani-pedi in Dallas. I don’t discount that it’s a lot of money for a lot of people. Yes, it’s expensive, but it’s a lot less expensive than it used to be,” Dr. Beitsch said.

Another issue is that doctors are not entirely sure how to manage variants of uncertain significance (VUSs) when they are found. In the Mayo Clinic study, about half (47.4%; n = 1415) of participants had VUSs. The authors noted that these results are consistent with past studies.

Dr. Beitsch said that VUSs are a matter of education. To date, only about 2% of VUSs have been associated with cancer. The remainder, about 98%, do not affect treatment for patients who have already been diagnosed with cancer.

“We all have VUSs. They’re just minor variations in a gene. The vast majority of them have no consequence and don’t alter the function of the gene,” he said. “I tell everybody to ignore the VUSs [when found in patients with cancer]. Do not act on them at all. We just need to educate everybody to make sure they don’t get stressed about it.”

These comments echo guidance from the American Society of Breast Surgeons, which says that VUSs are DNA sequences that are not clinically actionable. This type of result needs to be considered as inconclusive, and patient management should not be influenced by such results.

However, VUSs are more significant if they are found in individuals who do not have cancer but who have a strong family history of cancer. In such cases, clinicians should be more aware, Dr. Beitsch emphasized.

“Patients who have a VUS and don’t have a cancer should absolutely pay more attention to their health. They got tested for a reason, and that reason is usually strong family history,” Dr. Beitsch said.

He added that a major advantage of genetic testing is that it can enable cascade genetic testing of family members. Identifying pathogenic mutations in family members can lead them to undergo screening to detect early cancers, and preventive measures can be taken that may be lifesaving.

In the Mayo Clinic study, researchers offered genetic testing to family members of patients who tested positive for a pathogenic mutation. Testing was available free of charge for up to 90 days after a participant tested positive. In addition, family members were shown an educational video.

Nevertheless, only 17.6% (n = 70) of patients with pathogenic mutations had family members who underwent testing. Among these, 45% (79 of 176) of family members who were tested were found to carry pathogenic mutations.

“This really told us that financial barriers are not the only barrier to families understanding and undergoing preventive testing,” Dr. Samadder said. “There are probably a number of other barriers – socioeconomic or emotional – that we have to deal with.”

Genetic testing was provided by Invitae. The study was supported by several grants, including a Mayo Transform the Practice Grant, and by Mayo Clinic’s Center for Individualized Medicine. Two coauthors are employees of Invitae. Dr. Beitsch reported participating in a study 2 years ago that was funded by Invitae. He currently receives no financial support from Invitae. Several authors report receiving fees from one or more of the following companies: Pfizer, Maze Therapeutics, Genome Medical, Astellas, and Merck.

This article first appeared on Medscape.com.

About one in eight patients with cancer have inherited genetic mutations that may have contributed to the development of their cancers, but nearly half of these mutations would have been missed using current clinical guidelines.

These findings come from the largest study of its kind so far, conducted in nearly 3,000 patients with a wide range of cancer stages and types, including breast, colorectal, lung, ovarian, pancreatic, bladder, prostate, and endometrial cancers.

“This study tells us that the clinical practice guidelines are not very sensitive for identifying who does or doesn’t have a genetic mutation that is predisposing them to cancer,” commented first author Niloy Jewell Samadder, MD, director of the high-risk cancer clinic at the Mayo Clinic in Phoenix.

Finding a genetic mutation can alter clinical management of the cancer.

“This really does open up treatment and management options that might not have been accessible to these patients,” Dr. Samadder emphasized.

The results were published online on Oct. 30 in JAMA Oncology and were presented simultaneously at the American Society of Human Genetics. Dr. Samadder discussed details of the study in a video posted on YouTube.

A clinician not involved in the study said the new results should lead to changes in practice.

“For cancer patients, I think the debate is over. We should test everybody,” Peter Beitsch, MD, surgical oncologist at the Dallas Surgical Group, said in an interview.

The Mayo Clinic is changing its daily practice at all four of its cancer centers. The changes will begin in the first quarter of 2021 at its Arizona campus.

“Every cancer patient who comes to Mayo Clinic will be offered genomic evaluation that includes genetic testing to identify if they have an underlying genetic mutation that predisposes to their cancer and [helps physicians decide] how to incorporate that knowledge into designing the best surgical and treatment options for that patient and their family,” Dr. Samadder said.
 

Study details

The study included 2,984 patients with cancer who were receiving care for a variety of solid tumor cancers at Mayo Clinic cancer centers in Arizona, Florida, Minnesota, and a community cancer center in Wisconsin.

Patients were tested for about 84 genes using next-generation sequencing provided by Invitae.

Among participants, 13.3% (n = 397) tested positive for pathogenic mutations. Of these, about 70% (282 of 397 patients) carried moderate- and high-penetrance genes that increased their risk for cancer. For almost 28.2% (n = 42) of patients with high-penetrance mutations, changes were made in treatment as a result of genetic testing. These included changes in surgical management, immunotherapy, chemotherapy, or enrollment in a clinical trial for which they may otherwise have not been eligible.

Researchers also compared their universal testing approach with targeted testing recommended in guidelines from the National Comprehensive Cancer Network, the National Society of Genetic Counselors, and the American College of Medical Genetics.

They identified pathogenic mutations in 192 patients whose mutations would have been missed using guideline-recommended criteria, such as tumor pathology or family history. This represents 6.4% of all participants in the study (192 of 2,984 patients) and 48.4% of patients who tested positive for pathogenic mutations (397 of 2,984 patients).

“Genetic testing is underutilized in cancer care, both for patients and for their families, often due to outdated guidelines that restrict testing to a narrow group of high-risk patients. All cancer patients should have access to complete genetic information that can guide their care and inform their families’ health,” coauthor Robert Nussbaum, MD, chief medical officer of Invitae, said in a statement.

Some clinicians have been pushing for genetic testing of all patients with cancer, including Dr. Beitsch, who was lead author of a similar study in breast cancer patients published last year in the Journal of Oncology. That article made waves when the authors concluded that all breast cancer patients should have expanded panel genetic testing.

This new Mayo Clinic study extends the findings in breast cancer to “all cancer patients, not just breast cancer patients,” Dr. Beitsch said in an interview.
 

Long-running debate

The new findings and opinions add to a long-running debate in oncology over the role of genetic testing and screening for pathogenic mutations.

Part of the debate about genetic testing has hinged on the question of costs, said Dr. Beitsch. When genetic testing first became available, it was conducted by hand, and costs were often prohibitive. Since then, genetic testing has been automated using next-generation sequencing, and the cost has decreased considerably.

“The Invitae cash price for an 80-plus gene panel is $250. That’s [the cost of] a mani-pedi in Dallas. I don’t discount that it’s a lot of money for a lot of people. Yes, it’s expensive, but it’s a lot less expensive than it used to be,” Dr. Beitsch said.

Another issue is that doctors are not entirely sure how to manage variants of uncertain significance (VUSs) when they are found. In the Mayo Clinic study, about half (47.4%; n = 1415) of participants had VUSs. The authors noted that these results are consistent with past studies.

Dr. Beitsch said that VUSs are a matter of education. To date, only about 2% of VUSs have been associated with cancer. The remainder, about 98%, do not affect treatment for patients who have already been diagnosed with cancer.

“We all have VUSs. They’re just minor variations in a gene. The vast majority of them have no consequence and don’t alter the function of the gene,” he said. “I tell everybody to ignore the VUSs [when found in patients with cancer]. Do not act on them at all. We just need to educate everybody to make sure they don’t get stressed about it.”

These comments echo guidance from the American Society of Breast Surgeons, which says that VUSs are DNA sequences that are not clinically actionable. This type of result needs to be considered as inconclusive, and patient management should not be influenced by such results.

However, VUSs are more significant if they are found in individuals who do not have cancer but who have a strong family history of cancer. In such cases, clinicians should be more aware, Dr. Beitsch emphasized.

“Patients who have a VUS and don’t have a cancer should absolutely pay more attention to their health. They got tested for a reason, and that reason is usually strong family history,” Dr. Beitsch said.

He added that a major advantage of genetic testing is that it can enable cascade genetic testing of family members. Identifying pathogenic mutations in family members can lead them to undergo screening to detect early cancers, and preventive measures can be taken that may be lifesaving.

In the Mayo Clinic study, researchers offered genetic testing to family members of patients who tested positive for a pathogenic mutation. Testing was available free of charge for up to 90 days after a participant tested positive. In addition, family members were shown an educational video.

Nevertheless, only 17.6% (n = 70) of patients with pathogenic mutations had family members who underwent testing. Among these, 45% (79 of 176) of family members who were tested were found to carry pathogenic mutations.

“This really told us that financial barriers are not the only barrier to families understanding and undergoing preventive testing,” Dr. Samadder said. “There are probably a number of other barriers – socioeconomic or emotional – that we have to deal with.”

Genetic testing was provided by Invitae. The study was supported by several grants, including a Mayo Transform the Practice Grant, and by Mayo Clinic’s Center for Individualized Medicine. Two coauthors are employees of Invitae. Dr. Beitsch reported participating in a study 2 years ago that was funded by Invitae. He currently receives no financial support from Invitae. Several authors report receiving fees from one or more of the following companies: Pfizer, Maze Therapeutics, Genome Medical, Astellas, and Merck.

This article first appeared on Medscape.com.

People whose treatment for cancer is delayed by even 1 month have a 6%-13% higher risk of dying, suggests research published online in the BMJ.

In light of the treatment delays resulting from the pandemic, Canadian and U.K. researchers carried out a review and analysis of relevant studies published between January 2000 and April 2020.

Included studies examined data on surgical interventions, systemic therapy, or radiotherapy for seven forms of cancer – bladder, breast, colon, rectum, lung, cervix, and head and neck. Delays were measured from diagnosis to the first treatment or from the completion of one treatment to the start of the next.

The search identified 34 suitable studies for 17 indications, with data from more than 1.2 million patients. The analysis identified a significant association between delay and increased mortality for 13 of the 17 indications (P < .05).

For surgery, there was a 6%-8% increase in the risk of death for every 4-week treatment delay. Estimates for systemic treatment varied (hazard ratio range, 1.01-1.28). Four-week delays in radiotherapy were for radical radiotherapy for head and neck cancer (HR, 1.09; 95% confidence interval, 1.05-1.14), adjuvant radiotherapy after breast-conserving surgery (HR, 0.98; 95% CI, 0.88-1.09), and cervical cancer adjuvant radiotherapy (HR, 1.23; 95% CI, 1.00-1.50).

Delays of up to 8 and 12 weeks further increased mortality. An 8-week delay in breast cancer surgery was linked to a 17% increased mortality, and a 12-week delay would increase mortality by 26%.

A surgical delay of 12 weeks for patients with breast cancer continuing for 1 year – which is likely to be the case as the pandemic continues – would lead to 1,400 excess deaths in the United Kingdom.

The authors said the results of this study could be used to guide policy making on the organization of cancer services, particularly as the pandemic continues and further delays are expected.

This article originally appeared on Univadis, part of the Medscape Professional Network.

People whose treatment for cancer is delayed by even 1 month have a 6%-13% higher risk of dying, suggests research published online in the BMJ.

In light of the treatment delays resulting from the pandemic, Canadian and U.K. researchers carried out a review and analysis of relevant studies published between January 2000 and April 2020.

Included studies examined data on surgical interventions, systemic therapy, or radiotherapy for seven forms of cancer – bladder, breast, colon, rectum, lung, cervix, and head and neck. Delays were measured from diagnosis to the first treatment or from the completion of one treatment to the start of the next.

The search identified 34 suitable studies for 17 indications, with data from more than 1.2 million patients. The analysis identified a significant association between delay and increased mortality for 13 of the 17 indications (P < .05).

For surgery, there was a 6%-8% increase in the risk of death for every 4-week treatment delay. Estimates for systemic treatment varied (hazard ratio range, 1.01-1.28). Four-week delays in radiotherapy were for radical radiotherapy for head and neck cancer (HR, 1.09; 95% confidence interval, 1.05-1.14), adjuvant radiotherapy after breast-conserving surgery (HR, 0.98; 95% CI, 0.88-1.09), and cervical cancer adjuvant radiotherapy (HR, 1.23; 95% CI, 1.00-1.50).

Delays of up to 8 and 12 weeks further increased mortality. An 8-week delay in breast cancer surgery was linked to a 17% increased mortality, and a 12-week delay would increase mortality by 26%.

A surgical delay of 12 weeks for patients with breast cancer continuing for 1 year – which is likely to be the case as the pandemic continues – would lead to 1,400 excess deaths in the United Kingdom.

The authors said the results of this study could be used to guide policy making on the organization of cancer services, particularly as the pandemic continues and further delays are expected.

This article originally appeared on Univadis, part of the Medscape Professional Network.

People whose treatment for cancer is delayed by even 1 month have a 6%-13% higher risk of dying, suggests research published online in the BMJ.

In light of the treatment delays resulting from the pandemic, Canadian and U.K. researchers carried out a review and analysis of relevant studies published between January 2000 and April 2020.

Included studies examined data on surgical interventions, systemic therapy, or radiotherapy for seven forms of cancer – bladder, breast, colon, rectum, lung, cervix, and head and neck. Delays were measured from diagnosis to the first treatment or from the completion of one treatment to the start of the next.

The search identified 34 suitable studies for 17 indications, with data from more than 1.2 million patients. The analysis identified a significant association between delay and increased mortality for 13 of the 17 indications (P < .05).

For surgery, there was a 6%-8% increase in the risk of death for every 4-week treatment delay. Estimates for systemic treatment varied (hazard ratio range, 1.01-1.28). Four-week delays in radiotherapy were for radical radiotherapy for head and neck cancer (HR, 1.09; 95% confidence interval, 1.05-1.14), adjuvant radiotherapy after breast-conserving surgery (HR, 0.98; 95% CI, 0.88-1.09), and cervical cancer adjuvant radiotherapy (HR, 1.23; 95% CI, 1.00-1.50).

Delays of up to 8 and 12 weeks further increased mortality. An 8-week delay in breast cancer surgery was linked to a 17% increased mortality, and a 12-week delay would increase mortality by 26%.

A surgical delay of 12 weeks for patients with breast cancer continuing for 1 year – which is likely to be the case as the pandemic continues – would lead to 1,400 excess deaths in the United Kingdom.

The authors said the results of this study could be used to guide policy making on the organization of cancer services, particularly as the pandemic continues and further delays are expected.

This article originally appeared on Univadis, part of the Medscape Professional Network.

The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).¹ After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,^2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.⁴ Adherence to guidelines have been shown to improve patient survival across several cancer types.^5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.^8,9

Stage III NSCLC is associated with poor survival rates.¹⁰ Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.⁴ Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.¹¹ Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.¹¹

A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.¹¹

Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.

Methods

The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.

The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.

This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.

Results

A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.

The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.

CRT Patients

The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.

Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.

Durvalumab Treatment

After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.

Discussion

NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.³

Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.⁴ Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.² Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.

Clinical Trials vs Real World

The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.¹² In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.¹³

Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.¹⁴

A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.¹ These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.

Limitations

Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.¹⁵ Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.^16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.¹⁹ Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.

Conlcusions

This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.

Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.¹² It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.

The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).¹ After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,^2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.⁴ Adherence to guidelines have been shown to improve patient survival across several cancer types.^5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.^8,9

Stage III NSCLC is associated with poor survival rates.¹⁰ Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.⁴ Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.¹¹ Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.¹¹

A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.¹¹

Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.

Methods

The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.

The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.

This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.

Results

A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.

The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.

CRT Patients

The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.

Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.

Durvalumab Treatment

After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.

Discussion

NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.³

Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.⁴ Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.² Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.

Clinical Trials vs Real World

The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.¹² In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.¹³

Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.¹⁴

A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.¹ These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.

Limitations

Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.¹⁵ Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.^16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.¹⁹ Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.

Conlcusions

This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.

Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.¹² It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.

The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).¹ After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,^2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.⁴ Adherence to guidelines have been shown to improve patient survival across several cancer types.^5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.^8,9

Stage III NSCLC is associated with poor survival rates.¹⁰ Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.⁴ Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.¹¹ Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.¹¹

A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.¹¹

Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.

Methods

The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.

The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.

This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.

Results

A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.

The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.

CRT Patients

The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.

Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.

Durvalumab Treatment

After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.

Discussion

NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.³

Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.⁴ Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.² Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.

Clinical Trials vs Real World

The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.¹² In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.¹³

Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.¹⁴

A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.¹ These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.

Limitations

Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.¹⁵ Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.^16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.¹⁹ Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.

Conlcusions

This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.

Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.¹² It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.

Combination afatinib and cetuximab did not improve progression-free survival (PFS) over afatinib alone in a phase 2 trial of treatment-naive patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC).

In addition, toxicity was greater with the afatinib/cetuximab combination, according to study author Sarah S. Goldberg, MD, of Yale University, New Haven, Conn.

Dr. Goldberg and colleagues reported these results, from the SWOG S1403 trial, in the Journal of Clinical Oncology.

The authors noted that activating EGFR mutations are present in about 15% of patients with lung adenocarcinomas in Western populations and the mutations confer heightened sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR-TKIs have been shown to improve clinical outcomes, quality of life, and toxicity when compared with chemotherapy.

Based on better outcomes over chemotherapy, the third-generation EGFR-TKI osimertinib is now the standard treatment for patients with T790M-mediated resistance, but osimertinib is not effective in TKI-resistant T790M-negative disease, the authors pointed out.

In a phase 1b trial of patients with EGFR-mutant NSCLC with acquired resistance to first-generation agents, afatinib/cetuximab produced a response rate of 29% and comparable activity regardless of T790M status.

The aim of the SWOG S1403 study was to test whether adding cetuximab to afatinib would improve PFS over afatinib alone in patients with treatment-naive, EGFR-mutant NSCLC by preventing or delaying resistance.
 

Trial details

The phase 2, multicenter trial included 168 eligible patients with EGFR-mutant NSCLC without prior treatment of advanced disease. The patients’ median age was 66 years (range, 27-93 years), and 66% were women.

The most common histology was adenocarcinoma (96%). EGFR exon 19 deletions were detected in 64% of patients and L858R point mutations in 36%.

Patients were randomly assigned 2:1 to receive afatinib at 40 mg orally daily plus cetuximab at 500 mg/m² intravenously every 2 weeks or afatinib at 40 mg alone. Patients received diphenhydramine at 50 mg intravenously before the first dose of cetuximab to prevent hypersensitivity reaction, and it was recommended before subsequent doses.

Patients continued on treatment until disease progression, symptomatic deterioration, unacceptable toxicity, pregnancy, treatment delay greater than 28 days, or patient decision. The study’s primary endpoint was PFS.
 

Further accrual not supported

At the interim analysis, the SWOG data safety and monitoring committee decided there was insufficient evidence to support further accrual, and the trial was closed.

The primary endpoint analysis revealed a median PFS of 11.9 months in the afatinib/cetuximab group and 13.4 months in the afatinib-alone group (hazard ratio, 1.01; 95% confidence interval, 0.72-1.43; P = .94). A subset analysis showed no PFS differences based on clinical or tumor characteristics.

Overall survival, time to response, and overall response rate were not improved in the afatinib/cetuximab arm.

PFS and overall survival were longer in patients with tumors harboring exon 19 deletions than in patients with L858R mutations. However, there were no mutation subtype–based PFS and overall survival differences between the treatment arms.

Grade 3 or higher treatment-related adverse events were more common in the combination arm than in the monotherapy arm (72% and 40%, respectively; P < .0001).

The most common grade 3 or higher treatment-related adverse events (in the combination and monotherapy arms, respectively) were acneiform rash (27% and 2%), maculopapular rash (13% and 0%), and diarrhea (15% and 20%).

Patients receiving afatinib plus cetuximab required dose reductions more often (56.7% vs. 26.2%), and treatment discontinuation because of an adverse event was more frequent in the combination arm (14% vs. 11%).
 

Turn toward third-generation drug

“Treatment with a single-agent EGFR-TKI remains the standard of care for patients with EGFR-mutant NSCLC,” Dr. Goldberg and colleagues wrote.

Why the combination of afatinib and cetuximab, which has demonstrated activity in the resistance setting, failed in the first-line setting remains unclear, Dr. Goldberg observed in an interview.

She noted that about one-quarter of patients receiving the afatinib/cetuximab combination discontinued cetuximab because of toxicity.

“That’s a good amount. It could be part of the explanation,” Dr. Goldberg said.

Investigators are currently analyzing collected tissue and blood samples in an effort to identify biomarkers that could potentially predict subgroups receiving benefit.

“That’s our next step: looking at specific EGFR mutation types, comutation types, and amplification of other genes and of EGFR,” Dr. Goldberg said.

She noted that, because of a superior side-effect profile and possibly greater efficacy, osimertinib is being used in the first-line setting.

“So now the idea of combining an EGFR-TKI with an EGFR antibody is still an active area of research, but with osimertinib rather than a first- or second-generation drug,” she said.

This research was supported by Boehringer Ingelheim, Eli Lilly, grants from the National Institutes of Health/National Cancer Institute, The Hope Foundation Career Development Award, and the SWOG and NIH Yale SPORE in Lung Cancer Grant. Dr. Goldberg and colleagues disclosed relationships with many pharmaceutical companies.

SOURCE: Goldberg SB et al. J Clin Oncol. 2020 Oct 6. doi: 10.1200/JCO.20.01149.

Combination afatinib and cetuximab did not improve progression-free survival (PFS) over afatinib alone in a phase 2 trial of treatment-naive patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC).

In addition, toxicity was greater with the afatinib/cetuximab combination, according to study author Sarah S. Goldberg, MD, of Yale University, New Haven, Conn.

Dr. Goldberg and colleagues reported these results, from the SWOG S1403 trial, in the Journal of Clinical Oncology.

The authors noted that activating EGFR mutations are present in about 15% of patients with lung adenocarcinomas in Western populations and the mutations confer heightened sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR-TKIs have been shown to improve clinical outcomes, quality of life, and toxicity when compared with chemotherapy.

Based on better outcomes over chemotherapy, the third-generation EGFR-TKI osimertinib is now the standard treatment for patients with T790M-mediated resistance, but osimertinib is not effective in TKI-resistant T790M-negative disease, the authors pointed out.

In a phase 1b trial of patients with EGFR-mutant NSCLC with acquired resistance to first-generation agents, afatinib/cetuximab produced a response rate of 29% and comparable activity regardless of T790M status.

The aim of the SWOG S1403 study was to test whether adding cetuximab to afatinib would improve PFS over afatinib alone in patients with treatment-naive, EGFR-mutant NSCLC by preventing or delaying resistance.
 

Trial details

The phase 2, multicenter trial included 168 eligible patients with EGFR-mutant NSCLC without prior treatment of advanced disease. The patients’ median age was 66 years (range, 27-93 years), and 66% were women.

The most common histology was adenocarcinoma (96%). EGFR exon 19 deletions were detected in 64% of patients and L858R point mutations in 36%.

Patients were randomly assigned 2:1 to receive afatinib at 40 mg orally daily plus cetuximab at 500 mg/m² intravenously every 2 weeks or afatinib at 40 mg alone. Patients received diphenhydramine at 50 mg intravenously before the first dose of cetuximab to prevent hypersensitivity reaction, and it was recommended before subsequent doses.

Patients continued on treatment until disease progression, symptomatic deterioration, unacceptable toxicity, pregnancy, treatment delay greater than 28 days, or patient decision. The study’s primary endpoint was PFS.
 

Further accrual not supported

At the interim analysis, the SWOG data safety and monitoring committee decided there was insufficient evidence to support further accrual, and the trial was closed.

The primary endpoint analysis revealed a median PFS of 11.9 months in the afatinib/cetuximab group and 13.4 months in the afatinib-alone group (hazard ratio, 1.01; 95% confidence interval, 0.72-1.43; P = .94). A subset analysis showed no PFS differences based on clinical or tumor characteristics.

Overall survival, time to response, and overall response rate were not improved in the afatinib/cetuximab arm.

PFS and overall survival were longer in patients with tumors harboring exon 19 deletions than in patients with L858R mutations. However, there were no mutation subtype–based PFS and overall survival differences between the treatment arms.

Grade 3 or higher treatment-related adverse events were more common in the combination arm than in the monotherapy arm (72% and 40%, respectively; P < .0001).

The most common grade 3 or higher treatment-related adverse events (in the combination and monotherapy arms, respectively) were acneiform rash (27% and 2%), maculopapular rash (13% and 0%), and diarrhea (15% and 20%).

Patients receiving afatinib plus cetuximab required dose reductions more often (56.7% vs. 26.2%), and treatment discontinuation because of an adverse event was more frequent in the combination arm (14% vs. 11%).
 

Turn toward third-generation drug

“Treatment with a single-agent EGFR-TKI remains the standard of care for patients with EGFR-mutant NSCLC,” Dr. Goldberg and colleagues wrote.

Why the combination of afatinib and cetuximab, which has demonstrated activity in the resistance setting, failed in the first-line setting remains unclear, Dr. Goldberg observed in an interview.

She noted that about one-quarter of patients receiving the afatinib/cetuximab combination discontinued cetuximab because of toxicity.

“That’s a good amount. It could be part of the explanation,” Dr. Goldberg said.

Investigators are currently analyzing collected tissue and blood samples in an effort to identify biomarkers that could potentially predict subgroups receiving benefit.

“That’s our next step: looking at specific EGFR mutation types, comutation types, and amplification of other genes and of EGFR,” Dr. Goldberg said.

She noted that, because of a superior side-effect profile and possibly greater efficacy, osimertinib is being used in the first-line setting.

“So now the idea of combining an EGFR-TKI with an EGFR antibody is still an active area of research, but with osimertinib rather than a first- or second-generation drug,” she said.

This research was supported by Boehringer Ingelheim, Eli Lilly, grants from the National Institutes of Health/National Cancer Institute, The Hope Foundation Career Development Award, and the SWOG and NIH Yale SPORE in Lung Cancer Grant. Dr. Goldberg and colleagues disclosed relationships with many pharmaceutical companies.

SOURCE: Goldberg SB et al. J Clin Oncol. 2020 Oct 6. doi: 10.1200/JCO.20.01149.

Combination afatinib and cetuximab did not improve progression-free survival (PFS) over afatinib alone in a phase 2 trial of treatment-naive patients with advanced EGFR-mutant non–small cell lung cancer (NSCLC).

In addition, toxicity was greater with the afatinib/cetuximab combination, according to study author Sarah S. Goldberg, MD, of Yale University, New Haven, Conn.

Dr. Goldberg and colleagues reported these results, from the SWOG S1403 trial, in the Journal of Clinical Oncology.

The authors noted that activating EGFR mutations are present in about 15% of patients with lung adenocarcinomas in Western populations and the mutations confer heightened sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR-TKIs have been shown to improve clinical outcomes, quality of life, and toxicity when compared with chemotherapy.

Based on better outcomes over chemotherapy, the third-generation EGFR-TKI osimertinib is now the standard treatment for patients with T790M-mediated resistance, but osimertinib is not effective in TKI-resistant T790M-negative disease, the authors pointed out.

In a phase 1b trial of patients with EGFR-mutant NSCLC with acquired resistance to first-generation agents, afatinib/cetuximab produced a response rate of 29% and comparable activity regardless of T790M status.

The aim of the SWOG S1403 study was to test whether adding cetuximab to afatinib would improve PFS over afatinib alone in patients with treatment-naive, EGFR-mutant NSCLC by preventing or delaying resistance.
 

Trial details

The phase 2, multicenter trial included 168 eligible patients with EGFR-mutant NSCLC without prior treatment of advanced disease. The patients’ median age was 66 years (range, 27-93 years), and 66% were women.

The most common histology was adenocarcinoma (96%). EGFR exon 19 deletions were detected in 64% of patients and L858R point mutations in 36%.

Patients were randomly assigned 2:1 to receive afatinib at 40 mg orally daily plus cetuximab at 500 mg/m² intravenously every 2 weeks or afatinib at 40 mg alone. Patients received diphenhydramine at 50 mg intravenously before the first dose of cetuximab to prevent hypersensitivity reaction, and it was recommended before subsequent doses.

Patients continued on treatment until disease progression, symptomatic deterioration, unacceptable toxicity, pregnancy, treatment delay greater than 28 days, or patient decision. The study’s primary endpoint was PFS.
 

Further accrual not supported

At the interim analysis, the SWOG data safety and monitoring committee decided there was insufficient evidence to support further accrual, and the trial was closed.

The primary endpoint analysis revealed a median PFS of 11.9 months in the afatinib/cetuximab group and 13.4 months in the afatinib-alone group (hazard ratio, 1.01; 95% confidence interval, 0.72-1.43; P = .94). A subset analysis showed no PFS differences based on clinical or tumor characteristics.

Overall survival, time to response, and overall response rate were not improved in the afatinib/cetuximab arm.

PFS and overall survival were longer in patients with tumors harboring exon 19 deletions than in patients with L858R mutations. However, there were no mutation subtype–based PFS and overall survival differences between the treatment arms.

Grade 3 or higher treatment-related adverse events were more common in the combination arm than in the monotherapy arm (72% and 40%, respectively; P < .0001).

The most common grade 3 or higher treatment-related adverse events (in the combination and monotherapy arms, respectively) were acneiform rash (27% and 2%), maculopapular rash (13% and 0%), and diarrhea (15% and 20%).

Patients receiving afatinib plus cetuximab required dose reductions more often (56.7% vs. 26.2%), and treatment discontinuation because of an adverse event was more frequent in the combination arm (14% vs. 11%).
 

Turn toward third-generation drug

“Treatment with a single-agent EGFR-TKI remains the standard of care for patients with EGFR-mutant NSCLC,” Dr. Goldberg and colleagues wrote.

Why the combination of afatinib and cetuximab, which has demonstrated activity in the resistance setting, failed in the first-line setting remains unclear, Dr. Goldberg observed in an interview.

She noted that about one-quarter of patients receiving the afatinib/cetuximab combination discontinued cetuximab because of toxicity.

“That’s a good amount. It could be part of the explanation,” Dr. Goldberg said.

Investigators are currently analyzing collected tissue and blood samples in an effort to identify biomarkers that could potentially predict subgroups receiving benefit.

“That’s our next step: looking at specific EGFR mutation types, comutation types, and amplification of other genes and of EGFR,” Dr. Goldberg said.

She noted that, because of a superior side-effect profile and possibly greater efficacy, osimertinib is being used in the first-line setting.

“So now the idea of combining an EGFR-TKI with an EGFR antibody is still an active area of research, but with osimertinib rather than a first- or second-generation drug,” she said.

This research was supported by Boehringer Ingelheim, Eli Lilly, grants from the National Institutes of Health/National Cancer Institute, The Hope Foundation Career Development Award, and the SWOG and NIH Yale SPORE in Lung Cancer Grant. Dr. Goldberg and colleagues disclosed relationships with many pharmaceutical companies.

SOURCE: Goldberg SB et al. J Clin Oncol. 2020 Oct 6. doi: 10.1200/JCO.20.01149.

Real-world survival outcomes for cancer patients on immune checkpoint inhibitors (ICIs) are inferior to outcomes reported in patients on clinical trials of ICIs, according to research published in JCO Clinical Cancer Informatics.

However, the research also suggests that real-world patients who receive ICIs achieve longer survival than patients on standard-of-care medications.

“Patients receiving ICIs in real-world practice may differ from those enrolled in trials in a variety of ways, including age, race, performance status, and comorbidity burden,” said study author Jerry S.H. Lee, PhD, of the University of Southern California, Los Angeles.

Dr. Lee noted that only 3%-4% of cancer patients participate in clinical trials. In fact, more than half of patients with melanoma and nearly three-quarters of those with non–small cell lung cancer (NSCLC) do not meet criteria for eligibility in clinical trials, he said.

To examine the discrepancies between real-world practice and clinical trials and to better understand which patients receive ICIs in clinical practice, Dr. Lee and colleagues conducted a retrospective analysis using electronic health record data from Veterans Administration (VA) facilities nationwide.

The researchers identified 11,888 cancer patients who were treated with ICIs. The cohort included patients who are underrepresented in pivotal clinical trials, including older, non-White, and/or higher disease-burdened patients.

The majority of patients were treated for NSCLC (51.1%), followed by melanoma (14.4%), renal cell carcinoma (RCC; 8.1%), squamous cell carcinoma of the head and neck (6.8%), urothelial cancer (6.4%), hepatocellular carcinoma (4.5%), and other less common cancer types (8.8%).
 

Overall survival by indication

In general, median overall survival (OS) in the VA cohort was inferior to median OS reported in clinical trials. However, patients treated with first-line nivolumab for melanoma and second-line pembrolizumab or nivolumab for NSCLC had similar OS in the real-world and trial data.

The researchers did not report exact OS numbers from clinical trials. However, they did report the exact numbers from the VA cohort and show OS differences between the VA cohort and clinical trials graphically.

Among patients in the VA cohort, the median OS was:

• 25.5 months in melanoma patients on first-line nivolumab
• 16.3 months in RCC patients receiving nivolumab in the second line or higher
• 14 months in RCC patients on first-line ipilimumab and nivolumab
• 10.6 months in NSCLC patients on first-line pembrolizumab
• 9.9 months in NSCLC patients receiving pembrolizumab or nivolumab in the second line or higher
• 9.1 months in NSCLC patients on first-line pembrolizumab and platinum-based chemotherapy
• 6.7 months in urothelial cancer patients receiving ICIs in the second line or higher.

A number of factors may have contributed to the shorter OS observed in the VA cohort, according to the researchers. The VA cohort is predominantly male, is older, and has a higher degree of comorbidity, compared with patients in clinical trials.

In addition, no data are available to determine the cause for discontinuation of therapy, and VA patients may have received ICIs after failing multiple lines of previous therapy, while clinical trials may limit patients to only one or two previous lines of therapy.

After stratifying VA patients by frailty status, the OS among non-frail patients was more similar to the OS reported in clinical trials.

“Real-world outcomes from the VA were more similar when adjusted for frailty, which shows the importance of patient diversity in clinical trials,” Dr. Lee said. He added that the definition of frailty among VA patients included potential injury during combat and therefore differs from a generic frailty definition.
 

ICIs vs. standard care

The researchers also found that VA patients treated with ICIs had longer OS, compared with a cohort of VA patients receiving standard-of-care therapies.

The median OS was as follows:

• In melanoma patients on first-line treatment – 39.29 months with nivolumab and 5.75 months with chemotherapy (P < .001).
• In RCC patients on first-line treatment – 14.01 months with ipilimumab plus nivolumab and 8.63 months with targeted therapy (P = .051).
• In RCC patients on second-line or greater treatment – 12.43 months with nivolumab and 8.09 months with everolimus (P < .001).
• In NSCLC patients on first-line therapy – 8.88 months with pembrolizumab and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on first-line combination therapy – 10.59 months with pembrolizumab plus platinum chemotherapy and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on second-line or greater therapy – 10.06 months with pembrolizumab or nivolumab and 6.41 months with docetaxel (P < .001).
• In urothelial cancer patients on second-line or greater therapy – 7.66 months with an ICI and 6.31 months with chemotherapy (P = .043).
   

Help for treatment decisions

“The real-world survival outcomes not only indicate the breadth of indications but also represent patients who tend not to be eligible for immunotherapy trials, based on their health status,” Dr. Lee said. “We hope this dataset of national-level experience provides practicing oncologists evidence to help patients and family members in the process of decision-making about therapy.”

Real-world data can also inform oncologists who face decisions on whether to prescribe or withhold ICIs and patients who face the financial burden of paying for ICIs, he said.

This dataset will be continually updated. The researchers have already added another 10,000 VA patients who have received immunotherapies in the year since the trial began.

“In a longitudinal way, we plan to examine what causes differences in outcomes and continue to find ways to extend care to veterans with a balance of high quality of life,” Dr. Lee said.

“Patients who participate in clinical trials are, on average, younger and healthier than the general population,” said Bora Youn, PhD, a senior biostatistician at Biogen in Cambridge, Mass., who was not involved in this study.

“In the case of immunotherapies, those with poor performance status and autoimmune conditions are often excluded from trials,” Dr. Youn added. “In the real world, these patients can also receive treatments, and clinicians often need to extrapolate the results from clinical trials. It is therefore important to collect real-world data to understand the effectiveness and safety of these therapies in patients with limited evidence.”

Dr. Youn led a real-world study, published in Cancer, of 1,256 Medicare recipients who were diagnosed with NSCLC and received ICI therapy.

“We found that factors associated with poor prognosis in general, such as squamous histology and failure of aggressive prior treatment, are also predictive of decreased survival among those who initiated immunotherapies. Yet, OS of older patients was relatively comparable to those observed in clinical trials,” Dr. Youn said.

“Understanding the real-world effectiveness of these treatments will help improve the evidence base, especially for those underrepresented in clinical trials. These studies can also help identify patients who are most likely to benefit from immunotherapies,” Dr. Youn added.

This study was supported by the VA Office of Research and Development Cooperative Studies Program. Dr. Lee and Dr. Youn disclosed no conflicts of interest.

SOURCE: Jennifer La et al. JCO Clinical Cancer Informatics. 2020:4:918-28.

Real-world survival outcomes for cancer patients on immune checkpoint inhibitors (ICIs) are inferior to outcomes reported in patients on clinical trials of ICIs, according to research published in JCO Clinical Cancer Informatics.

However, the research also suggests that real-world patients who receive ICIs achieve longer survival than patients on standard-of-care medications.

“Patients receiving ICIs in real-world practice may differ from those enrolled in trials in a variety of ways, including age, race, performance status, and comorbidity burden,” said study author Jerry S.H. Lee, PhD, of the University of Southern California, Los Angeles.

Dr. Lee noted that only 3%-4% of cancer patients participate in clinical trials. In fact, more than half of patients with melanoma and nearly three-quarters of those with non–small cell lung cancer (NSCLC) do not meet criteria for eligibility in clinical trials, he said.

To examine the discrepancies between real-world practice and clinical trials and to better understand which patients receive ICIs in clinical practice, Dr. Lee and colleagues conducted a retrospective analysis using electronic health record data from Veterans Administration (VA) facilities nationwide.

The researchers identified 11,888 cancer patients who were treated with ICIs. The cohort included patients who are underrepresented in pivotal clinical trials, including older, non-White, and/or higher disease-burdened patients.

The majority of patients were treated for NSCLC (51.1%), followed by melanoma (14.4%), renal cell carcinoma (RCC; 8.1%), squamous cell carcinoma of the head and neck (6.8%), urothelial cancer (6.4%), hepatocellular carcinoma (4.5%), and other less common cancer types (8.8%).
 

Overall survival by indication

In general, median overall survival (OS) in the VA cohort was inferior to median OS reported in clinical trials. However, patients treated with first-line nivolumab for melanoma and second-line pembrolizumab or nivolumab for NSCLC had similar OS in the real-world and trial data.

The researchers did not report exact OS numbers from clinical trials. However, they did report the exact numbers from the VA cohort and show OS differences between the VA cohort and clinical trials graphically.

Among patients in the VA cohort, the median OS was:

• 25.5 months in melanoma patients on first-line nivolumab
• 16.3 months in RCC patients receiving nivolumab in the second line or higher
• 14 months in RCC patients on first-line ipilimumab and nivolumab
• 10.6 months in NSCLC patients on first-line pembrolizumab
• 9.9 months in NSCLC patients receiving pembrolizumab or nivolumab in the second line or higher
• 9.1 months in NSCLC patients on first-line pembrolizumab and platinum-based chemotherapy
• 6.7 months in urothelial cancer patients receiving ICIs in the second line or higher.

A number of factors may have contributed to the shorter OS observed in the VA cohort, according to the researchers. The VA cohort is predominantly male, is older, and has a higher degree of comorbidity, compared with patients in clinical trials.

In addition, no data are available to determine the cause for discontinuation of therapy, and VA patients may have received ICIs after failing multiple lines of previous therapy, while clinical trials may limit patients to only one or two previous lines of therapy.

After stratifying VA patients by frailty status, the OS among non-frail patients was more similar to the OS reported in clinical trials.

“Real-world outcomes from the VA were more similar when adjusted for frailty, which shows the importance of patient diversity in clinical trials,” Dr. Lee said. He added that the definition of frailty among VA patients included potential injury during combat and therefore differs from a generic frailty definition.
 

ICIs vs. standard care

The researchers also found that VA patients treated with ICIs had longer OS, compared with a cohort of VA patients receiving standard-of-care therapies.

The median OS was as follows:

• In melanoma patients on first-line treatment – 39.29 months with nivolumab and 5.75 months with chemotherapy (P < .001).
• In RCC patients on first-line treatment – 14.01 months with ipilimumab plus nivolumab and 8.63 months with targeted therapy (P = .051).
• In RCC patients on second-line or greater treatment – 12.43 months with nivolumab and 8.09 months with everolimus (P < .001).
• In NSCLC patients on first-line therapy – 8.88 months with pembrolizumab and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on first-line combination therapy – 10.59 months with pembrolizumab plus platinum chemotherapy and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on second-line or greater therapy – 10.06 months with pembrolizumab or nivolumab and 6.41 months with docetaxel (P < .001).
• In urothelial cancer patients on second-line or greater therapy – 7.66 months with an ICI and 6.31 months with chemotherapy (P = .043).
   

Help for treatment decisions

“The real-world survival outcomes not only indicate the breadth of indications but also represent patients who tend not to be eligible for immunotherapy trials, based on their health status,” Dr. Lee said. “We hope this dataset of national-level experience provides practicing oncologists evidence to help patients and family members in the process of decision-making about therapy.”

Real-world data can also inform oncologists who face decisions on whether to prescribe or withhold ICIs and patients who face the financial burden of paying for ICIs, he said.

This dataset will be continually updated. The researchers have already added another 10,000 VA patients who have received immunotherapies in the year since the trial began.

“In a longitudinal way, we plan to examine what causes differences in outcomes and continue to find ways to extend care to veterans with a balance of high quality of life,” Dr. Lee said.

“Patients who participate in clinical trials are, on average, younger and healthier than the general population,” said Bora Youn, PhD, a senior biostatistician at Biogen in Cambridge, Mass., who was not involved in this study.

“In the case of immunotherapies, those with poor performance status and autoimmune conditions are often excluded from trials,” Dr. Youn added. “In the real world, these patients can also receive treatments, and clinicians often need to extrapolate the results from clinical trials. It is therefore important to collect real-world data to understand the effectiveness and safety of these therapies in patients with limited evidence.”

Dr. Youn led a real-world study, published in Cancer, of 1,256 Medicare recipients who were diagnosed with NSCLC and received ICI therapy.

“We found that factors associated with poor prognosis in general, such as squamous histology and failure of aggressive prior treatment, are also predictive of decreased survival among those who initiated immunotherapies. Yet, OS of older patients was relatively comparable to those observed in clinical trials,” Dr. Youn said.

“Understanding the real-world effectiveness of these treatments will help improve the evidence base, especially for those underrepresented in clinical trials. These studies can also help identify patients who are most likely to benefit from immunotherapies,” Dr. Youn added.

This study was supported by the VA Office of Research and Development Cooperative Studies Program. Dr. Lee and Dr. Youn disclosed no conflicts of interest.

SOURCE: Jennifer La et al. JCO Clinical Cancer Informatics. 2020:4:918-28.

Real-world survival outcomes for cancer patients on immune checkpoint inhibitors (ICIs) are inferior to outcomes reported in patients on clinical trials of ICIs, according to research published in JCO Clinical Cancer Informatics.

However, the research also suggests that real-world patients who receive ICIs achieve longer survival than patients on standard-of-care medications.

“Patients receiving ICIs in real-world practice may differ from those enrolled in trials in a variety of ways, including age, race, performance status, and comorbidity burden,” said study author Jerry S.H. Lee, PhD, of the University of Southern California, Los Angeles.

Dr. Lee noted that only 3%-4% of cancer patients participate in clinical trials. In fact, more than half of patients with melanoma and nearly three-quarters of those with non–small cell lung cancer (NSCLC) do not meet criteria for eligibility in clinical trials, he said.

To examine the discrepancies between real-world practice and clinical trials and to better understand which patients receive ICIs in clinical practice, Dr. Lee and colleagues conducted a retrospective analysis using electronic health record data from Veterans Administration (VA) facilities nationwide.

The researchers identified 11,888 cancer patients who were treated with ICIs. The cohort included patients who are underrepresented in pivotal clinical trials, including older, non-White, and/or higher disease-burdened patients.

The majority of patients were treated for NSCLC (51.1%), followed by melanoma (14.4%), renal cell carcinoma (RCC; 8.1%), squamous cell carcinoma of the head and neck (6.8%), urothelial cancer (6.4%), hepatocellular carcinoma (4.5%), and other less common cancer types (8.8%).
 

Overall survival by indication

In general, median overall survival (OS) in the VA cohort was inferior to median OS reported in clinical trials. However, patients treated with first-line nivolumab for melanoma and second-line pembrolizumab or nivolumab for NSCLC had similar OS in the real-world and trial data.

The researchers did not report exact OS numbers from clinical trials. However, they did report the exact numbers from the VA cohort and show OS differences between the VA cohort and clinical trials graphically.

Among patients in the VA cohort, the median OS was:

• 25.5 months in melanoma patients on first-line nivolumab
• 16.3 months in RCC patients receiving nivolumab in the second line or higher
• 14 months in RCC patients on first-line ipilimumab and nivolumab
• 10.6 months in NSCLC patients on first-line pembrolizumab
• 9.9 months in NSCLC patients receiving pembrolizumab or nivolumab in the second line or higher
• 9.1 months in NSCLC patients on first-line pembrolizumab and platinum-based chemotherapy
• 6.7 months in urothelial cancer patients receiving ICIs in the second line or higher.

A number of factors may have contributed to the shorter OS observed in the VA cohort, according to the researchers. The VA cohort is predominantly male, is older, and has a higher degree of comorbidity, compared with patients in clinical trials.

In addition, no data are available to determine the cause for discontinuation of therapy, and VA patients may have received ICIs after failing multiple lines of previous therapy, while clinical trials may limit patients to only one or two previous lines of therapy.

After stratifying VA patients by frailty status, the OS among non-frail patients was more similar to the OS reported in clinical trials.

“Real-world outcomes from the VA were more similar when adjusted for frailty, which shows the importance of patient diversity in clinical trials,” Dr. Lee said. He added that the definition of frailty among VA patients included potential injury during combat and therefore differs from a generic frailty definition.
 

ICIs vs. standard care

The researchers also found that VA patients treated with ICIs had longer OS, compared with a cohort of VA patients receiving standard-of-care therapies.

The median OS was as follows:

• In melanoma patients on first-line treatment – 39.29 months with nivolumab and 5.75 months with chemotherapy (P < .001).
• In RCC patients on first-line treatment – 14.01 months with ipilimumab plus nivolumab and 8.63 months with targeted therapy (P = .051).
• In RCC patients on second-line or greater treatment – 12.43 months with nivolumab and 8.09 months with everolimus (P < .001).
• In NSCLC patients on first-line therapy – 8.88 months with pembrolizumab and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on first-line combination therapy – 10.59 months with pembrolizumab plus platinum chemotherapy and 6.38 months with a platinum doublet (P < .001).
• In NSCLC patients on second-line or greater therapy – 10.06 months with pembrolizumab or nivolumab and 6.41 months with docetaxel (P < .001).
• In urothelial cancer patients on second-line or greater therapy – 7.66 months with an ICI and 6.31 months with chemotherapy (P = .043).
   

Help for treatment decisions

“The real-world survival outcomes not only indicate the breadth of indications but also represent patients who tend not to be eligible for immunotherapy trials, based on their health status,” Dr. Lee said. “We hope this dataset of national-level experience provides practicing oncologists evidence to help patients and family members in the process of decision-making about therapy.”

Real-world data can also inform oncologists who face decisions on whether to prescribe or withhold ICIs and patients who face the financial burden of paying for ICIs, he said.

This dataset will be continually updated. The researchers have already added another 10,000 VA patients who have received immunotherapies in the year since the trial began.

“In a longitudinal way, we plan to examine what causes differences in outcomes and continue to find ways to extend care to veterans with a balance of high quality of life,” Dr. Lee said.

“Patients who participate in clinical trials are, on average, younger and healthier than the general population,” said Bora Youn, PhD, a senior biostatistician at Biogen in Cambridge, Mass., who was not involved in this study.

“In the case of immunotherapies, those with poor performance status and autoimmune conditions are often excluded from trials,” Dr. Youn added. “In the real world, these patients can also receive treatments, and clinicians often need to extrapolate the results from clinical trials. It is therefore important to collect real-world data to understand the effectiveness and safety of these therapies in patients with limited evidence.”

Dr. Youn led a real-world study, published in Cancer, of 1,256 Medicare recipients who were diagnosed with NSCLC and received ICI therapy.

“We found that factors associated with poor prognosis in general, such as squamous histology and failure of aggressive prior treatment, are also predictive of decreased survival among those who initiated immunotherapies. Yet, OS of older patients was relatively comparable to those observed in clinical trials,” Dr. Youn said.

“Understanding the real-world effectiveness of these treatments will help improve the evidence base, especially for those underrepresented in clinical trials. These studies can also help identify patients who are most likely to benefit from immunotherapies,” Dr. Youn added.

This study was supported by the VA Office of Research and Development Cooperative Studies Program. Dr. Lee and Dr. Youn disclosed no conflicts of interest.

SOURCE: Jennifer La et al. JCO Clinical Cancer Informatics. 2020:4:918-28.

Stereotactic radiosurgery (SRS) should replace whole-brain radiotherapy (WBRT) as the new standard of care for patients with four or more brain metastases, say researchers who report results from a randomized trial conducted in patients with four to 15 brain metastases

“SRS was associated with reduced risk of neurocognitive deterioration compared to WBRT, as demonstrated by a constellation of neurocognitive tests, individually or by composite scores,” said lead author Jing Li, MD, PhD, associate professor of radiation oncology and codirector of the Brain Metastasis Clinic at the University of Texas MD Anderson Cancer Center, Houston.

She was speaking at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online this year because of the COVID pandemic.

“The results from this phase 3 randomized trial strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival,” said Li.

SRS is already the standard of care for patients with one to three brain metastases. Two previous phase 3 randomized trials showed that SRS was better at preserving cognitive function without compromising overall survival in comparison to WBRT.

However, there has been some controversy over the use of SRS for patients with multiple brain metastases, commented study discussant Sue S. Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology–Head and Neck Surgery, University of California, San Francisco.

This study has shown, “in a practice-changing manner, that giving SRS can improve the quality of life of patients with metastatic disease,” she said.

Up to 30% of cancer patients develop brain metastases. Historically, these have been associated with poor overall survival, in the range of 1 to 4 months.
 

Reduces cognitive decline

The new trial involved 72 patients with four to 15 untreated, nonmelanoma brain metastases (up to 20 lesions were allowed at the time of treatment); the median number of brain metastases was eight. Most (83%) of the trial participants were White, nearly half were aged 60 years or older, and 58% were women.

Patients were randomly assigned to receive either SRS (15–24 Gy per Radiation Therapy Oncology Group protocol 9005) or WBRT (30 Gy in 10 fractions). On the basis of previous research, 62% of patients in the WBRT arm were also given memantine, a dementia drug that can help preserve cognitive function.

All participants completed neurocognitive testing, including testing of learning, memory, attention span, executive function, verbal fluency, processing speed, and motor dexterity, at enrollment and longitudinally.

The primary endpoints were Hopkins Verbal Learning Test – Revised Total Recall (HVLT-R TR) score and local control at 4 months. Secondary endpoints included overall survival, distant brain failure, toxicity, and time to initiation of systemic therapy.

In the primary endpoint analysis, at 4 months, the HVLT-R TR standardized z-score increased by +0.21 (standard error [SE], 0.27) for patients who received SRS, but it declined by –0.74 (SE, 0.36) for WBRT-treated patients (P = .041). On the basis of Clinical Trial Battery Composite score, neurocognitive function of patients in the SRS arm improved on average +0.23 (SE, 0.14) but declined an average –0.73 (SE, 0.35) in the WBRT arm (P = .008).

Li pointed out that there was also a “clinically meaningful and statistically significant benefit” with SRS at 1 month (P = .033) and 6 months (P = .012).

A total of 69 patients (35 for SRS and 34 for WBRT) were evaluable for overall survival, which was similar between the groups (SRS median, 7.8 months; WBRT median, 8.9 months; P = .59). Treatment with SRS resulted in better local control rates (95% at 4 months with SRS and 86.7% with WBRT; P = .09), but the median time to distant brain failure was shorter (10.5 months for WBRT and 6.3 months for SRS; P = .37).

In her discussion of the study, Yom noted that overall survival time was similar in the two arms and that, numerically, it may have even been a little longer in the SRS group. “While it is true that they had more relapses in untreated portions of the brain, they lived as long or longer than those who received WBRT and had better cognitive function,” she noted

Yom also noted that of particular importance was the finding that SRS was associated with shorter interruptions of systemic therapy (time to systemic therapy: SRS, 1.7 weeks; WBRT, 4.1 weeks; P = .001). Patients with metastatic disease usually have cancer in locations other than the brain. They may be receiving some type of systemic therapy, which is interrupted with WBRT, Li commented.

Toxicities of grade 3 or higher were observed in four patients in the WBRT arm and two in the SRS arm. Radiographic evidence of radiation necrosis, a side effect associated with SRS, was observed in 17% patients in the SRS arm of the trial (4% of all treated lesions).

The trial was halted early owing to the publication of another phase 3 trial (NRG Oncology CC 001), which provided level 1 evidence for replacing standard WBRT with hippocampal-avoidance WBRT. Despite the early trial termination, Li concluded that these results “strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival.”

Li has received research funding from BMS and Medtronic and honorarium from Novocure and Monteris.

This article first appeared on Medscape.com.

Stereotactic radiosurgery (SRS) should replace whole-brain radiotherapy (WBRT) as the new standard of care for patients with four or more brain metastases, say researchers who report results from a randomized trial conducted in patients with four to 15 brain metastases

“SRS was associated with reduced risk of neurocognitive deterioration compared to WBRT, as demonstrated by a constellation of neurocognitive tests, individually or by composite scores,” said lead author Jing Li, MD, PhD, associate professor of radiation oncology and codirector of the Brain Metastasis Clinic at the University of Texas MD Anderson Cancer Center, Houston.

She was speaking at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online this year because of the COVID pandemic.

“The results from this phase 3 randomized trial strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival,” said Li.

SRS is already the standard of care for patients with one to three brain metastases. Two previous phase 3 randomized trials showed that SRS was better at preserving cognitive function without compromising overall survival in comparison to WBRT.

However, there has been some controversy over the use of SRS for patients with multiple brain metastases, commented study discussant Sue S. Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology–Head and Neck Surgery, University of California, San Francisco.

This study has shown, “in a practice-changing manner, that giving SRS can improve the quality of life of patients with metastatic disease,” she said.

Up to 30% of cancer patients develop brain metastases. Historically, these have been associated with poor overall survival, in the range of 1 to 4 months.
 

Reduces cognitive decline

The new trial involved 72 patients with four to 15 untreated, nonmelanoma brain metastases (up to 20 lesions were allowed at the time of treatment); the median number of brain metastases was eight. Most (83%) of the trial participants were White, nearly half were aged 60 years or older, and 58% were women.

Patients were randomly assigned to receive either SRS (15–24 Gy per Radiation Therapy Oncology Group protocol 9005) or WBRT (30 Gy in 10 fractions). On the basis of previous research, 62% of patients in the WBRT arm were also given memantine, a dementia drug that can help preserve cognitive function.

All participants completed neurocognitive testing, including testing of learning, memory, attention span, executive function, verbal fluency, processing speed, and motor dexterity, at enrollment and longitudinally.

The primary endpoints were Hopkins Verbal Learning Test – Revised Total Recall (HVLT-R TR) score and local control at 4 months. Secondary endpoints included overall survival, distant brain failure, toxicity, and time to initiation of systemic therapy.

In the primary endpoint analysis, at 4 months, the HVLT-R TR standardized z-score increased by +0.21 (standard error [SE], 0.27) for patients who received SRS, but it declined by –0.74 (SE, 0.36) for WBRT-treated patients (P = .041). On the basis of Clinical Trial Battery Composite score, neurocognitive function of patients in the SRS arm improved on average +0.23 (SE, 0.14) but declined an average –0.73 (SE, 0.35) in the WBRT arm (P = .008).

Li pointed out that there was also a “clinically meaningful and statistically significant benefit” with SRS at 1 month (P = .033) and 6 months (P = .012).

A total of 69 patients (35 for SRS and 34 for WBRT) were evaluable for overall survival, which was similar between the groups (SRS median, 7.8 months; WBRT median, 8.9 months; P = .59). Treatment with SRS resulted in better local control rates (95% at 4 months with SRS and 86.7% with WBRT; P = .09), but the median time to distant brain failure was shorter (10.5 months for WBRT and 6.3 months for SRS; P = .37).

In her discussion of the study, Yom noted that overall survival time was similar in the two arms and that, numerically, it may have even been a little longer in the SRS group. “While it is true that they had more relapses in untreated portions of the brain, they lived as long or longer than those who received WBRT and had better cognitive function,” she noted

Yom also noted that of particular importance was the finding that SRS was associated with shorter interruptions of systemic therapy (time to systemic therapy: SRS, 1.7 weeks; WBRT, 4.1 weeks; P = .001). Patients with metastatic disease usually have cancer in locations other than the brain. They may be receiving some type of systemic therapy, which is interrupted with WBRT, Li commented.

Toxicities of grade 3 or higher were observed in four patients in the WBRT arm and two in the SRS arm. Radiographic evidence of radiation necrosis, a side effect associated with SRS, was observed in 17% patients in the SRS arm of the trial (4% of all treated lesions).

The trial was halted early owing to the publication of another phase 3 trial (NRG Oncology CC 001), which provided level 1 evidence for replacing standard WBRT with hippocampal-avoidance WBRT. Despite the early trial termination, Li concluded that these results “strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival.”

Li has received research funding from BMS and Medtronic and honorarium from Novocure and Monteris.

This article first appeared on Medscape.com.

Stereotactic radiosurgery (SRS) should replace whole-brain radiotherapy (WBRT) as the new standard of care for patients with four or more brain metastases, say researchers who report results from a randomized trial conducted in patients with four to 15 brain metastases

“SRS was associated with reduced risk of neurocognitive deterioration compared to WBRT, as demonstrated by a constellation of neurocognitive tests, individually or by composite scores,” said lead author Jing Li, MD, PhD, associate professor of radiation oncology and codirector of the Brain Metastasis Clinic at the University of Texas MD Anderson Cancer Center, Houston.

She was speaking at the American Society for Radiation Oncology (ASTRO) 2020 Annual Meeting, which was held online this year because of the COVID pandemic.

“The results from this phase 3 randomized trial strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival,” said Li.

SRS is already the standard of care for patients with one to three brain metastases. Two previous phase 3 randomized trials showed that SRS was better at preserving cognitive function without compromising overall survival in comparison to WBRT.

However, there has been some controversy over the use of SRS for patients with multiple brain metastases, commented study discussant Sue S. Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology–Head and Neck Surgery, University of California, San Francisco.

This study has shown, “in a practice-changing manner, that giving SRS can improve the quality of life of patients with metastatic disease,” she said.

Up to 30% of cancer patients develop brain metastases. Historically, these have been associated with poor overall survival, in the range of 1 to 4 months.
 

Reduces cognitive decline

The new trial involved 72 patients with four to 15 untreated, nonmelanoma brain metastases (up to 20 lesions were allowed at the time of treatment); the median number of brain metastases was eight. Most (83%) of the trial participants were White, nearly half were aged 60 years or older, and 58% were women.

Patients were randomly assigned to receive either SRS (15–24 Gy per Radiation Therapy Oncology Group protocol 9005) or WBRT (30 Gy in 10 fractions). On the basis of previous research, 62% of patients in the WBRT arm were also given memantine, a dementia drug that can help preserve cognitive function.

All participants completed neurocognitive testing, including testing of learning, memory, attention span, executive function, verbal fluency, processing speed, and motor dexterity, at enrollment and longitudinally.

The primary endpoints were Hopkins Verbal Learning Test – Revised Total Recall (HVLT-R TR) score and local control at 4 months. Secondary endpoints included overall survival, distant brain failure, toxicity, and time to initiation of systemic therapy.

In the primary endpoint analysis, at 4 months, the HVLT-R TR standardized z-score increased by +0.21 (standard error [SE], 0.27) for patients who received SRS, but it declined by –0.74 (SE, 0.36) for WBRT-treated patients (P = .041). On the basis of Clinical Trial Battery Composite score, neurocognitive function of patients in the SRS arm improved on average +0.23 (SE, 0.14) but declined an average –0.73 (SE, 0.35) in the WBRT arm (P = .008).

Li pointed out that there was also a “clinically meaningful and statistically significant benefit” with SRS at 1 month (P = .033) and 6 months (P = .012).

A total of 69 patients (35 for SRS and 34 for WBRT) were evaluable for overall survival, which was similar between the groups (SRS median, 7.8 months; WBRT median, 8.9 months; P = .59). Treatment with SRS resulted in better local control rates (95% at 4 months with SRS and 86.7% with WBRT; P = .09), but the median time to distant brain failure was shorter (10.5 months for WBRT and 6.3 months for SRS; P = .37).

In her discussion of the study, Yom noted that overall survival time was similar in the two arms and that, numerically, it may have even been a little longer in the SRS group. “While it is true that they had more relapses in untreated portions of the brain, they lived as long or longer than those who received WBRT and had better cognitive function,” she noted

Yom also noted that of particular importance was the finding that SRS was associated with shorter interruptions of systemic therapy (time to systemic therapy: SRS, 1.7 weeks; WBRT, 4.1 weeks; P = .001). Patients with metastatic disease usually have cancer in locations other than the brain. They may be receiving some type of systemic therapy, which is interrupted with WBRT, Li commented.

Toxicities of grade 3 or higher were observed in four patients in the WBRT arm and two in the SRS arm. Radiographic evidence of radiation necrosis, a side effect associated with SRS, was observed in 17% patients in the SRS arm of the trial (4% of all treated lesions).

The trial was halted early owing to the publication of another phase 3 trial (NRG Oncology CC 001), which provided level 1 evidence for replacing standard WBRT with hippocampal-avoidance WBRT. Despite the early trial termination, Li concluded that these results “strongly support the use of SRS in patients with four to 15 brain metastases to better preserve cognitive function and to minimize interruption of systemic therapy, without compromising overall survival.”

Li has received research funding from BMS and Medtronic and honorarium from Novocure and Monteris.

This article first appeared on Medscape.com.

Stereotactic body radiotherapy (SBRT) for lung oligometastases nets similar safety and efficacy whether it is delivered in multiple fractions or just one fraction. This was among key findings of a randomized, phase 2 trial reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Most patients [with lung metastases] are treated with lifelong anticancer drug therapy only, with little prospect for long-term cancer control,” investigator Shankar Siva, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, said in a news briefing.

“However, some patients may have limited spread to the lungs and may be suitable for either surgery, which is an invasive approach, or SBRT, which is a noninvasive approach, with the aim to prolong long-term cancer control,” he added.
 

Patients and treatment

Dr. Siva and colleagues enrolled in their phase 2 trial (SAFRON II/TROG 13.01) 90 patients from 13 centers in Australia and New Zealand.

All patients had one to three lung metastases (from nonhematologic malignancies) that measured up to 5 cm in diameter and were located in the periphery.

The most common primaries were colorectal cancer (47%), lung cancer (11%), and kidney cancer (10%). The trial required that all primary and extrathoracic disease had been definitively treated.

The patients were randomized evenly to lung SBRT delivered with a single-fraction regimen (28 Gy in one fraction) or a multifraction regimen (48 Gy in four fractions) that netted the same biological equivalent dose.
 

Safety and efficacy

The two treatment groups did not differ significantly with respect to any-grade toxicities at 1 year, with the exception of higher rates of esophagitis and radiation dermatitis in the multifraction group, Dr. Siva reported.

The rate of grade 3 or worse toxicity at 1 year – the trial’s primary endpoint – was 5% with the single fraction and 3% with multiple fractions, with overlapping 80% confidence intervals, meeting the prespecified endpoint for acceptable toxicity.

The single-fraction group had two grade 3 events that resolved with intervention and no grade 4-5 events. The multifraction group had a single grade 5 event (fatal pneumonitis in a patient with underlying interstitial lung disease) and no grade 3-4 events.

The single-fraction and multifraction groups were also similar at 1 year on rates of freedom from local failure (93% and 95%, respectively), disease-free survival (59% and 60%, respectively), and overall survival (95% and 93%, respectively), with overlapping 95% CIs for each outcome.

Analyses of quality of life and cost-effectiveness are ongoing.
 

Applying the results: Useful in a pandemic?

“Single-session SBRT is safe, convenient, and noninvasive, and appears to be effective, to date, for lung secondaries. This approach may be considered as a one-stop, knockout type of approach for patients who have one to three metastases to the lung,” Dr. Siva proposed.

“These findings may have implications for treatment selection in a resource-constrained environment, such as the current global pandemic, when trying to reduce footfall or thoroughfare within a radiotherapy department, and it’s quite a convenient approach for patients,” he added.
 

“Stereotactic radiation has an obvious advantage over conventional radiation in several ways and may have a special advantage in the midst of the COVID-19 pandemic to reduce exposure to patients and our hospital personnel,” agreed news briefing moderator Sue S. Yom, MD, PhD, of the University of California, San Francisco.

However, use of stereotactic techniques remains controversial because they require technical precision and additional resources for planning and quality assurance, and they are often more expensive than conventional radiation therapy, she noted. Therefore, there must be evidence to justify their use in a palliative or metastatic setting.

The current trial is noteworthy for pushing the SBRT efficiency envelope, according to Dr. Yom.

“These findings are going to be confirmed by the study team with further follow-up at 3 years,” she pointed out. “If the findings of this study are maintained, it shows that patients with up to three metastatic tumors in the lung can have their treatment given in an extremely efficient manner over one session, which saves them time and hospital resources, and could be very significant to patients’ quality of life.”

The trial is sponsored by the Trans-Tasman Radiation Oncology Group and the Australasian Lung Cancer Trials Group. Dr. Siva disclosed relationships with Varian Industries, Merck, AstraZeneca, Bayer Pharmaceuticals, Bristol Meyers Squibb, and Reflexion. Dr. Yom disclosed no relevant conflicts.

SOURCE: Siva S et al. ASTRO 2020, Abstract 5.

Stereotactic body radiotherapy (SBRT) for lung oligometastases nets similar safety and efficacy whether it is delivered in multiple fractions or just one fraction. This was among key findings of a randomized, phase 2 trial reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Most patients [with lung metastases] are treated with lifelong anticancer drug therapy only, with little prospect for long-term cancer control,” investigator Shankar Siva, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, said in a news briefing.

“However, some patients may have limited spread to the lungs and may be suitable for either surgery, which is an invasive approach, or SBRT, which is a noninvasive approach, with the aim to prolong long-term cancer control,” he added.
 

Patients and treatment

Dr. Siva and colleagues enrolled in their phase 2 trial (SAFRON II/TROG 13.01) 90 patients from 13 centers in Australia and New Zealand.

All patients had one to three lung metastases (from nonhematologic malignancies) that measured up to 5 cm in diameter and were located in the periphery.

The most common primaries were colorectal cancer (47%), lung cancer (11%), and kidney cancer (10%). The trial required that all primary and extrathoracic disease had been definitively treated.

The patients were randomized evenly to lung SBRT delivered with a single-fraction regimen (28 Gy in one fraction) or a multifraction regimen (48 Gy in four fractions) that netted the same biological equivalent dose.
 

Safety and efficacy

The two treatment groups did not differ significantly with respect to any-grade toxicities at 1 year, with the exception of higher rates of esophagitis and radiation dermatitis in the multifraction group, Dr. Siva reported.

The rate of grade 3 or worse toxicity at 1 year – the trial’s primary endpoint – was 5% with the single fraction and 3% with multiple fractions, with overlapping 80% confidence intervals, meeting the prespecified endpoint for acceptable toxicity.

The single-fraction group had two grade 3 events that resolved with intervention and no grade 4-5 events. The multifraction group had a single grade 5 event (fatal pneumonitis in a patient with underlying interstitial lung disease) and no grade 3-4 events.

The single-fraction and multifraction groups were also similar at 1 year on rates of freedom from local failure (93% and 95%, respectively), disease-free survival (59% and 60%, respectively), and overall survival (95% and 93%, respectively), with overlapping 95% CIs for each outcome.

Analyses of quality of life and cost-effectiveness are ongoing.
 

Applying the results: Useful in a pandemic?

“Single-session SBRT is safe, convenient, and noninvasive, and appears to be effective, to date, for lung secondaries. This approach may be considered as a one-stop, knockout type of approach for patients who have one to three metastases to the lung,” Dr. Siva proposed.

“These findings may have implications for treatment selection in a resource-constrained environment, such as the current global pandemic, when trying to reduce footfall or thoroughfare within a radiotherapy department, and it’s quite a convenient approach for patients,” he added.
 

“Stereotactic radiation has an obvious advantage over conventional radiation in several ways and may have a special advantage in the midst of the COVID-19 pandemic to reduce exposure to patients and our hospital personnel,” agreed news briefing moderator Sue S. Yom, MD, PhD, of the University of California, San Francisco.

However, use of stereotactic techniques remains controversial because they require technical precision and additional resources for planning and quality assurance, and they are often more expensive than conventional radiation therapy, she noted. Therefore, there must be evidence to justify their use in a palliative or metastatic setting.

The current trial is noteworthy for pushing the SBRT efficiency envelope, according to Dr. Yom.

“These findings are going to be confirmed by the study team with further follow-up at 3 years,” she pointed out. “If the findings of this study are maintained, it shows that patients with up to three metastatic tumors in the lung can have their treatment given in an extremely efficient manner over one session, which saves them time and hospital resources, and could be very significant to patients’ quality of life.”

The trial is sponsored by the Trans-Tasman Radiation Oncology Group and the Australasian Lung Cancer Trials Group. Dr. Siva disclosed relationships with Varian Industries, Merck, AstraZeneca, Bayer Pharmaceuticals, Bristol Meyers Squibb, and Reflexion. Dr. Yom disclosed no relevant conflicts.

SOURCE: Siva S et al. ASTRO 2020, Abstract 5.

Stereotactic body radiotherapy (SBRT) for lung oligometastases nets similar safety and efficacy whether it is delivered in multiple fractions or just one fraction. This was among key findings of a randomized, phase 2 trial reported at the American Society for Radiation Oncology Annual Meeting 2020.

“Most patients [with lung metastases] are treated with lifelong anticancer drug therapy only, with little prospect for long-term cancer control,” investigator Shankar Siva, MBBS, PhD, of Peter MacCallum Cancer Centre in Melbourne, said in a news briefing.

“However, some patients may have limited spread to the lungs and may be suitable for either surgery, which is an invasive approach, or SBRT, which is a noninvasive approach, with the aim to prolong long-term cancer control,” he added.
 

Patients and treatment

Dr. Siva and colleagues enrolled in their phase 2 trial (SAFRON II/TROG 13.01) 90 patients from 13 centers in Australia and New Zealand.

All patients had one to three lung metastases (from nonhematologic malignancies) that measured up to 5 cm in diameter and were located in the periphery.

The most common primaries were colorectal cancer (47%), lung cancer (11%), and kidney cancer (10%). The trial required that all primary and extrathoracic disease had been definitively treated.

The patients were randomized evenly to lung SBRT delivered with a single-fraction regimen (28 Gy in one fraction) or a multifraction regimen (48 Gy in four fractions) that netted the same biological equivalent dose.
 

Safety and efficacy

The two treatment groups did not differ significantly with respect to any-grade toxicities at 1 year, with the exception of higher rates of esophagitis and radiation dermatitis in the multifraction group, Dr. Siva reported.

The rate of grade 3 or worse toxicity at 1 year – the trial’s primary endpoint – was 5% with the single fraction and 3% with multiple fractions, with overlapping 80% confidence intervals, meeting the prespecified endpoint for acceptable toxicity.

The single-fraction group had two grade 3 events that resolved with intervention and no grade 4-5 events. The multifraction group had a single grade 5 event (fatal pneumonitis in a patient with underlying interstitial lung disease) and no grade 3-4 events.

The single-fraction and multifraction groups were also similar at 1 year on rates of freedom from local failure (93% and 95%, respectively), disease-free survival (59% and 60%, respectively), and overall survival (95% and 93%, respectively), with overlapping 95% CIs for each outcome.

Analyses of quality of life and cost-effectiveness are ongoing.
 

Applying the results: Useful in a pandemic?

“Single-session SBRT is safe, convenient, and noninvasive, and appears to be effective, to date, for lung secondaries. This approach may be considered as a one-stop, knockout type of approach for patients who have one to three metastases to the lung,” Dr. Siva proposed.

“These findings may have implications for treatment selection in a resource-constrained environment, such as the current global pandemic, when trying to reduce footfall or thoroughfare within a radiotherapy department, and it’s quite a convenient approach for patients,” he added.
 

“Stereotactic radiation has an obvious advantage over conventional radiation in several ways and may have a special advantage in the midst of the COVID-19 pandemic to reduce exposure to patients and our hospital personnel,” agreed news briefing moderator Sue S. Yom, MD, PhD, of the University of California, San Francisco.

However, use of stereotactic techniques remains controversial because they require technical precision and additional resources for planning and quality assurance, and they are often more expensive than conventional radiation therapy, she noted. Therefore, there must be evidence to justify their use in a palliative or metastatic setting.

The current trial is noteworthy for pushing the SBRT efficiency envelope, according to Dr. Yom.

“These findings are going to be confirmed by the study team with further follow-up at 3 years,” she pointed out. “If the findings of this study are maintained, it shows that patients with up to three metastatic tumors in the lung can have their treatment given in an extremely efficient manner over one session, which saves them time and hospital resources, and could be very significant to patients’ quality of life.”

The trial is sponsored by the Trans-Tasman Radiation Oncology Group and the Australasian Lung Cancer Trials Group. Dr. Siva disclosed relationships with Varian Industries, Merck, AstraZeneca, Bayer Pharmaceuticals, Bristol Meyers Squibb, and Reflexion. Dr. Yom disclosed no relevant conflicts.

SOURCE: Siva S et al. ASTRO 2020, Abstract 5.

A national effort to perform genotype drug matching across cancer types shows the value of next-generation sequencing and provides a roadmap for future precision oncology trials, according to experts.

Massachusetts General Hospital

The effort is the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial. For this study, researchers performed next-generation sequencing on tumor biopsy specimens to identify therapeutically actionable molecular alterations in patients with “underexplored” cancer types.

The trial included 5,954 patients with cancers that had progressed on standard treatments or rare cancers for which there is no standard treatment. If actionable alterations were found in these patients, they could receive new drugs in development that showed promise in other clinical trials or drugs that were approved by the Food and Drug Administration to treat at least one cancer type.

Data newly reported in the Journal of Clinical Oncology showed that 37.6% of patients had alterations that could be matched to targeted drugs, and 17.8% of patients were assigned to targeted treatment. Multiple actionable tumor mutations were seen in 11.9% of specimens, and resistance-conferring mutations were seen in 71.3% of specimens.

“The bottom line from this report is that next-generation sequencing is an efficient way to identify both approved and promising investigational therapies. For this reason, it should be considered standard of care for patients with advanced cancers,” said study chair Keith T. Flaherty, MD, director of the Henri and Belinda Termeer Center for Targeted Therapy at Massachusetts General Hospital Cancer Center in Boston.

“This study sets the benchmark for the ‘actionability’ of next-generation sequencing,” Dr. Flaherty added. “We expect this number [of actionable alterations] will continue to rise steadily as further advances are made in the development of therapies that target some of the genetic alterations for which we could not offer treatment options in NCI-MATCH.”
 

Relapsed/refractory vs. primary tumors

The NCI-MATCH researchers focused on the most commonly found genetic alterations and performed biopsies at study entry to provide the most accurate picture of the genetic landscape of relapsed/refractory cancer patients. That makes this cohort distinct from The Cancer Genome Atlas (TCGA), a database of patients with mostly untreated primary tumors, and other published cohorts that include genetic analysis of primary tumors and biopsies from the time of initial metastatic recurrence.

The researchers compared the tumor gene makeup of NCI-MATCH and TCGA patients with seven cancer types – breast, bile duct, cervix, colorectal, lung, pancreas, and prostate.

ECOG-ACRIN Cancer Research Group

“Perhaps the biggest surprise was the relatively minimal change in the genetic alterations found in these relapsed/refractory patients, compared to primary tumors,” Dr. Flaherty said. “These findings suggest that it is very reasonable to perform next-generation sequencing at the time of initial metastatic cancer diagnosis and to rely on those findings for the purposes of considering FDA-approved therapies and clinical trial participation.”
 

Multiple alterations and resistance

The complex genetics of cancers has led researchers to explore combinations of targeted and other therapies to address multiple defects at the same time.

“Not surprisingly, the most common collision of multiple genetic alterations within the same tumor was in the commonly altered tumor suppressor genes: TP53, APC, and PTEN,” Dr. Flaherty said.

“An increasing body of evidence supports a role for loss-of-function alterations in these genes to confer resistance to many targeted therapies,” he added. “While we don’t have targeted therapies yet established to directly counter this form of therapeutic resistance, we hypothesize that various types of combination therapy may be able to indirectly undercut resistance and enhance the benefit of many targeted therapies.”

The NCI-MATCH researchers will continue to mine this large dataset to better understand the many small, genetically defined cancer subpopulations.

“We will continue to report the outcome of the individual treatment subprotocols, and combining this genetic analysis with those outcomes will likely inform the next clinical trials,” Dr. Flaherty said.
 

Actionable mutations make a difference

Precision oncology experts agree that NCI-MATCH results are impressive and add a fuller appreciation that actionable mutations make a clinical difference.

“This is a powerful, extremely well-designed study, a tour de force of collaborative science,” said Stephen Gruber, MD, PhD, director of the Center for Precision Medicine at City of Hope National Medical Center in Duarte, Calif.

“The future holds even more promise,” he added. “Our ability to interrogate the genomic landscape of cancer is improving rapidly. Tumor testing helps get the right drug to the right tumor faster than a guidelines-based approach from historical data of combination chemotherapy. This is a likely game changer for the way oncologists will practice in the future, especially as we learn more results of subset trials. The NCI-MATCH researchers have taken a laser-focused look at the current data, but we now know we can look far more comprehensively at genomic profiles of tumors.”

From the viewpoint of the practicing oncologist, co-occurring resistance mutations make a difference in defining what combinations are likely and, more importantly, less likely to be effective. “When we see two mutations and one is likely to confer resistance, we can make a choice to avoid a drug that is not likely to work,” Dr. Gruber said.

“The NCI-MATCH trial allows both approved and investigational agents, which expands the possibility of matching patients to newer agents. This is especially relevant if there are no FDA-approved drugs yet for some molecular aberrations,” said Lillian L. Siu, MD, a senior medical oncologist at the Princess Margaret Cancer Centre in Toronto. “This trial enables such evaluations under the auspice of a clinical trial to provide important knowledge.”

Both experts agree that in-depth biological interrogations of cancer will move the field of precision oncology forward. Dr. Gruber said that “studies have not yet fully addressed the power of germline genetic testing of DNA. Inherited susceptibility will drive therapeutic choices – for example, PARP inhibitors that access homologous recombination deficiency for breast, ovarian, and prostate cancer. We will learn more about treatment choices for those cancers.”

Dr. Siu added: “I truly believe that liquid biopsies [circulating tumor DNA] will help us perform target-drug matching in a less invasive way. We need to explore beyond the genome to look at the transcriptome, proteome, epigenome, and immunome, among others. It is likely that multiomic predictors are going to be able to identify more therapeutic options compared to single genomic predictors.”

Dr. Flaherty noted that all tumor samples from patients assigned to treatment are being subjected to whole-exome sequencing to further the discovery of the genetic features of responsive and nonresponsive tumors.

NCI-MATCH was funded by the National Cancer Institute. Dr. Flaherty disclosed relationships with Clovis Oncology, Loxo, X4 Pharma, and many other companies. His coauthors disclosed many conflicts as well. Dr. Gruber is cofounder of Brogent International. Dr. Siu disclosed relationships with Agios, Treadwell Therapeutics, Merck, Pfizer, and many other companies.

SOURCE: Flaherty KT et al. J Clin Oncol. 2020 Oct 13. doi: 10.1200/JCO.19.03010.

A national effort to perform genotype drug matching across cancer types shows the value of next-generation sequencing and provides a roadmap for future precision oncology trials, according to experts.

Massachusetts General Hospital

The effort is the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial. For this study, researchers performed next-generation sequencing on tumor biopsy specimens to identify therapeutically actionable molecular alterations in patients with “underexplored” cancer types.

The trial included 5,954 patients with cancers that had progressed on standard treatments or rare cancers for which there is no standard treatment. If actionable alterations were found in these patients, they could receive new drugs in development that showed promise in other clinical trials or drugs that were approved by the Food and Drug Administration to treat at least one cancer type.

Data newly reported in the Journal of Clinical Oncology showed that 37.6% of patients had alterations that could be matched to targeted drugs, and 17.8% of patients were assigned to targeted treatment. Multiple actionable tumor mutations were seen in 11.9% of specimens, and resistance-conferring mutations were seen in 71.3% of specimens.

“The bottom line from this report is that next-generation sequencing is an efficient way to identify both approved and promising investigational therapies. For this reason, it should be considered standard of care for patients with advanced cancers,” said study chair Keith T. Flaherty, MD, director of the Henri and Belinda Termeer Center for Targeted Therapy at Massachusetts General Hospital Cancer Center in Boston.

“This study sets the benchmark for the ‘actionability’ of next-generation sequencing,” Dr. Flaherty added. “We expect this number [of actionable alterations] will continue to rise steadily as further advances are made in the development of therapies that target some of the genetic alterations for which we could not offer treatment options in NCI-MATCH.”
 

Relapsed/refractory vs. primary tumors

The NCI-MATCH researchers focused on the most commonly found genetic alterations and performed biopsies at study entry to provide the most accurate picture of the genetic landscape of relapsed/refractory cancer patients. That makes this cohort distinct from The Cancer Genome Atlas (TCGA), a database of patients with mostly untreated primary tumors, and other published cohorts that include genetic analysis of primary tumors and biopsies from the time of initial metastatic recurrence.

The researchers compared the tumor gene makeup of NCI-MATCH and TCGA patients with seven cancer types – breast, bile duct, cervix, colorectal, lung, pancreas, and prostate.

ECOG-ACRIN Cancer Research Group

“Perhaps the biggest surprise was the relatively minimal change in the genetic alterations found in these relapsed/refractory patients, compared to primary tumors,” Dr. Flaherty said. “These findings suggest that it is very reasonable to perform next-generation sequencing at the time of initial metastatic cancer diagnosis and to rely on those findings for the purposes of considering FDA-approved therapies and clinical trial participation.”
 

Multiple alterations and resistance

The complex genetics of cancers has led researchers to explore combinations of targeted and other therapies to address multiple defects at the same time.

“Not surprisingly, the most common collision of multiple genetic alterations within the same tumor was in the commonly altered tumor suppressor genes: TP53, APC, and PTEN,” Dr. Flaherty said.

“An increasing body of evidence supports a role for loss-of-function alterations in these genes to confer resistance to many targeted therapies,” he added. “While we don’t have targeted therapies yet established to directly counter this form of therapeutic resistance, we hypothesize that various types of combination therapy may be able to indirectly undercut resistance and enhance the benefit of many targeted therapies.”

The NCI-MATCH researchers will continue to mine this large dataset to better understand the many small, genetically defined cancer subpopulations.

“We will continue to report the outcome of the individual treatment subprotocols, and combining this genetic analysis with those outcomes will likely inform the next clinical trials,” Dr. Flaherty said.
 

Actionable mutations make a difference

Precision oncology experts agree that NCI-MATCH results are impressive and add a fuller appreciation that actionable mutations make a clinical difference.

“This is a powerful, extremely well-designed study, a tour de force of collaborative science,” said Stephen Gruber, MD, PhD, director of the Center for Precision Medicine at City of Hope National Medical Center in Duarte, Calif.

“The future holds even more promise,” he added. “Our ability to interrogate the genomic landscape of cancer is improving rapidly. Tumor testing helps get the right drug to the right tumor faster than a guidelines-based approach from historical data of combination chemotherapy. This is a likely game changer for the way oncologists will practice in the future, especially as we learn more results of subset trials. The NCI-MATCH researchers have taken a laser-focused look at the current data, but we now know we can look far more comprehensively at genomic profiles of tumors.”

From the viewpoint of the practicing oncologist, co-occurring resistance mutations make a difference in defining what combinations are likely and, more importantly, less likely to be effective. “When we see two mutations and one is likely to confer resistance, we can make a choice to avoid a drug that is not likely to work,” Dr. Gruber said.

“The NCI-MATCH trial allows both approved and investigational agents, which expands the possibility of matching patients to newer agents. This is especially relevant if there are no FDA-approved drugs yet for some molecular aberrations,” said Lillian L. Siu, MD, a senior medical oncologist at the Princess Margaret Cancer Centre in Toronto. “This trial enables such evaluations under the auspice of a clinical trial to provide important knowledge.”

Both experts agree that in-depth biological interrogations of cancer will move the field of precision oncology forward. Dr. Gruber said that “studies have not yet fully addressed the power of germline genetic testing of DNA. Inherited susceptibility will drive therapeutic choices – for example, PARP inhibitors that access homologous recombination deficiency for breast, ovarian, and prostate cancer. We will learn more about treatment choices for those cancers.”

Dr. Siu added: “I truly believe that liquid biopsies [circulating tumor DNA] will help us perform target-drug matching in a less invasive way. We need to explore beyond the genome to look at the transcriptome, proteome, epigenome, and immunome, among others. It is likely that multiomic predictors are going to be able to identify more therapeutic options compared to single genomic predictors.”

Dr. Flaherty noted that all tumor samples from patients assigned to treatment are being subjected to whole-exome sequencing to further the discovery of the genetic features of responsive and nonresponsive tumors.

NCI-MATCH was funded by the National Cancer Institute. Dr. Flaherty disclosed relationships with Clovis Oncology, Loxo, X4 Pharma, and many other companies. His coauthors disclosed many conflicts as well. Dr. Gruber is cofounder of Brogent International. Dr. Siu disclosed relationships with Agios, Treadwell Therapeutics, Merck, Pfizer, and many other companies.

SOURCE: Flaherty KT et al. J Clin Oncol. 2020 Oct 13. doi: 10.1200/JCO.19.03010.

A national effort to perform genotype drug matching across cancer types shows the value of next-generation sequencing and provides a roadmap for future precision oncology trials, according to experts.

Massachusetts General Hospital

The effort is the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial. For this study, researchers performed next-generation sequencing on tumor biopsy specimens to identify therapeutically actionable molecular alterations in patients with “underexplored” cancer types.

The trial included 5,954 patients with cancers that had progressed on standard treatments or rare cancers for which there is no standard treatment. If actionable alterations were found in these patients, they could receive new drugs in development that showed promise in other clinical trials or drugs that were approved by the Food and Drug Administration to treat at least one cancer type.

Data newly reported in the Journal of Clinical Oncology showed that 37.6% of patients had alterations that could be matched to targeted drugs, and 17.8% of patients were assigned to targeted treatment. Multiple actionable tumor mutations were seen in 11.9% of specimens, and resistance-conferring mutations were seen in 71.3% of specimens.

“The bottom line from this report is that next-generation sequencing is an efficient way to identify both approved and promising investigational therapies. For this reason, it should be considered standard of care for patients with advanced cancers,” said study chair Keith T. Flaherty, MD, director of the Henri and Belinda Termeer Center for Targeted Therapy at Massachusetts General Hospital Cancer Center in Boston.

“This study sets the benchmark for the ‘actionability’ of next-generation sequencing,” Dr. Flaherty added. “We expect this number [of actionable alterations] will continue to rise steadily as further advances are made in the development of therapies that target some of the genetic alterations for which we could not offer treatment options in NCI-MATCH.”
 

Relapsed/refractory vs. primary tumors

The NCI-MATCH researchers focused on the most commonly found genetic alterations and performed biopsies at study entry to provide the most accurate picture of the genetic landscape of relapsed/refractory cancer patients. That makes this cohort distinct from The Cancer Genome Atlas (TCGA), a database of patients with mostly untreated primary tumors, and other published cohorts that include genetic analysis of primary tumors and biopsies from the time of initial metastatic recurrence.

The researchers compared the tumor gene makeup of NCI-MATCH and TCGA patients with seven cancer types – breast, bile duct, cervix, colorectal, lung, pancreas, and prostate.

ECOG-ACRIN Cancer Research Group

“Perhaps the biggest surprise was the relatively minimal change in the genetic alterations found in these relapsed/refractory patients, compared to primary tumors,” Dr. Flaherty said. “These findings suggest that it is very reasonable to perform next-generation sequencing at the time of initial metastatic cancer diagnosis and to rely on those findings for the purposes of considering FDA-approved therapies and clinical trial participation.”
 

Multiple alterations and resistance

The complex genetics of cancers has led researchers to explore combinations of targeted and other therapies to address multiple defects at the same time.

“Not surprisingly, the most common collision of multiple genetic alterations within the same tumor was in the commonly altered tumor suppressor genes: TP53, APC, and PTEN,” Dr. Flaherty said.

“An increasing body of evidence supports a role for loss-of-function alterations in these genes to confer resistance to many targeted therapies,” he added. “While we don’t have targeted therapies yet established to directly counter this form of therapeutic resistance, we hypothesize that various types of combination therapy may be able to indirectly undercut resistance and enhance the benefit of many targeted therapies.”

The NCI-MATCH researchers will continue to mine this large dataset to better understand the many small, genetically defined cancer subpopulations.

“We will continue to report the outcome of the individual treatment subprotocols, and combining this genetic analysis with those outcomes will likely inform the next clinical trials,” Dr. Flaherty said.
 

Actionable mutations make a difference

Precision oncology experts agree that NCI-MATCH results are impressive and add a fuller appreciation that actionable mutations make a clinical difference.

“This is a powerful, extremely well-designed study, a tour de force of collaborative science,” said Stephen Gruber, MD, PhD, director of the Center for Precision Medicine at City of Hope National Medical Center in Duarte, Calif.

“The future holds even more promise,” he added. “Our ability to interrogate the genomic landscape of cancer is improving rapidly. Tumor testing helps get the right drug to the right tumor faster than a guidelines-based approach from historical data of combination chemotherapy. This is a likely game changer for the way oncologists will practice in the future, especially as we learn more results of subset trials. The NCI-MATCH researchers have taken a laser-focused look at the current data, but we now know we can look far more comprehensively at genomic profiles of tumors.”

From the viewpoint of the practicing oncologist, co-occurring resistance mutations make a difference in defining what combinations are likely and, more importantly, less likely to be effective. “When we see two mutations and one is likely to confer resistance, we can make a choice to avoid a drug that is not likely to work,” Dr. Gruber said.

“The NCI-MATCH trial allows both approved and investigational agents, which expands the possibility of matching patients to newer agents. This is especially relevant if there are no FDA-approved drugs yet for some molecular aberrations,” said Lillian L. Siu, MD, a senior medical oncologist at the Princess Margaret Cancer Centre in Toronto. “This trial enables such evaluations under the auspice of a clinical trial to provide important knowledge.”

Both experts agree that in-depth biological interrogations of cancer will move the field of precision oncology forward. Dr. Gruber said that “studies have not yet fully addressed the power of germline genetic testing of DNA. Inherited susceptibility will drive therapeutic choices – for example, PARP inhibitors that access homologous recombination deficiency for breast, ovarian, and prostate cancer. We will learn more about treatment choices for those cancers.”

Dr. Siu added: “I truly believe that liquid biopsies [circulating tumor DNA] will help us perform target-drug matching in a less invasive way. We need to explore beyond the genome to look at the transcriptome, proteome, epigenome, and immunome, among others. It is likely that multiomic predictors are going to be able to identify more therapeutic options compared to single genomic predictors.”

Dr. Flaherty noted that all tumor samples from patients assigned to treatment are being subjected to whole-exome sequencing to further the discovery of the genetic features of responsive and nonresponsive tumors.

NCI-MATCH was funded by the National Cancer Institute. Dr. Flaherty disclosed relationships with Clovis Oncology, Loxo, X4 Pharma, and many other companies. His coauthors disclosed many conflicts as well. Dr. Gruber is cofounder of Brogent International. Dr. Siu disclosed relationships with Agios, Treadwell Therapeutics, Merck, Pfizer, and many other companies.

SOURCE: Flaherty KT et al. J Clin Oncol. 2020 Oct 13. doi: 10.1200/JCO.19.03010.

It’s not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs, compared with patients who weren’t taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking ACE inhibitors, but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

All study patients received PD-1/PD-L1 inhibitors, and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta), he explained.

“Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack,” Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor, but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT1 and AT2 receptors.

In contrast, ARBs block only the AT1 receptor and leave the AT2 counter-regulatory receptor alone, said Strauss.
 

More data, including on overall survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year OS rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT1 blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.
 

Hypothesis-generating study

Meeting cochair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting cochair, agreed with Calvo.

“Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate,” Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are National Cancer Institute employees. Calvo disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

It’s not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs, compared with patients who weren’t taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking ACE inhibitors, but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

All study patients received PD-1/PD-L1 inhibitors, and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta), he explained.

“Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack,” Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor, but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT1 and AT2 receptors.

In contrast, ARBs block only the AT1 receptor and leave the AT2 counter-regulatory receptor alone, said Strauss.
 

More data, including on overall survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year OS rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT1 blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.
 

Hypothesis-generating study

Meeting cochair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting cochair, agreed with Calvo.

“Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate,” Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are National Cancer Institute employees. Calvo disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

It’s not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs, compared with patients who weren’t taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking ACE inhibitors, but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute in Bethesda, Md.

All study patients received PD-1/PD-L1 inhibitors, and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor–beta (TGF-beta), he explained.

“Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack,” Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-beta through binding to the AT1 receptor, but has the opposite effect when it binds to the AT2 receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT1 and AT2 receptors.

In contrast, ARBs block only the AT1 receptor and leave the AT2 counter-regulatory receptor alone, said Strauss.
 

More data, including on overall survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year OS rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT1 blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.
 

Hypothesis-generating study

Meeting cochair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting cochair, agreed with Calvo.

“Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate,” Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are National Cancer Institute employees. Calvo disclosed no relevant financial relationships.

This article first appeared on Medscape.com.