TBD Meeting (4748-22)

Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.

A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.

“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.

Diagnostic delays can lead to diagnosis at more advanced stages. “That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.

The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.

The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).

Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.

“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.

Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.

The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.

He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.

Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.

Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.

A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.

“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.

Diagnostic delays can lead to diagnosis at more advanced stages. “That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.

The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.

The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).

Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.

“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.

Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.

The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.

He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.

Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.

Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.

A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.

“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.

Diagnostic delays can lead to diagnosis at more advanced stages. “That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.

The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.

The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).

Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.

“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.

Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.

The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.

He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.

Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.

PARIS – “It’s not just what you give, it’s when you give it,” said the investigator reporting “that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence.”

Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, Houston, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.

At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.

“Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma,” Dr. Patel commented.

She suggested that the explanation for the findings was that “inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells ... [and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors.”

The findings were presented during a presidential symposium at the European Society for Medical Oncology (ESMO) Congress 2022, Paris.

“This trial provides us with more evidence of when one strategy may be preferred over the other,” commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was not involved with the trial.

“Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy,” she told this news organization when approached for comment.

“As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy,” she said. However, she added that “we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.”

 

Details of the new results

The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.

The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group, compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).

“With a limited number of events, overall survival is not statistically different at this time,” Dr. Patel said. “Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm.”

The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors, including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.

Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
 

Questions remain

Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, noted that the study had “striking results” and was a landmark trial with a simple but powerful design.

However, he pointed to some questions which need to be addressed in the future. “One important question is what is the optimal duration of neoadjuvant treatment, and can we individualize it?”

Another question is just how much postoperative treatment is really needed and whether pathology help determine that. “Can surgery be safely avoided altogether?” he asked. “Another issue is the need for anti-CTL4 therapy – which patients might benefit from anti-CTL4, in addition to anti-PD-1?”

“And by extension, this paradigm provides a great platform for testing new agents, including combinations in cases where PD-1 is not sufficient to achieve a sufficient response,” said Dr. Larkin. “In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment.”

Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. “The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials,” said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia. “Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines.”

S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck’s anti-PD-1 therapy. Dr. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and InstilBio and running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – “It’s not just what you give, it’s when you give it,” said the investigator reporting “that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence.”

Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, Houston, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.

At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.

“Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma,” Dr. Patel commented.

She suggested that the explanation for the findings was that “inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells ... [and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors.”

The findings were presented during a presidential symposium at the European Society for Medical Oncology (ESMO) Congress 2022, Paris.

“This trial provides us with more evidence of when one strategy may be preferred over the other,” commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was not involved with the trial.

“Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy,” she told this news organization when approached for comment.

“As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy,” she said. However, she added that “we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.”

 

Details of the new results

The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.

The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group, compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).

“With a limited number of events, overall survival is not statistically different at this time,” Dr. Patel said. “Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm.”

The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors, including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.

Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
 

Questions remain

Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, noted that the study had “striking results” and was a landmark trial with a simple but powerful design.

However, he pointed to some questions which need to be addressed in the future. “One important question is what is the optimal duration of neoadjuvant treatment, and can we individualize it?”

Another question is just how much postoperative treatment is really needed and whether pathology help determine that. “Can surgery be safely avoided altogether?” he asked. “Another issue is the need for anti-CTL4 therapy – which patients might benefit from anti-CTL4, in addition to anti-PD-1?”

“And by extension, this paradigm provides a great platform for testing new agents, including combinations in cases where PD-1 is not sufficient to achieve a sufficient response,” said Dr. Larkin. “In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment.”

Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. “The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials,” said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia. “Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines.”

S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck’s anti-PD-1 therapy. Dr. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and InstilBio and running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – “It’s not just what you give, it’s when you give it,” said the investigator reporting “that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence.”

Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, Houston, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.

At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.

“Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma,” Dr. Patel commented.

She suggested that the explanation for the findings was that “inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells ... [and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors.”

The findings were presented during a presidential symposium at the European Society for Medical Oncology (ESMO) Congress 2022, Paris.

“This trial provides us with more evidence of when one strategy may be preferred over the other,” commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was not involved with the trial.

“Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy,” she told this news organization when approached for comment.

“As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy,” she said. However, she added that “we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.”

 

Details of the new results

The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.

The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group, compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).

“With a limited number of events, overall survival is not statistically different at this time,” Dr. Patel said. “Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm.”

The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors, including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.

Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
 

Questions remain

Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, noted that the study had “striking results” and was a landmark trial with a simple but powerful design.

However, he pointed to some questions which need to be addressed in the future. “One important question is what is the optimal duration of neoadjuvant treatment, and can we individualize it?”

Another question is just how much postoperative treatment is really needed and whether pathology help determine that. “Can surgery be safely avoided altogether?” he asked. “Another issue is the need for anti-CTL4 therapy – which patients might benefit from anti-CTL4, in addition to anti-PD-1?”

“And by extension, this paradigm provides a great platform for testing new agents, including combinations in cases where PD-1 is not sufficient to achieve a sufficient response,” said Dr. Larkin. “In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment.”

Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. “The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials,” said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia. “Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines.”

S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck’s anti-PD-1 therapy. Dr. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and InstilBio and running trials for them.

A version of this article first appeared on Medscape.com.

The immune checkpoint inhibitor nivolumab (Opdivo) appears to prevent the transformation of oral proliferative leukoplakia (PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.

“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston.

The research was presented at the European Society for Medical Oncology Annual Congress in Paris.

Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about  4% of the global population, Dr. Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.

While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Dr. Hanna said.

His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with greater than or equal to 2 multifocal lesions, or contiguous lesions of greater than or equal to 3 cm, or a single lesion greater than or equal to 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.

The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.

Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.

The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.

The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days and ranged from 29 to 171 days.

The overall response rate, defined as a greater than or equal to 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.

After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.

Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.

Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of greater than or equal to 1. A cutoff score of greater than or equal to 20 did not reveal any significant differences in cancer-free survival rates.

Turning to safety, Dr. Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.

The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).

With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Dr. Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti–PD-L1 blockade among patients with a high-risk oral precancerous disease.”

Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, who was not involved in the research, said these data were “very interesting,” but she expressed some reservations over the way the study was conducted.

She said that the composite score to measure response rates was “defined arbitrarily,” its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.

In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.

Consequently, Dr. Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.

The study was funded by Bristol Myers Squibb.

Dr. Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.

A version of this article first appeared on Medscape.com.

The immune checkpoint inhibitor nivolumab (Opdivo) appears to prevent the transformation of oral proliferative leukoplakia (PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.

“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston.

The research was presented at the European Society for Medical Oncology Annual Congress in Paris.

Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about  4% of the global population, Dr. Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.

While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Dr. Hanna said.

His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with greater than or equal to 2 multifocal lesions, or contiguous lesions of greater than or equal to 3 cm, or a single lesion greater than or equal to 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.

The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.

Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.

The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.

The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days and ranged from 29 to 171 days.

The overall response rate, defined as a greater than or equal to 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.

After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.

Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.

Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of greater than or equal to 1. A cutoff score of greater than or equal to 20 did not reveal any significant differences in cancer-free survival rates.

Turning to safety, Dr. Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.

The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).

With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Dr. Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti–PD-L1 blockade among patients with a high-risk oral precancerous disease.”

Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, who was not involved in the research, said these data were “very interesting,” but she expressed some reservations over the way the study was conducted.

She said that the composite score to measure response rates was “defined arbitrarily,” its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.

In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.

Consequently, Dr. Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.

The study was funded by Bristol Myers Squibb.

Dr. Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.

A version of this article first appeared on Medscape.com.

The immune checkpoint inhibitor nivolumab (Opdivo) appears to prevent the transformation of oral proliferative leukoplakia (PL), a high-risk precancerous disease, into oral cancer, suggest the results from a phase 2 study.

“We think that immunotherapy as a preventative strategy, either as first-line or even secondary prevention, should be further explored,” said lead researcher Glenn J. Hanna, MD, director, Center for Salivary and Rare Head and Neck Cancers, Dana-Farber Cancer Institute, Boston.

The research was presented at the European Society for Medical Oncology Annual Congress in Paris.

Oral leukoplakia refers to a white plaque of “questionable cancer risk” that affects about  4% of the global population, Dr. Hanna explained. However, about 5% of leukoplakia cases develop into oral proliferative leukoplakia, an aggressive form of the disease characterized by multifocal lesions. It has a high risk of transformation to oral squamous cell carcinoma (OSCC), at approaching 10% per year, and the 5-year cancer-free survival rate is estimated to be 47%.

While there are no effective therapies to prevent progression to oral cancer, the condition does have a “rich immune microenvironment,” potentially making it amenable to programmed death (PD)-1 blockade, Dr. Hanna said.

His team conducted a single-arm, phase 2 trial involving 33 patients with proliferative leukoplakia with greater than or equal to 2 multifocal lesions, or contiguous lesions of greater than or equal to 3 cm, or a single lesion greater than or equal to 4 cm with any degree of epithelial dysplasia. The median age was 63.2 years, and 55% were women. Just over half (52%) were never smokers.

The main disease subsite was the oral tongue in 39% of participants, followed by the buccal gingiva in 30%, and 24% of patients had a prior diagnosis of OSCC.

Following a pretreatment biopsy at one to three sites, the patients received four doses of nivolumab every 28 days, followed by rebiopsy. At each visit, the patients had intraoral photographs taken of the lesions and measurements taken.

The median time from study registration to the first dose of nivolumab was 9 days. The majority (88%) of patients completed all four doses of nivolumab.

The median time from the first dose of nivolumab to the posttreatment biopsy was 115 days and ranged from 29 to 171 days.

The overall response rate, defined as a greater than or equal to 40% decrease in a composite score combining the size and degree of dysplasia between the pre- and posttreatment assessments, was observed in 36.4% of patients.

After a median follow-up of 14.7 months, the median cancer-free survival was not reached, with cancer events recorded in 21.2% of patients. The median time from the last dose of nivolumab to the first OSCC event was 3.7 months.

Cancer-free survival at 1 year was calculated to be 77.7%, which was unchanged at 2 years. At the final follow-up, all patients were still alive.

Additional analysis of the biopsies revealed that the lesions had programmed death ligand 1 (PD-L1) combined positive scores that ranged from 0 to 80, with 66.7% of patients having a score of greater than or equal to 1. A cutoff score of greater than or equal to 20 did not reveal any significant differences in cancer-free survival rates.

Turning to safety, Dr. Hanna said that nivolumab was associated with “acceptable toxicity” in this “non-cancer population,” with 21.2% of patients experiencing a grade 3-4 adverse event.

The most common adverse events of any grade were fatigue (55%), diarrhea (27%), elevated alanine transaminase levels (18%), elevated aspartate transaminase levels (18%), and other skin disorders (18%).

With a relatively low rate of adverse events and a “clinical benefit” in up to a third of patients, Dr. Hanna said that this was the “first study to our knowledge to demonstrate the potential efficacy of anti–PD-L1 blockade among patients with a high-risk oral precancerous disease.”

Discussing this study at the meeting, Amanda Psyrri, MD, PhD, professor of medical oncology, Attikon University Hospital, Athens, who was not involved in the research, said these data were “very interesting,” but she expressed some reservations over the way the study was conducted.

She said that the composite score to measure response rates was “defined arbitrarily,” its prognostic value “has not been demonstrated,” and also pointed out that mixed responses by lesions within the same patient led to changes in scores.

In addition, the time interval between the end of treatment and lesion rebiopsy was “highly variable,” and the follow-up period was short.

Consequently, Dr. Psyrri believes the importance of the findings is “unclear,” especially as several patients who responded to nivolumab went on to develop cancer anyway, a finding that needs further investigation.

The study was funded by Bristol Myers Squibb.

Dr. Hanna declared relationships with BMS, Bicara, Exicure, Gateway for Cancer Research, GSK, Kite, NantKwest, Regeneron, Sanofi Genzyme, Maverick, and Merck.

A version of this article first appeared on Medscape.com.

PARIS – Cell therapies have already had a huge impact on the treatment of blood cancers, but progress in solid tumors has proved more difficult. Now, in a first multicenter randomized trial to compare the two, a novel cell therapy showed a superior outcome to immunotherapy in patients with advanced melanoma.

The cell therapy used in this trial was composed of adoptive tumor infiltrating lymphocytes (TIL), which were made individually for each patient, just as chimeric antigen receptor T cells (CAR T cells) are for patients with blood cancers. However, the process involved is somewhat different, as TILs are made from lymphocytes that have infiltrated the patient’s tumor and are obtained by surgery in the tumor, whereas CAR T cells are made from circulating blood cells. 

The phase 3 trial involved 168 patients with unresectable stage IIIC-4 melanoma and showed that patients who were treated with TILs achieved a significantly improved progression-free survival (PFS) when compared with standard immunotherapy with ipilimumab (Yervoy).

The median PFS was more than doubled to 7.2 months with TILs versus 3.1 months with ipilimumab (hazard ratio, 0.50; P < .001).

“We do think that TIL could possibly become a new treatment option for patients with advanced stage melanoma,” commented lead author John Haanen, MD, PhD, research group leader at the Netherlands Cancer Institute in Amsterdam and a professor in translational immunotherapy of cancer at Leiden (the Netherlands) University Medical Center.  

He presented the findings at a presidential symposium during the European Society for Medical Oncology Annual Congress, Paris.

“The results of this trial may fuel further research of TIL in other cancer types, potentially demonstrating benefit in many other solid tumors and expanding available treatments for patients,” said Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was approached for comment by this news organization and was not involved in the research.

Immune checkpoint inhibitors and targeted therapies have become the standard of care for advanced melanoma and greatly improved patient outcomes, she said. But as about half of patients treated with these agents will not achieve a durable benefit, there remains a need for new treatment options.

“Although immunotherapy can yield impressive long-term responses, a substantial percentage of patients will have no response, or no durable response, to checkpoint inhibitors,” said Dr. Dimitrova. “TIL therapy has proven effectiveness in melanoma. However, no phase III trials have been done to date to compare its effectiveness to a standard of care regimen.”

She noted that these results are consistent with past reports of an approximately 50% response rate with an impressive 20% complete response rate in the TIL group. Data from a phase 2 trial reported last year, for example, showed an objective response rate of 36.4%.

“It will be important to determine the persistence of antitumor activity and whether there are biomarkers that could help with patient selection given the resource intensity of the therapy,” Dr. Dimitrova said. “TIL therapy will likely become a new standard of care in metastatic melanoma refractory to immune checkpoint inhibitors.” 
 

Superior to immunotherapy

In the current study, Dr. Haanen and colleagues randomly assigned 168 patients to TIL or ipilimumab (3 mg/kg every 3 weeks, maximum 4 doses). Patients were stratified for BRAFV600 mutation status, treatment line and center, and the majority (86%) were refractory to anti–PD-1 treatment.

Patients in the TIL group underwent resection of a melanoma lesion (2-3 cm) for the ex vivo outgrowth and expansion of tumor-resident T cells. Before the cultured TILs were infused back into the patients from which they were made, the patient underwent nonmyeloablative, lymphodepleting chemotherapy with cyclophosphamide plus fludarabine that was followed by high-dose interleukin-2.

The study’s primary endpoint was progression-free survival, and secondary endpoints included overall and complete response rate, overall survival, and safety.

At a median follow-up of 33 months, TIL significantly improved progression-free survival, compared with ipilimumab. The overall response rate also favored TIL, compared with ipilimumab (49% vs. 21%), with 20% versus 7% complete responses, respectively.

The median overall survival was 25.8 months for TIL and 18.9 months for ipilimumab (HR, 0.83; P = 0.39).

Grade 3 or higher treatment-related adverse events occurred in all TIL and 57% of ipilimumab patients, although Dr. Haanen noted they were manageable and, in most cases, resolved by the time patients were discharged from the hospital.

“There were no new safety concerns with TIL,” said Dr. Haanen, “And these toxicities are driven by the chemotherapy and interleukin-2 that are part of the TIL regimen. There were no long-term sequelae in patients treated with TIL, and health-related quality of life was higher in patients treated with TIL.”
 

Ultra-personalized

Also commenting on the study, Anthony J. Olszanski, MD, RPh, associate professor and vice chair of clinical research, department of hematology/oncology at Fox Chase Cancer Center, Philadelphia, agreed that the treatment of patients with melanoma who do not respond to or progress after receiving treatment with immunotherapy is “challenging and represents an unmet need.”

“TIL therapy is, in some ways, ultra-personalized therapy, because we harvest immune cells from the patient’s tumor, expand them outside of the body, and then re-infuse them,” he said. “This trial, which randomized patients between TIL versus the CTLA-4 inhibitor, ipilimumab, has shown an impressive progression-free survival and overall response rate benefit and will help establish TIL therapy as a viable treatment strategy for some patients.”

The study was supported by the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society, and Capital Region of Denmark Research Foundation.

Dr. Haanen and several of the co-authors have declared multiple relationships with industry as noted in the abstract. Dr. Olszanski reports participation in advisory boards for BMS, Merck, and Instil Bio, and he reports running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – Cell therapies have already had a huge impact on the treatment of blood cancers, but progress in solid tumors has proved more difficult. Now, in a first multicenter randomized trial to compare the two, a novel cell therapy showed a superior outcome to immunotherapy in patients with advanced melanoma.

The cell therapy used in this trial was composed of adoptive tumor infiltrating lymphocytes (TIL), which were made individually for each patient, just as chimeric antigen receptor T cells (CAR T cells) are for patients with blood cancers. However, the process involved is somewhat different, as TILs are made from lymphocytes that have infiltrated the patient’s tumor and are obtained by surgery in the tumor, whereas CAR T cells are made from circulating blood cells. 

The phase 3 trial involved 168 patients with unresectable stage IIIC-4 melanoma and showed that patients who were treated with TILs achieved a significantly improved progression-free survival (PFS) when compared with standard immunotherapy with ipilimumab (Yervoy).

The median PFS was more than doubled to 7.2 months with TILs versus 3.1 months with ipilimumab (hazard ratio, 0.50; P < .001).

“We do think that TIL could possibly become a new treatment option for patients with advanced stage melanoma,” commented lead author John Haanen, MD, PhD, research group leader at the Netherlands Cancer Institute in Amsterdam and a professor in translational immunotherapy of cancer at Leiden (the Netherlands) University Medical Center.  

He presented the findings at a presidential symposium during the European Society for Medical Oncology Annual Congress, Paris.

“The results of this trial may fuel further research of TIL in other cancer types, potentially demonstrating benefit in many other solid tumors and expanding available treatments for patients,” said Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was approached for comment by this news organization and was not involved in the research.

Immune checkpoint inhibitors and targeted therapies have become the standard of care for advanced melanoma and greatly improved patient outcomes, she said. But as about half of patients treated with these agents will not achieve a durable benefit, there remains a need for new treatment options.

“Although immunotherapy can yield impressive long-term responses, a substantial percentage of patients will have no response, or no durable response, to checkpoint inhibitors,” said Dr. Dimitrova. “TIL therapy has proven effectiveness in melanoma. However, no phase III trials have been done to date to compare its effectiveness to a standard of care regimen.”

She noted that these results are consistent with past reports of an approximately 50% response rate with an impressive 20% complete response rate in the TIL group. Data from a phase 2 trial reported last year, for example, showed an objective response rate of 36.4%.

“It will be important to determine the persistence of antitumor activity and whether there are biomarkers that could help with patient selection given the resource intensity of the therapy,” Dr. Dimitrova said. “TIL therapy will likely become a new standard of care in metastatic melanoma refractory to immune checkpoint inhibitors.” 
 

Superior to immunotherapy

In the current study, Dr. Haanen and colleagues randomly assigned 168 patients to TIL or ipilimumab (3 mg/kg every 3 weeks, maximum 4 doses). Patients were stratified for BRAFV600 mutation status, treatment line and center, and the majority (86%) were refractory to anti–PD-1 treatment.

Patients in the TIL group underwent resection of a melanoma lesion (2-3 cm) for the ex vivo outgrowth and expansion of tumor-resident T cells. Before the cultured TILs were infused back into the patients from which they were made, the patient underwent nonmyeloablative, lymphodepleting chemotherapy with cyclophosphamide plus fludarabine that was followed by high-dose interleukin-2.

The study’s primary endpoint was progression-free survival, and secondary endpoints included overall and complete response rate, overall survival, and safety.

At a median follow-up of 33 months, TIL significantly improved progression-free survival, compared with ipilimumab. The overall response rate also favored TIL, compared with ipilimumab (49% vs. 21%), with 20% versus 7% complete responses, respectively.

The median overall survival was 25.8 months for TIL and 18.9 months for ipilimumab (HR, 0.83; P = 0.39).

Grade 3 or higher treatment-related adverse events occurred in all TIL and 57% of ipilimumab patients, although Dr. Haanen noted they were manageable and, in most cases, resolved by the time patients were discharged from the hospital.

“There were no new safety concerns with TIL,” said Dr. Haanen, “And these toxicities are driven by the chemotherapy and interleukin-2 that are part of the TIL regimen. There were no long-term sequelae in patients treated with TIL, and health-related quality of life was higher in patients treated with TIL.”
 

Ultra-personalized

Also commenting on the study, Anthony J. Olszanski, MD, RPh, associate professor and vice chair of clinical research, department of hematology/oncology at Fox Chase Cancer Center, Philadelphia, agreed that the treatment of patients with melanoma who do not respond to or progress after receiving treatment with immunotherapy is “challenging and represents an unmet need.”

“TIL therapy is, in some ways, ultra-personalized therapy, because we harvest immune cells from the patient’s tumor, expand them outside of the body, and then re-infuse them,” he said. “This trial, which randomized patients between TIL versus the CTLA-4 inhibitor, ipilimumab, has shown an impressive progression-free survival and overall response rate benefit and will help establish TIL therapy as a viable treatment strategy for some patients.”

The study was supported by the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society, and Capital Region of Denmark Research Foundation.

Dr. Haanen and several of the co-authors have declared multiple relationships with industry as noted in the abstract. Dr. Olszanski reports participation in advisory boards for BMS, Merck, and Instil Bio, and he reports running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – Cell therapies have already had a huge impact on the treatment of blood cancers, but progress in solid tumors has proved more difficult. Now, in a first multicenter randomized trial to compare the two, a novel cell therapy showed a superior outcome to immunotherapy in patients with advanced melanoma.

The cell therapy used in this trial was composed of adoptive tumor infiltrating lymphocytes (TIL), which were made individually for each patient, just as chimeric antigen receptor T cells (CAR T cells) are for patients with blood cancers. However, the process involved is somewhat different, as TILs are made from lymphocytes that have infiltrated the patient’s tumor and are obtained by surgery in the tumor, whereas CAR T cells are made from circulating blood cells. 

The phase 3 trial involved 168 patients with unresectable stage IIIC-4 melanoma and showed that patients who were treated with TILs achieved a significantly improved progression-free survival (PFS) when compared with standard immunotherapy with ipilimumab (Yervoy).

The median PFS was more than doubled to 7.2 months with TILs versus 3.1 months with ipilimumab (hazard ratio, 0.50; P < .001).

“We do think that TIL could possibly become a new treatment option for patients with advanced stage melanoma,” commented lead author John Haanen, MD, PhD, research group leader at the Netherlands Cancer Institute in Amsterdam and a professor in translational immunotherapy of cancer at Leiden (the Netherlands) University Medical Center.  

He presented the findings at a presidential symposium during the European Society for Medical Oncology Annual Congress, Paris.

“The results of this trial may fuel further research of TIL in other cancer types, potentially demonstrating benefit in many other solid tumors and expanding available treatments for patients,” said Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was approached for comment by this news organization and was not involved in the research.

Immune checkpoint inhibitors and targeted therapies have become the standard of care for advanced melanoma and greatly improved patient outcomes, she said. But as about half of patients treated with these agents will not achieve a durable benefit, there remains a need for new treatment options.

“Although immunotherapy can yield impressive long-term responses, a substantial percentage of patients will have no response, or no durable response, to checkpoint inhibitors,” said Dr. Dimitrova. “TIL therapy has proven effectiveness in melanoma. However, no phase III trials have been done to date to compare its effectiveness to a standard of care regimen.”

She noted that these results are consistent with past reports of an approximately 50% response rate with an impressive 20% complete response rate in the TIL group. Data from a phase 2 trial reported last year, for example, showed an objective response rate of 36.4%.

“It will be important to determine the persistence of antitumor activity and whether there are biomarkers that could help with patient selection given the resource intensity of the therapy,” Dr. Dimitrova said. “TIL therapy will likely become a new standard of care in metastatic melanoma refractory to immune checkpoint inhibitors.” 
 

Superior to immunotherapy

In the current study, Dr. Haanen and colleagues randomly assigned 168 patients to TIL or ipilimumab (3 mg/kg every 3 weeks, maximum 4 doses). Patients were stratified for BRAFV600 mutation status, treatment line and center, and the majority (86%) were refractory to anti–PD-1 treatment.

Patients in the TIL group underwent resection of a melanoma lesion (2-3 cm) for the ex vivo outgrowth and expansion of tumor-resident T cells. Before the cultured TILs were infused back into the patients from which they were made, the patient underwent nonmyeloablative, lymphodepleting chemotherapy with cyclophosphamide plus fludarabine that was followed by high-dose interleukin-2.

The study’s primary endpoint was progression-free survival, and secondary endpoints included overall and complete response rate, overall survival, and safety.

At a median follow-up of 33 months, TIL significantly improved progression-free survival, compared with ipilimumab. The overall response rate also favored TIL, compared with ipilimumab (49% vs. 21%), with 20% versus 7% complete responses, respectively.

The median overall survival was 25.8 months for TIL and 18.9 months for ipilimumab (HR, 0.83; P = 0.39).

Grade 3 or higher treatment-related adverse events occurred in all TIL and 57% of ipilimumab patients, although Dr. Haanen noted they were manageable and, in most cases, resolved by the time patients were discharged from the hospital.

“There were no new safety concerns with TIL,” said Dr. Haanen, “And these toxicities are driven by the chemotherapy and interleukin-2 that are part of the TIL regimen. There were no long-term sequelae in patients treated with TIL, and health-related quality of life was higher in patients treated with TIL.”
 

Ultra-personalized

Also commenting on the study, Anthony J. Olszanski, MD, RPh, associate professor and vice chair of clinical research, department of hematology/oncology at Fox Chase Cancer Center, Philadelphia, agreed that the treatment of patients with melanoma who do not respond to or progress after receiving treatment with immunotherapy is “challenging and represents an unmet need.”

“TIL therapy is, in some ways, ultra-personalized therapy, because we harvest immune cells from the patient’s tumor, expand them outside of the body, and then re-infuse them,” he said. “This trial, which randomized patients between TIL versus the CTLA-4 inhibitor, ipilimumab, has shown an impressive progression-free survival and overall response rate benefit and will help establish TIL therapy as a viable treatment strategy for some patients.”

The study was supported by the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society, and Capital Region of Denmark Research Foundation.

Dr. Haanen and several of the co-authors have declared multiple relationships with industry as noted in the abstract. Dr. Olszanski reports participation in advisory boards for BMS, Merck, and Instil Bio, and he reports running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – “Unprecedented” pathologic responses were seen after a neoadjuvant 4-week course of ipilimumab (Yervoy) plus nivolumab (Opdivo) was given before surgery to patients with DNA mismatch repair deficient (dMMR) colon cancer, say researchers reporting new results from the NICHE-2 trial.

The trial involved 112 patients with dMMR colon cancer who were given one cycle of low-dose ipilimumab and two cycles of nivolumab followed by surgery.

The results show that 95% of patients had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR) to immunotherapy.

To date, none of these patients have had disease recurrence after a median follow-up of 13.1 months.

Study presenter Myriam Chalabi, MD, an oncologist at the Netherlands Cancer Institute, Amsterdam, described the findings as “unprecedented,” especially as many of the patients had stage 3 and high-risk disease, and the expected disease recurrence rate with standard-of-care adjuvant chemotherapy in these patients would usually have been around 15%.

“Importantly, this treatment was very well-tolerated,” she added.

Dr. Chalabi presented the new results during a presidential session at the European Society for Medical Oncology Congress 2022, held in Paris.

Neoadjuvant immunotherapy “has the potential to become standard of care” in these patients, she said, adding that the “future has never been brighter” for dMMR colon cancer.

Around 10%-15% of colon cancers are dMMR, and around 33% of these are associated with Lynch syndrome, she noted.

She also urged pharmaceutical companies to seek approval for immunotherapy in this patient population, to warm applause from the audience.

Commenting on the results, Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, said in an ESMO press release that the “innovative” study “questions the need for surgery and postoperative chemotherapy in all patients in whom the primary tumor has disappeared.”

He observed that adjuvant chemotherapy has remained standard of care, “despite the fact that chemotherapy is not so active, and a complete disappearance of the tumor in the surgical specimen is not observed.”

Overall, Dr. Cervantes said that dMMR status is a “strong predictor of the positive effect observed with this short-course immunotherapy,” adding that “determining dMMR can be easily done by immunohistochemistry in the conventional pathology lab, without the need for complex molecular testing.”

The “minimal toxicity” seen in the study “may also facilitate the implementation of this strategy, potentially sparing patients from surgery.”
 

Details of the new results

For the NICHE-2 study, patients with stage cT3 dMMR colon cancer and/or nodal involvement but without metastases and no signs of obstruction received one dose of ipilimumab 1 mg/kg and two doses of nivolumab 3 mg/kg before undergoing surgery within 6 weeks of enrollment.

The 112 participants were a median age of 60 years, and just over half were women. High-risk stage 3 disease was present in 74% of patients, which included 64% of patients with clinical T4a or T4b tumors and 62% with radiologic N2 stage cancer.

Median time from the first immunotherapy dose to surgery was 5.4 weeks.

Immune-related adverse events were seen in 61% of patients, but just 4% of patients experienced grade 3-4 immune-related adverse events, and 2% consequently had a delay in surgery, meaning the study met its primary safety endpoint.

In the end, all patients underwent surgery, with 100% having R0 resections.

A pathologic response was seen in 99% of patients, with 95% having an MPR, defined as less than or equal to 10% residual viable tumor, and 4% a partial response, defined as 10% to less than or equal to 50% residual viable tumor. A pCR, which included both the tumor bed and lymph nodes, was seen in 67% of participants.

There was a borderline significant difference in pCR patients between the 66 patients with sporadic tumors and the 32 with Lynch syndrome, at 58% versus 78% (P = .056).

At the meeting, discussant James Larkin, MD, PhD, consultant medical oncologist, The Royal Marsden, London, who was not involved with the study, agreed that the results were “striking,” with “brief treatment ... [showing] a major effect.”

However, he emphasized that it will be “important” to see the prespecified 3-year disease-free survival data, and he questioned whether the single low dose of ipilimumab was, in fact, necessary.

Dr. Larkin also emphasized that organ-sparing strategies in colon cancer are less “clear cut” than they are in rectal cancer and would require ongoing follow-up with colonoscopies and, potentially, biopsies. He also said it is “critical” to get patients’ views on the desirability of organ sparing.

The study was funded by Bristol Myers Squibb. Dr. Chalabi has reported no financial interests. Disclosures for the other authors are listed with the abstract. Dr. Larkin has declared relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ibsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics.

A version of this article first appeared on Medscape.com.

PARIS – “Unprecedented” pathologic responses were seen after a neoadjuvant 4-week course of ipilimumab (Yervoy) plus nivolumab (Opdivo) was given before surgery to patients with DNA mismatch repair deficient (dMMR) colon cancer, say researchers reporting new results from the NICHE-2 trial.

The trial involved 112 patients with dMMR colon cancer who were given one cycle of low-dose ipilimumab and two cycles of nivolumab followed by surgery.

The results show that 95% of patients had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR) to immunotherapy.

To date, none of these patients have had disease recurrence after a median follow-up of 13.1 months.

Study presenter Myriam Chalabi, MD, an oncologist at the Netherlands Cancer Institute, Amsterdam, described the findings as “unprecedented,” especially as many of the patients had stage 3 and high-risk disease, and the expected disease recurrence rate with standard-of-care adjuvant chemotherapy in these patients would usually have been around 15%.

“Importantly, this treatment was very well-tolerated,” she added.

Dr. Chalabi presented the new results during a presidential session at the European Society for Medical Oncology Congress 2022, held in Paris.

Neoadjuvant immunotherapy “has the potential to become standard of care” in these patients, she said, adding that the “future has never been brighter” for dMMR colon cancer.

Around 10%-15% of colon cancers are dMMR, and around 33% of these are associated with Lynch syndrome, she noted.

She also urged pharmaceutical companies to seek approval for immunotherapy in this patient population, to warm applause from the audience.

Commenting on the results, Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, said in an ESMO press release that the “innovative” study “questions the need for surgery and postoperative chemotherapy in all patients in whom the primary tumor has disappeared.”

He observed that adjuvant chemotherapy has remained standard of care, “despite the fact that chemotherapy is not so active, and a complete disappearance of the tumor in the surgical specimen is not observed.”

Overall, Dr. Cervantes said that dMMR status is a “strong predictor of the positive effect observed with this short-course immunotherapy,” adding that “determining dMMR can be easily done by immunohistochemistry in the conventional pathology lab, without the need for complex molecular testing.”

The “minimal toxicity” seen in the study “may also facilitate the implementation of this strategy, potentially sparing patients from surgery.”
 

Details of the new results

For the NICHE-2 study, patients with stage cT3 dMMR colon cancer and/or nodal involvement but without metastases and no signs of obstruction received one dose of ipilimumab 1 mg/kg and two doses of nivolumab 3 mg/kg before undergoing surgery within 6 weeks of enrollment.

The 112 participants were a median age of 60 years, and just over half were women. High-risk stage 3 disease was present in 74% of patients, which included 64% of patients with clinical T4a or T4b tumors and 62% with radiologic N2 stage cancer.

Median time from the first immunotherapy dose to surgery was 5.4 weeks.

Immune-related adverse events were seen in 61% of patients, but just 4% of patients experienced grade 3-4 immune-related adverse events, and 2% consequently had a delay in surgery, meaning the study met its primary safety endpoint.

In the end, all patients underwent surgery, with 100% having R0 resections.

A pathologic response was seen in 99% of patients, with 95% having an MPR, defined as less than or equal to 10% residual viable tumor, and 4% a partial response, defined as 10% to less than or equal to 50% residual viable tumor. A pCR, which included both the tumor bed and lymph nodes, was seen in 67% of participants.

There was a borderline significant difference in pCR patients between the 66 patients with sporadic tumors and the 32 with Lynch syndrome, at 58% versus 78% (P = .056).

At the meeting, discussant James Larkin, MD, PhD, consultant medical oncologist, The Royal Marsden, London, who was not involved with the study, agreed that the results were “striking,” with “brief treatment ... [showing] a major effect.”

However, he emphasized that it will be “important” to see the prespecified 3-year disease-free survival data, and he questioned whether the single low dose of ipilimumab was, in fact, necessary.

Dr. Larkin also emphasized that organ-sparing strategies in colon cancer are less “clear cut” than they are in rectal cancer and would require ongoing follow-up with colonoscopies and, potentially, biopsies. He also said it is “critical” to get patients’ views on the desirability of organ sparing.

The study was funded by Bristol Myers Squibb. Dr. Chalabi has reported no financial interests. Disclosures for the other authors are listed with the abstract. Dr. Larkin has declared relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ibsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics.

A version of this article first appeared on Medscape.com.

PARIS – “Unprecedented” pathologic responses were seen after a neoadjuvant 4-week course of ipilimumab (Yervoy) plus nivolumab (Opdivo) was given before surgery to patients with DNA mismatch repair deficient (dMMR) colon cancer, say researchers reporting new results from the NICHE-2 trial.

The trial involved 112 patients with dMMR colon cancer who were given one cycle of low-dose ipilimumab and two cycles of nivolumab followed by surgery.

The results show that 95% of patients had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR) to immunotherapy.

To date, none of these patients have had disease recurrence after a median follow-up of 13.1 months.

Study presenter Myriam Chalabi, MD, an oncologist at the Netherlands Cancer Institute, Amsterdam, described the findings as “unprecedented,” especially as many of the patients had stage 3 and high-risk disease, and the expected disease recurrence rate with standard-of-care adjuvant chemotherapy in these patients would usually have been around 15%.

“Importantly, this treatment was very well-tolerated,” she added.

Dr. Chalabi presented the new results during a presidential session at the European Society for Medical Oncology Congress 2022, held in Paris.

Neoadjuvant immunotherapy “has the potential to become standard of care” in these patients, she said, adding that the “future has never been brighter” for dMMR colon cancer.

Around 10%-15% of colon cancers are dMMR, and around 33% of these are associated with Lynch syndrome, she noted.

She also urged pharmaceutical companies to seek approval for immunotherapy in this patient population, to warm applause from the audience.

Commenting on the results, Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, said in an ESMO press release that the “innovative” study “questions the need for surgery and postoperative chemotherapy in all patients in whom the primary tumor has disappeared.”

He observed that adjuvant chemotherapy has remained standard of care, “despite the fact that chemotherapy is not so active, and a complete disappearance of the tumor in the surgical specimen is not observed.”

Overall, Dr. Cervantes said that dMMR status is a “strong predictor of the positive effect observed with this short-course immunotherapy,” adding that “determining dMMR can be easily done by immunohistochemistry in the conventional pathology lab, without the need for complex molecular testing.”

The “minimal toxicity” seen in the study “may also facilitate the implementation of this strategy, potentially sparing patients from surgery.”
 

Details of the new results

For the NICHE-2 study, patients with stage cT3 dMMR colon cancer and/or nodal involvement but without metastases and no signs of obstruction received one dose of ipilimumab 1 mg/kg and two doses of nivolumab 3 mg/kg before undergoing surgery within 6 weeks of enrollment.

The 112 participants were a median age of 60 years, and just over half were women. High-risk stage 3 disease was present in 74% of patients, which included 64% of patients with clinical T4a or T4b tumors and 62% with radiologic N2 stage cancer.

Median time from the first immunotherapy dose to surgery was 5.4 weeks.

Immune-related adverse events were seen in 61% of patients, but just 4% of patients experienced grade 3-4 immune-related adverse events, and 2% consequently had a delay in surgery, meaning the study met its primary safety endpoint.

In the end, all patients underwent surgery, with 100% having R0 resections.

A pathologic response was seen in 99% of patients, with 95% having an MPR, defined as less than or equal to 10% residual viable tumor, and 4% a partial response, defined as 10% to less than or equal to 50% residual viable tumor. A pCR, which included both the tumor bed and lymph nodes, was seen in 67% of participants.

There was a borderline significant difference in pCR patients between the 66 patients with sporadic tumors and the 32 with Lynch syndrome, at 58% versus 78% (P = .056).

At the meeting, discussant James Larkin, MD, PhD, consultant medical oncologist, The Royal Marsden, London, who was not involved with the study, agreed that the results were “striking,” with “brief treatment ... [showing] a major effect.”

However, he emphasized that it will be “important” to see the prespecified 3-year disease-free survival data, and he questioned whether the single low dose of ipilimumab was, in fact, necessary.

Dr. Larkin also emphasized that organ-sparing strategies in colon cancer are less “clear cut” than they are in rectal cancer and would require ongoing follow-up with colonoscopies and, potentially, biopsies. He also said it is “critical” to get patients’ views on the desirability of organ sparing.

The study was funded by Bristol Myers Squibb. Dr. Chalabi has reported no financial interests. Disclosures for the other authors are listed with the abstract. Dr. Larkin has declared relationships with Eisai, Novartis, Merck, Pfizer, BMS, iOnctura, Debiopharm, Incyte, MSD, Pierre Fabre, Ibsen, Roche, EUSA Pharma, AstraZeneca, GSK, Calithera, Ultimovacs, Seagen, and Nektar Therapeutics.

A version of this article first appeared on Medscape.com.

PARIS – Adding pembrolizumab (Keytruda) to chemoradiotherapy did not significantly improve event-free survival, compared with CRT plus placebo as first-line therapy for patients with locally advanced head and neck squamous cell cancers (HNSCC), reported investigators of the KEYNOTE-412 trial.

Among 804 patients with newly diagnosed, pathologically proven, unresected locally advanced head and neck squamous cell carcinomas who were followed for a median of 47.7 months, the event-free survival (EFS) rate with the pembrolizumab/CRT combination followed by maintenance pembrolizumab was 63.2%, compared with 56.2% for CRT plus placebo. This translated into a nonsignificant hazard ratio of 0.83, said Jean-Pascal Machiels, MD, PhD, at the annual meeting of the European Society for Medical Oncology.

Despite the trial failing to meet its primary endpoint, Dr. Machiels expressed optimism about the results.

“Pembrolizumab with chemoradiation was associated with a favorable trend toward improved event-free survival versus placebo plus chemoradiation in patients with locally advanced head and neck cancer,” he said.

He noted that the 2-year EFS rate was 63% with pembrolizumab, compared with 56% with placebo.

The data also support the hypothesis that programmed death–ligand 1 (PD-L1) expression as measured by a combined positive score (CPS) could be a predictive biomarker for identifying those patients most likely to respond to the immune checkpoint inhibitor, he added.

KEYNOTE-412 details

The rationale for combining the checkpoint inhibitors pembrolizumab with chemoradiotherapy comes from the KEYNOTE-048 trial results of which showed a survival improvement for the use of pembrolizumab plus a platinum-containing regimen as a first-line therapy for recurrent or metastatic HNSCC, as well as pembrolizumab monotherapy for patients with PD-L1 CPS of 1 or greater.

In the current study, Dr. Machiels and colleagues studied whether adding pembrolizumab to CRT could benefit patients with treatment-naive unresected, locally advanced HNSCC.

Eligible patients included those with stage T3 or T4, N0-N3 or any N2a-3 (T1-T4) cancers of the larynx, hypopharynx, or oral cavity, and either p16-negative oropharynx cancers or T4 or N3 p16-positive oropharynx cancer. Patients were required to be eligible for high-dose cisplatin-based CRT.

A total of 804 patients were randomized, 402 in each arm, to receive either pembrolizumab 200 mg intravenously every 3 weeks for 3 cycles plus CRT followed by maintenance pembrolizumab for 14 cycles, or to placebo plus CRT followed by placebo maintenance.

As noted before, there was no significant difference between the study arms for the primary endpoint of EFS. The 24-month EFS rate was 63.2% for the pembrolizumab group, compared with 56.2% for controls. The respective 6-month EFS rates were 57.4% versus 52.1%.­

In a post hoc analysis, both EFS and overall survival were numerically with pembrolizumab among patients with PD-L1 CPS of 20 or greater. The respective 2- and 3-year EFS rates were 71.2% versus 62.6%, and 66.7% versus 57.2%.

The 24-months overall survival rates were 83.3% with pembrolizumab and 79.9% with placebo, and 36-month rates were 79.1% and 73%, respectively.

Neither EFS rates nor OS rates among patients in this subgroup differed significantly; however, there were no new safety signals with the combination, Dr. Machiels said. The incidence of grade 3 or greater adverse events was 92.2% in the pembrolizumab arm versus 88.4% in the placebo arm. Four patients in the pembrolizumab arm and six in the control arm died from treatment-related causes.
 

Benefit still to be proven

In a media briefing held prior to his presentation, Dr. Machiels was asked how he could justify his conclusions about a benefit for adding pembrolizumab given that there was no difference between the treatment groups for the primary endpoint.

He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed, and that if it had been they might have designed the trial to explore the effect of the pembrolizumab chemoradiation combination according to CPS subgroups.

He also pointed to the numerically superior 2-year EFS and overall rates.

In the presidential symposium, James Larkin, MD, PhD, an invited discussant from the Royal Marsden Hospital, London, said that chemotherapy and anti–PD-1 therapies are known to offer benefit in advanced cancers despite the trial’s failure.

“There is a signal, particularly as we’ve seen in the high PD-L1 group,” he said, noting that the signal was consistent with that seen in the JAVELIN 100 study, which was also a negative trial. He cautioned against relying too heavily on the comparison, however, as JAVELIN 100 was conducted with avelumab, a PD-L1 inhibitor, whereas pembrolizumab is a PD-1 inhibitor.

“Could there be an issue here with treatment schedule? An example and a comparison might be the PACIFIC study in non–small cell lung cancer, which is a positive trial, where actually the checkpoint inhibit with durvalumab was given immediately after the chemoradiotherapy, leading to benefit, rather than being concurrent,” he said.

Dr. Larkin also questioned whether, as codiscussant Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Center, Melbourne, suggested radiotherapy to lymph nodes might alter the immune response to checkpoint inhibitors.

“Clearly radiotherapy is the central component of treatment in this setting, so it would be quite difficult to scale too much on that, but the question is: ‘Could it be modified?’ For example, just to irradiate the primary tumor and involved lymph nodes and potentially spare noninvolved lymph nodes,” he said.

The KEYNOTE-412 study was funded by Merck Sharp & Dohme. Dr. Machiels reported uncompensated consulting to the company. Dr. Larkin reported consulting for and receiving honoraria from Merck and others. Dr. Loi reported uncompensated advisory board activity for Merck and others.

PARIS – Adding pembrolizumab (Keytruda) to chemoradiotherapy did not significantly improve event-free survival, compared with CRT plus placebo as first-line therapy for patients with locally advanced head and neck squamous cell cancers (HNSCC), reported investigators of the KEYNOTE-412 trial.

Among 804 patients with newly diagnosed, pathologically proven, unresected locally advanced head and neck squamous cell carcinomas who were followed for a median of 47.7 months, the event-free survival (EFS) rate with the pembrolizumab/CRT combination followed by maintenance pembrolizumab was 63.2%, compared with 56.2% for CRT plus placebo. This translated into a nonsignificant hazard ratio of 0.83, said Jean-Pascal Machiels, MD, PhD, at the annual meeting of the European Society for Medical Oncology.

Despite the trial failing to meet its primary endpoint, Dr. Machiels expressed optimism about the results.

“Pembrolizumab with chemoradiation was associated with a favorable trend toward improved event-free survival versus placebo plus chemoradiation in patients with locally advanced head and neck cancer,” he said.

He noted that the 2-year EFS rate was 63% with pembrolizumab, compared with 56% with placebo.

The data also support the hypothesis that programmed death–ligand 1 (PD-L1) expression as measured by a combined positive score (CPS) could be a predictive biomarker for identifying those patients most likely to respond to the immune checkpoint inhibitor, he added.

KEYNOTE-412 details

The rationale for combining the checkpoint inhibitors pembrolizumab with chemoradiotherapy comes from the KEYNOTE-048 trial results of which showed a survival improvement for the use of pembrolizumab plus a platinum-containing regimen as a first-line therapy for recurrent or metastatic HNSCC, as well as pembrolizumab monotherapy for patients with PD-L1 CPS of 1 or greater.

In the current study, Dr. Machiels and colleagues studied whether adding pembrolizumab to CRT could benefit patients with treatment-naive unresected, locally advanced HNSCC.

Eligible patients included those with stage T3 or T4, N0-N3 or any N2a-3 (T1-T4) cancers of the larynx, hypopharynx, or oral cavity, and either p16-negative oropharynx cancers or T4 or N3 p16-positive oropharynx cancer. Patients were required to be eligible for high-dose cisplatin-based CRT.

A total of 804 patients were randomized, 402 in each arm, to receive either pembrolizumab 200 mg intravenously every 3 weeks for 3 cycles plus CRT followed by maintenance pembrolizumab for 14 cycles, or to placebo plus CRT followed by placebo maintenance.

As noted before, there was no significant difference between the study arms for the primary endpoint of EFS. The 24-month EFS rate was 63.2% for the pembrolizumab group, compared with 56.2% for controls. The respective 6-month EFS rates were 57.4% versus 52.1%.­

In a post hoc analysis, both EFS and overall survival were numerically with pembrolizumab among patients with PD-L1 CPS of 20 or greater. The respective 2- and 3-year EFS rates were 71.2% versus 62.6%, and 66.7% versus 57.2%.

The 24-months overall survival rates were 83.3% with pembrolizumab and 79.9% with placebo, and 36-month rates were 79.1% and 73%, respectively.

Neither EFS rates nor OS rates among patients in this subgroup differed significantly; however, there were no new safety signals with the combination, Dr. Machiels said. The incidence of grade 3 or greater adverse events was 92.2% in the pembrolizumab arm versus 88.4% in the placebo arm. Four patients in the pembrolizumab arm and six in the control arm died from treatment-related causes.
 

Benefit still to be proven

In a media briefing held prior to his presentation, Dr. Machiels was asked how he could justify his conclusions about a benefit for adding pembrolizumab given that there was no difference between the treatment groups for the primary endpoint.

He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed, and that if it had been they might have designed the trial to explore the effect of the pembrolizumab chemoradiation combination according to CPS subgroups.

He also pointed to the numerically superior 2-year EFS and overall rates.

In the presidential symposium, James Larkin, MD, PhD, an invited discussant from the Royal Marsden Hospital, London, said that chemotherapy and anti–PD-1 therapies are known to offer benefit in advanced cancers despite the trial’s failure.

“There is a signal, particularly as we’ve seen in the high PD-L1 group,” he said, noting that the signal was consistent with that seen in the JAVELIN 100 study, which was also a negative trial. He cautioned against relying too heavily on the comparison, however, as JAVELIN 100 was conducted with avelumab, a PD-L1 inhibitor, whereas pembrolizumab is a PD-1 inhibitor.

“Could there be an issue here with treatment schedule? An example and a comparison might be the PACIFIC study in non–small cell lung cancer, which is a positive trial, where actually the checkpoint inhibit with durvalumab was given immediately after the chemoradiotherapy, leading to benefit, rather than being concurrent,” he said.

Dr. Larkin also questioned whether, as codiscussant Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Center, Melbourne, suggested radiotherapy to lymph nodes might alter the immune response to checkpoint inhibitors.

“Clearly radiotherapy is the central component of treatment in this setting, so it would be quite difficult to scale too much on that, but the question is: ‘Could it be modified?’ For example, just to irradiate the primary tumor and involved lymph nodes and potentially spare noninvolved lymph nodes,” he said.

The KEYNOTE-412 study was funded by Merck Sharp & Dohme. Dr. Machiels reported uncompensated consulting to the company. Dr. Larkin reported consulting for and receiving honoraria from Merck and others. Dr. Loi reported uncompensated advisory board activity for Merck and others.

PARIS – Adding pembrolizumab (Keytruda) to chemoradiotherapy did not significantly improve event-free survival, compared with CRT plus placebo as first-line therapy for patients with locally advanced head and neck squamous cell cancers (HNSCC), reported investigators of the KEYNOTE-412 trial.

Among 804 patients with newly diagnosed, pathologically proven, unresected locally advanced head and neck squamous cell carcinomas who were followed for a median of 47.7 months, the event-free survival (EFS) rate with the pembrolizumab/CRT combination followed by maintenance pembrolizumab was 63.2%, compared with 56.2% for CRT plus placebo. This translated into a nonsignificant hazard ratio of 0.83, said Jean-Pascal Machiels, MD, PhD, at the annual meeting of the European Society for Medical Oncology.

Despite the trial failing to meet its primary endpoint, Dr. Machiels expressed optimism about the results.

“Pembrolizumab with chemoradiation was associated with a favorable trend toward improved event-free survival versus placebo plus chemoradiation in patients with locally advanced head and neck cancer,” he said.

He noted that the 2-year EFS rate was 63% with pembrolizumab, compared with 56% with placebo.

The data also support the hypothesis that programmed death–ligand 1 (PD-L1) expression as measured by a combined positive score (CPS) could be a predictive biomarker for identifying those patients most likely to respond to the immune checkpoint inhibitor, he added.

KEYNOTE-412 details

The rationale for combining the checkpoint inhibitors pembrolizumab with chemoradiotherapy comes from the KEYNOTE-048 trial results of which showed a survival improvement for the use of pembrolizumab plus a platinum-containing regimen as a first-line therapy for recurrent or metastatic HNSCC, as well as pembrolizumab monotherapy for patients with PD-L1 CPS of 1 or greater.

In the current study, Dr. Machiels and colleagues studied whether adding pembrolizumab to CRT could benefit patients with treatment-naive unresected, locally advanced HNSCC.

Eligible patients included those with stage T3 or T4, N0-N3 or any N2a-3 (T1-T4) cancers of the larynx, hypopharynx, or oral cavity, and either p16-negative oropharynx cancers or T4 or N3 p16-positive oropharynx cancer. Patients were required to be eligible for high-dose cisplatin-based CRT.

A total of 804 patients were randomized, 402 in each arm, to receive either pembrolizumab 200 mg intravenously every 3 weeks for 3 cycles plus CRT followed by maintenance pembrolizumab for 14 cycles, or to placebo plus CRT followed by placebo maintenance.

As noted before, there was no significant difference between the study arms for the primary endpoint of EFS. The 24-month EFS rate was 63.2% for the pembrolizumab group, compared with 56.2% for controls. The respective 6-month EFS rates were 57.4% versus 52.1%.­

In a post hoc analysis, both EFS and overall survival were numerically with pembrolizumab among patients with PD-L1 CPS of 20 or greater. The respective 2- and 3-year EFS rates were 71.2% versus 62.6%, and 66.7% versus 57.2%.

The 24-months overall survival rates were 83.3% with pembrolizumab and 79.9% with placebo, and 36-month rates were 79.1% and 73%, respectively.

Neither EFS rates nor OS rates among patients in this subgroup differed significantly; however, there were no new safety signals with the combination, Dr. Machiels said. The incidence of grade 3 or greater adverse events was 92.2% in the pembrolizumab arm versus 88.4% in the placebo arm. Four patients in the pembrolizumab arm and six in the control arm died from treatment-related causes.
 

Benefit still to be proven

In a media briefing held prior to his presentation, Dr. Machiels was asked how he could justify his conclusions about a benefit for adding pembrolizumab given that there was no difference between the treatment groups for the primary endpoint.

He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed, and that if it had been they might have designed the trial to explore the effect of the pembrolizumab chemoradiation combination according to CPS subgroups.

He also pointed to the numerically superior 2-year EFS and overall rates.

In the presidential symposium, James Larkin, MD, PhD, an invited discussant from the Royal Marsden Hospital, London, said that chemotherapy and anti–PD-1 therapies are known to offer benefit in advanced cancers despite the trial’s failure.

“There is a signal, particularly as we’ve seen in the high PD-L1 group,” he said, noting that the signal was consistent with that seen in the JAVELIN 100 study, which was also a negative trial. He cautioned against relying too heavily on the comparison, however, as JAVELIN 100 was conducted with avelumab, a PD-L1 inhibitor, whereas pembrolizumab is a PD-1 inhibitor.

“Could there be an issue here with treatment schedule? An example and a comparison might be the PACIFIC study in non–small cell lung cancer, which is a positive trial, where actually the checkpoint inhibit with durvalumab was given immediately after the chemoradiotherapy, leading to benefit, rather than being concurrent,” he said.

Dr. Larkin also questioned whether, as codiscussant Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Center, Melbourne, suggested radiotherapy to lymph nodes might alter the immune response to checkpoint inhibitors.

“Clearly radiotherapy is the central component of treatment in this setting, so it would be quite difficult to scale too much on that, but the question is: ‘Could it be modified?’ For example, just to irradiate the primary tumor and involved lymph nodes and potentially spare noninvolved lymph nodes,” he said.

The KEYNOTE-412 study was funded by Merck Sharp & Dohme. Dr. Machiels reported uncompensated consulting to the company. Dr. Larkin reported consulting for and receiving honoraria from Merck and others. Dr. Loi reported uncompensated advisory board activity for Merck and others.

In non–small cell lung cancer (NSCLC), mutations to the epidermal growth factor receptor (EGFR) gene are generally associated with a poor response to immune checkpoint inhibitor (ICI) therapies. However, there is a range of different EGFR mutations, and different mutation combinations can lead to different tumor characteristics that might in turn affect response to therapy.

A new real-world analysis of 159 NSCLC patients found that a combination of a mutation of the TP53 tumor suppressor gene and the EGFR Ex20 mutation is associated with worse disease outcomes, compared to patients with the EGFR Ex20 mutation alone. But the news wasn’t all bad. The same group of patients also responded better to ICB (immune checkpoint blockade) therapy than did the broader population of EGFR Ex20 patients.

The EGFR Ex20 mutation occurs in about 4% of NSCLC cases, while TP53 is quite common: The new study found a frequency of 43.9%. “We first have to mention that the findings regarding TP53 do not reach statistical significance; however, the trend is very strong, and results might be hampered due to small sample sizes. We think it is [appropriate] to exhaust more treatment options for these patients, especially targeted approaches with newer drugs that specifically target exon 20 insertions, as these drugs were not applied in our cohort,” Anna Kron, Dr. rer. medic., said in an email exchange. Dr. Kron presented the results at a poster session in Paris at the ESMO Congress. She is a researcher at University Hospital of Cologne, Germany.

The ImmunoTarget study, published in 2019, examined over 500 NSCLC patients with a range of driver mutations including EGFR and found that they responded poorly to ICIs in comparison to KRAS mutations.

But Dr. Kron’s group was not convinced. “Ex20 mutations differ clinically from other tyrosine kinase mutations in EGFR. We set out this study to rechallenge the paradigm of impaired benefit from ICI in EGFR-mutated patients, as we consider these mutations not interchangeable with other EGFR mutations,” Dr. Kron said.

“We would postulate that in EGFR Exon 20 mutations, ICI and specific inhibitors should be part of the therapeutic course. In patients with co-occurring TP53 mutations, treatment escalation could be considered,” Dr. Kron said.

The study included 159 patients with advanced NSCLC with the EGFR exon 20 insertion, who were treated between 2014 and 2020 at German hospitals. Among the patients, 37.7% were female; mean age at diagnosis was 65.87 years; 50.3% had a smoking history and 38.4% did not (data were unavailable for the rest); and 9.4% of tumors were stage I, 4.4% stage II, 8.2% stage IIIA, 3.8% stage IIIB, and 74.2% stage IV.

Over a follow-up of 4.1 years, there was a trend toward longer survival among patients with TP53 wild type (OS, 20 versus 12 months; P = .092). Sixty-six patients who received ICI therapy had better OS compared with those who did not (22 versus 10 months; P = .018). Among patients with co-occurring TP53 mutations, receipt of ICI therapy was associated with longer OS (16 versus 8 months; P = .048). There was a trend toward patients with TP53 wild type treated with ICI faring better than those who didn’t receive ICI (27.0 months versus 11.0 months; P = .109).

The researchers are continuing to study patients with EGFR Ex20 to better understand the role of TP53 and ICI therapy in these patients.

The study received no funding. Dr. Kron has no relevant financial disclosures.

In non–small cell lung cancer (NSCLC), mutations to the epidermal growth factor receptor (EGFR) gene are generally associated with a poor response to immune checkpoint inhibitor (ICI) therapies. However, there is a range of different EGFR mutations, and different mutation combinations can lead to different tumor characteristics that might in turn affect response to therapy.

A new real-world analysis of 159 NSCLC patients found that a combination of a mutation of the TP53 tumor suppressor gene and the EGFR Ex20 mutation is associated with worse disease outcomes, compared to patients with the EGFR Ex20 mutation alone. But the news wasn’t all bad. The same group of patients also responded better to ICB (immune checkpoint blockade) therapy than did the broader population of EGFR Ex20 patients.

The EGFR Ex20 mutation occurs in about 4% of NSCLC cases, while TP53 is quite common: The new study found a frequency of 43.9%. “We first have to mention that the findings regarding TP53 do not reach statistical significance; however, the trend is very strong, and results might be hampered due to small sample sizes. We think it is [appropriate] to exhaust more treatment options for these patients, especially targeted approaches with newer drugs that specifically target exon 20 insertions, as these drugs were not applied in our cohort,” Anna Kron, Dr. rer. medic., said in an email exchange. Dr. Kron presented the results at a poster session in Paris at the ESMO Congress. She is a researcher at University Hospital of Cologne, Germany.

The ImmunoTarget study, published in 2019, examined over 500 NSCLC patients with a range of driver mutations including EGFR and found that they responded poorly to ICIs in comparison to KRAS mutations.

But Dr. Kron’s group was not convinced. “Ex20 mutations differ clinically from other tyrosine kinase mutations in EGFR. We set out this study to rechallenge the paradigm of impaired benefit from ICI in EGFR-mutated patients, as we consider these mutations not interchangeable with other EGFR mutations,” Dr. Kron said.

“We would postulate that in EGFR Exon 20 mutations, ICI and specific inhibitors should be part of the therapeutic course. In patients with co-occurring TP53 mutations, treatment escalation could be considered,” Dr. Kron said.

The study included 159 patients with advanced NSCLC with the EGFR exon 20 insertion, who were treated between 2014 and 2020 at German hospitals. Among the patients, 37.7% were female; mean age at diagnosis was 65.87 years; 50.3% had a smoking history and 38.4% did not (data were unavailable for the rest); and 9.4% of tumors were stage I, 4.4% stage II, 8.2% stage IIIA, 3.8% stage IIIB, and 74.2% stage IV.

Over a follow-up of 4.1 years, there was a trend toward longer survival among patients with TP53 wild type (OS, 20 versus 12 months; P = .092). Sixty-six patients who received ICI therapy had better OS compared with those who did not (22 versus 10 months; P = .018). Among patients with co-occurring TP53 mutations, receipt of ICI therapy was associated with longer OS (16 versus 8 months; P = .048). There was a trend toward patients with TP53 wild type treated with ICI faring better than those who didn’t receive ICI (27.0 months versus 11.0 months; P = .109).

The researchers are continuing to study patients with EGFR Ex20 to better understand the role of TP53 and ICI therapy in these patients.

The study received no funding. Dr. Kron has no relevant financial disclosures.

In non–small cell lung cancer (NSCLC), mutations to the epidermal growth factor receptor (EGFR) gene are generally associated with a poor response to immune checkpoint inhibitor (ICI) therapies. However, there is a range of different EGFR mutations, and different mutation combinations can lead to different tumor characteristics that might in turn affect response to therapy.

A new real-world analysis of 159 NSCLC patients found that a combination of a mutation of the TP53 tumor suppressor gene and the EGFR Ex20 mutation is associated with worse disease outcomes, compared to patients with the EGFR Ex20 mutation alone. But the news wasn’t all bad. The same group of patients also responded better to ICB (immune checkpoint blockade) therapy than did the broader population of EGFR Ex20 patients.

The EGFR Ex20 mutation occurs in about 4% of NSCLC cases, while TP53 is quite common: The new study found a frequency of 43.9%. “We first have to mention that the findings regarding TP53 do not reach statistical significance; however, the trend is very strong, and results might be hampered due to small sample sizes. We think it is [appropriate] to exhaust more treatment options for these patients, especially targeted approaches with newer drugs that specifically target exon 20 insertions, as these drugs were not applied in our cohort,” Anna Kron, Dr. rer. medic., said in an email exchange. Dr. Kron presented the results at a poster session in Paris at the ESMO Congress. She is a researcher at University Hospital of Cologne, Germany.

The ImmunoTarget study, published in 2019, examined over 500 NSCLC patients with a range of driver mutations including EGFR and found that they responded poorly to ICIs in comparison to KRAS mutations.

But Dr. Kron’s group was not convinced. “Ex20 mutations differ clinically from other tyrosine kinase mutations in EGFR. We set out this study to rechallenge the paradigm of impaired benefit from ICI in EGFR-mutated patients, as we consider these mutations not interchangeable with other EGFR mutations,” Dr. Kron said.

“We would postulate that in EGFR Exon 20 mutations, ICI and specific inhibitors should be part of the therapeutic course. In patients with co-occurring TP53 mutations, treatment escalation could be considered,” Dr. Kron said.

The study included 159 patients with advanced NSCLC with the EGFR exon 20 insertion, who were treated between 2014 and 2020 at German hospitals. Among the patients, 37.7% were female; mean age at diagnosis was 65.87 years; 50.3% had a smoking history and 38.4% did not (data were unavailable for the rest); and 9.4% of tumors were stage I, 4.4% stage II, 8.2% stage IIIA, 3.8% stage IIIB, and 74.2% stage IV.

Over a follow-up of 4.1 years, there was a trend toward longer survival among patients with TP53 wild type (OS, 20 versus 12 months; P = .092). Sixty-six patients who received ICI therapy had better OS compared with those who did not (22 versus 10 months; P = .018). Among patients with co-occurring TP53 mutations, receipt of ICI therapy was associated with longer OS (16 versus 8 months; P = .048). There was a trend toward patients with TP53 wild type treated with ICI faring better than those who didn’t receive ICI (27.0 months versus 11.0 months; P = .109).

The researchers are continuing to study patients with EGFR Ex20 to better understand the role of TP53 and ICI therapy in these patients.

The study received no funding. Dr. Kron has no relevant financial disclosures.

Cardiometabolic and respiratory comorbidities are associated with worse survival in patients with non–small cell lung cancer (NSCLC), and new research suggests a potential mechanism.

Prior studies had shown mixed results when it came to these comorbidities and survival, according to study coauthor author Geoffrey Liu, MD, who is an epidemiology researcher at the University of Toronto Princess Margaret Cancer Centre. The new work represents data from multiple continents, from various ethnicities and cultures.

“We found that comorbidities had much greater impact on earlier than later stages of lung cancer, consistent with this previous study,” said Dr. Liu in an email. The study was presented by Miguel Garcia-Pardo, who is a researcher at University of Toronto Princess Margaret Cancer Centre, during a poster session at the annual meeting of the European Society for Medical Oncology.

“Deaths from [cardiometabolic] comorbidities were mainly from non–lung cancer competing causes, whereas the deaths from respiratory comorbidities were primarily driven by lung cancer specific survival, i.e., deaths from lung cancer itself. We conclude that it is critical to understand how these patients with different comorbidities died, as it would impact decisions on treatment planning and mitigation strategies,” Dr. Liu said.

Dr. Liu noted that controlling cardiometabolic risk factors like diabetes and hypertension is typically de-emphasized after diagnosis with early-stage lung cancer. The rationale is often that the lung cancer is a more acute concern than longer-term cardiometabolic risks. “The data from our analyses suggest a rethinking of this strategy. We need to pay more attention to controlling cardiovascular risk factors in early-stage lung cancer,” Dr. Liu said.

The findings also suggest that respiratory comorbidities should be managed more aggressively. That would allow more patients to undergo treatments like surgery and stereotactic radiation.

The Clinical Outcome Studies of the International Lung Cancer Consortium drew from two dozen studies conducted across five continents. It examined clinical, epidemiologic, genetic, and genomic factors and their potential influence on NSCLC outcomes. Cardiometabolic comorbidities included coronary artery disease, diabetes, vascular related diseases, and other heart diseases. Respiratory comorbidities included chronic obstructive pulmonary disease and asthma.

The analysis included 16,354 patients. Among patients with stage I NSCLC, there was an association between reduced overall survival (OS) and cardiometabolic comorbidity (adjusted hazard ratio, 1.17; P = .01) and respiratory comorbidity (aHR, 1.36; P < .001). For stage II/III patients, there was no significant association between OS and cardiometabolic comorbidities, but respiratory comorbidity was associated with worse OS (aHR, 1.15; P < .001). In stage 4, worse OS was associated with both cardiometabolic health comorbidity (aHR, 1.11; P = .03), but not respiratory comorbidity.

Among patients with stage IV NSCLC, there were no associations between overall survival or lung cancer–specific survival (LCSS) and respiratory or cardiometabolic risk factors. However, an examination of cause of death found a different pattern in patients with stage IB-IIIA disease: LCSS was worse among patients with respiratory comorbidities (aHR, 1.21; 95% CI, 1.09-1.34). Among those with cardiovascular comorbidities, the risk of non-NSCLC mortality was higher (aHR, 1.36; 95% CI, 1.15-1.63). The presence of respiratory comorbidity was associated with a reduced probability of undergoing surgical resection for both stage I (adjusted odds ratio, 0.45; 95% CI, 0.35-0.59) and stage II/III patients (aOR, 0.66; 95% CI, 0.53-0.80).

There was an association between non-NSCLC mortality and cardiometabolic comorbidities in stage IA (aHR, 1.37; 95% CI, 1.06-1.77) and in stages IB-IIIA (aHR, 1.32; 95% CI, 1.03-1.71) NSCLC. There were also associations between NSCLC mortality and respiratory comorbidity among stage IA (aHR, 1.51; 95% CI, 1.17-1.95) and stages IB-IIIA (aHR, 1.20; 95% CI, 1.06-1.36) NSCLC. There were no associations between respiratory comorbidity and non-NSCLC mortality.

Respiratory comorbidity was associated with a lower chance of undergoing surgical resection in stage IA (aHR, 0.54; 95% CI, 0.35-0.83) and stage IB-IIIA (aHR, 0.57; 95% CI, 0.46-0.70) cancers. Cardiometabolic comorbidity was associated with a lower rate of surgical resection only in stage 1B-3A patients (aHR, 0.73; 95% CI, 0.56-0.96). Among those who underwent resection, stage IA patients were less likely to die of lung cancer (aHR, 0.38; 95% CI, 0.28-0.52) but more likely to die of other causes (aHR, 1.73; 95% CI, 1.07-1.78). Stage IB-IIIA patients who underwent resection were less likely to die of lung cancer (aHR, 0.37; 95%, 0.32-0.42), but there was no significant association with non–lung cancer mortality.

The study was funded by the Lusi Wong Family Fund and the Alan Brown Chair. Dr. Liu has no relevant financial disclosures.

Cardiometabolic and respiratory comorbidities are associated with worse survival in patients with non–small cell lung cancer (NSCLC), and new research suggests a potential mechanism.

Prior studies had shown mixed results when it came to these comorbidities and survival, according to study coauthor author Geoffrey Liu, MD, who is an epidemiology researcher at the University of Toronto Princess Margaret Cancer Centre. The new work represents data from multiple continents, from various ethnicities and cultures.

“We found that comorbidities had much greater impact on earlier than later stages of lung cancer, consistent with this previous study,” said Dr. Liu in an email. The study was presented by Miguel Garcia-Pardo, who is a researcher at University of Toronto Princess Margaret Cancer Centre, during a poster session at the annual meeting of the European Society for Medical Oncology.

“Deaths from [cardiometabolic] comorbidities were mainly from non–lung cancer competing causes, whereas the deaths from respiratory comorbidities were primarily driven by lung cancer specific survival, i.e., deaths from lung cancer itself. We conclude that it is critical to understand how these patients with different comorbidities died, as it would impact decisions on treatment planning and mitigation strategies,” Dr. Liu said.

Dr. Liu noted that controlling cardiometabolic risk factors like diabetes and hypertension is typically de-emphasized after diagnosis with early-stage lung cancer. The rationale is often that the lung cancer is a more acute concern than longer-term cardiometabolic risks. “The data from our analyses suggest a rethinking of this strategy. We need to pay more attention to controlling cardiovascular risk factors in early-stage lung cancer,” Dr. Liu said.

The findings also suggest that respiratory comorbidities should be managed more aggressively. That would allow more patients to undergo treatments like surgery and stereotactic radiation.

The Clinical Outcome Studies of the International Lung Cancer Consortium drew from two dozen studies conducted across five continents. It examined clinical, epidemiologic, genetic, and genomic factors and their potential influence on NSCLC outcomes. Cardiometabolic comorbidities included coronary artery disease, diabetes, vascular related diseases, and other heart diseases. Respiratory comorbidities included chronic obstructive pulmonary disease and asthma.

The analysis included 16,354 patients. Among patients with stage I NSCLC, there was an association between reduced overall survival (OS) and cardiometabolic comorbidity (adjusted hazard ratio, 1.17; P = .01) and respiratory comorbidity (aHR, 1.36; P < .001). For stage II/III patients, there was no significant association between OS and cardiometabolic comorbidities, but respiratory comorbidity was associated with worse OS (aHR, 1.15; P < .001). In stage 4, worse OS was associated with both cardiometabolic health comorbidity (aHR, 1.11; P = .03), but not respiratory comorbidity.

Among patients with stage IV NSCLC, there were no associations between overall survival or lung cancer–specific survival (LCSS) and respiratory or cardiometabolic risk factors. However, an examination of cause of death found a different pattern in patients with stage IB-IIIA disease: LCSS was worse among patients with respiratory comorbidities (aHR, 1.21; 95% CI, 1.09-1.34). Among those with cardiovascular comorbidities, the risk of non-NSCLC mortality was higher (aHR, 1.36; 95% CI, 1.15-1.63). The presence of respiratory comorbidity was associated with a reduced probability of undergoing surgical resection for both stage I (adjusted odds ratio, 0.45; 95% CI, 0.35-0.59) and stage II/III patients (aOR, 0.66; 95% CI, 0.53-0.80).

There was an association between non-NSCLC mortality and cardiometabolic comorbidities in stage IA (aHR, 1.37; 95% CI, 1.06-1.77) and in stages IB-IIIA (aHR, 1.32; 95% CI, 1.03-1.71) NSCLC. There were also associations between NSCLC mortality and respiratory comorbidity among stage IA (aHR, 1.51; 95% CI, 1.17-1.95) and stages IB-IIIA (aHR, 1.20; 95% CI, 1.06-1.36) NSCLC. There were no associations between respiratory comorbidity and non-NSCLC mortality.

Respiratory comorbidity was associated with a lower chance of undergoing surgical resection in stage IA (aHR, 0.54; 95% CI, 0.35-0.83) and stage IB-IIIA (aHR, 0.57; 95% CI, 0.46-0.70) cancers. Cardiometabolic comorbidity was associated with a lower rate of surgical resection only in stage 1B-3A patients (aHR, 0.73; 95% CI, 0.56-0.96). Among those who underwent resection, stage IA patients were less likely to die of lung cancer (aHR, 0.38; 95% CI, 0.28-0.52) but more likely to die of other causes (aHR, 1.73; 95% CI, 1.07-1.78). Stage IB-IIIA patients who underwent resection were less likely to die of lung cancer (aHR, 0.37; 95%, 0.32-0.42), but there was no significant association with non–lung cancer mortality.

The study was funded by the Lusi Wong Family Fund and the Alan Brown Chair. Dr. Liu has no relevant financial disclosures.

Cardiometabolic and respiratory comorbidities are associated with worse survival in patients with non–small cell lung cancer (NSCLC), and new research suggests a potential mechanism.

Prior studies had shown mixed results when it came to these comorbidities and survival, according to study coauthor author Geoffrey Liu, MD, who is an epidemiology researcher at the University of Toronto Princess Margaret Cancer Centre. The new work represents data from multiple continents, from various ethnicities and cultures.

“We found that comorbidities had much greater impact on earlier than later stages of lung cancer, consistent with this previous study,” said Dr. Liu in an email. The study was presented by Miguel Garcia-Pardo, who is a researcher at University of Toronto Princess Margaret Cancer Centre, during a poster session at the annual meeting of the European Society for Medical Oncology.

“Deaths from [cardiometabolic] comorbidities were mainly from non–lung cancer competing causes, whereas the deaths from respiratory comorbidities were primarily driven by lung cancer specific survival, i.e., deaths from lung cancer itself. We conclude that it is critical to understand how these patients with different comorbidities died, as it would impact decisions on treatment planning and mitigation strategies,” Dr. Liu said.

Dr. Liu noted that controlling cardiometabolic risk factors like diabetes and hypertension is typically de-emphasized after diagnosis with early-stage lung cancer. The rationale is often that the lung cancer is a more acute concern than longer-term cardiometabolic risks. “The data from our analyses suggest a rethinking of this strategy. We need to pay more attention to controlling cardiovascular risk factors in early-stage lung cancer,” Dr. Liu said.

The findings also suggest that respiratory comorbidities should be managed more aggressively. That would allow more patients to undergo treatments like surgery and stereotactic radiation.

The Clinical Outcome Studies of the International Lung Cancer Consortium drew from two dozen studies conducted across five continents. It examined clinical, epidemiologic, genetic, and genomic factors and their potential influence on NSCLC outcomes. Cardiometabolic comorbidities included coronary artery disease, diabetes, vascular related diseases, and other heart diseases. Respiratory comorbidities included chronic obstructive pulmonary disease and asthma.

The analysis included 16,354 patients. Among patients with stage I NSCLC, there was an association between reduced overall survival (OS) and cardiometabolic comorbidity (adjusted hazard ratio, 1.17; P = .01) and respiratory comorbidity (aHR, 1.36; P < .001). For stage II/III patients, there was no significant association between OS and cardiometabolic comorbidities, but respiratory comorbidity was associated with worse OS (aHR, 1.15; P < .001). In stage 4, worse OS was associated with both cardiometabolic health comorbidity (aHR, 1.11; P = .03), but not respiratory comorbidity.

Among patients with stage IV NSCLC, there were no associations between overall survival or lung cancer–specific survival (LCSS) and respiratory or cardiometabolic risk factors. However, an examination of cause of death found a different pattern in patients with stage IB-IIIA disease: LCSS was worse among patients with respiratory comorbidities (aHR, 1.21; 95% CI, 1.09-1.34). Among those with cardiovascular comorbidities, the risk of non-NSCLC mortality was higher (aHR, 1.36; 95% CI, 1.15-1.63). The presence of respiratory comorbidity was associated with a reduced probability of undergoing surgical resection for both stage I (adjusted odds ratio, 0.45; 95% CI, 0.35-0.59) and stage II/III patients (aOR, 0.66; 95% CI, 0.53-0.80).

There was an association between non-NSCLC mortality and cardiometabolic comorbidities in stage IA (aHR, 1.37; 95% CI, 1.06-1.77) and in stages IB-IIIA (aHR, 1.32; 95% CI, 1.03-1.71) NSCLC. There were also associations between NSCLC mortality and respiratory comorbidity among stage IA (aHR, 1.51; 95% CI, 1.17-1.95) and stages IB-IIIA (aHR, 1.20; 95% CI, 1.06-1.36) NSCLC. There were no associations between respiratory comorbidity and non-NSCLC mortality.

Respiratory comorbidity was associated with a lower chance of undergoing surgical resection in stage IA (aHR, 0.54; 95% CI, 0.35-0.83) and stage IB-IIIA (aHR, 0.57; 95% CI, 0.46-0.70) cancers. Cardiometabolic comorbidity was associated with a lower rate of surgical resection only in stage 1B-3A patients (aHR, 0.73; 95% CI, 0.56-0.96). Among those who underwent resection, stage IA patients were less likely to die of lung cancer (aHR, 0.38; 95% CI, 0.28-0.52) but more likely to die of other causes (aHR, 1.73; 95% CI, 1.07-1.78). Stage IB-IIIA patients who underwent resection were less likely to die of lung cancer (aHR, 0.37; 95%, 0.32-0.42), but there was no significant association with non–lung cancer mortality.

The study was funded by the Lusi Wong Family Fund and the Alan Brown Chair. Dr. Liu has no relevant financial disclosures.

PARIS – Air pollution has been recognized as a risk factor for lung cancer for about 2 decades, and investigators in the UK have now identified a potential mechanism whereby the air we breathe may trigger driver mutations already present in normal lung cells to cause cancer.

Think of it as “smoking gun–level” evidence that may explain why many nonsmokers still develop non–small cell lung cancer, said Charles Swanton, PhD, from the Francis Crick Institute and Cancer Research UK Chief Clinician, London.

“What this work shows is that air pollution is directly causing lung cancer but through a slightly unexpected pathway,” he said at a briefing prior to his presentation of the data in a presidential symposium held earlier this month in Paris at the European Society for Medical Oncology Congress 2022.

Importantly, he and his team also propose a mechanism for blocking the effects of air pollution with monoclonal antibodies directed against the inflammatory cytokine interleukein-1 beta.
 

Carcinogenesis explored

Lung cancer in never-smokers has a low mutational burden, with about 5- to 10-fold fewer mutations in a nonsmoker, compared with an ever smoker or current smoker, Dr. Swanton noted.

“The other thing to say about never-smokers is that they don’t have a clear environmental carcinogenic signature. So how do you square the circle? You’ve got the problem that you know that air pollution is associated with lung cancer – we don’t know if it causes it – but we also see that we’ve got no DNA mutations due to an environmental carcinogen,” he said during his symposium presentation.

The traditional model proposed to explain how carcinogens cause cancer holds that exposure to a carcinogen causes DNA mutations that lead to clonal expansion and tumor growth.

“But there are some major problems with this model,” Dr. Swanton said.

For example, normal skin contains a “patchwork of mutant clones,” but skin cancer is still uncommon, he said, and in studies in mice, 17 of 20 environmental carcinogens did not induce DNA mutations. He also noted that a common melanoma driver mutation, BRAF V600E, is not induced by exposure to a ultraviolet light.

“Any explanation for never-smoking lung cancer would have to fulfill three criteria: one, you have to explain why geographic variation exists; two, you have to prove causation; and three, you have to explain how cancers can be initiated without directly causing DNA mutations,” he said.

Normal lung tissues in nonsmoking adults can harbor pre-existing mutations, with the number of mutations increasing likely as a consequence of aging. In fact, more than 50% of normal lung biopsy tissues have been shown to harbor driver KRAS and/or EGFR mutations, Dr. Swanton said.

“In our research, these mutations alone only weakly potentiated cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, we saw more cancers and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harboring driver gene mutations. The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants while others don’t,” he said.
 

Geographical exposures

Looking at data on 447,932 participants in the UK Biobank, the investigators found that increasing exposure to ambient air particles smaller than 2.5 mcm (PM_2.5) was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM­­_2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.

And crucially, as Dr. Swanton and associates showed in mouse models, exposure of lung cells bearing somatic EGFR and KRAS mutations to PM2.5 causes recruitment of macrophages that in turn secrete IL-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.

Importantly, pollution-induced tumor formation can be blocked by antibodies directed against IL-1B, Dr. Swanton said.

He pointed to a 2017 study in The Lancet suggesting that anti-inflammatory therapy with the anti–IL-1 antibody canakinumab (Ilaris) could reduce incident lung cancer and lung cancer deaths.
 

‘Elegant first demonstration’

“This is a very meaningful demonstration, from epidemiological data to preclinical models of the role of PM_­2.5 air pollutants in the promotion of lung cancer, and it provides us with very important insights into the mechanism through which nonsmokers can get lung cancer,” commented Suzette Delaloge, MD, from the cancer interception program at Institut Goustave Roussy in Villejuif, France, the invited discussant.

“But beyond that, it also has a great impact on our vision of carcinogenesis, with this very elegant first demonstration of the alternative nonmutagenic, carcinogenetic promotion hypothesis for fine particulate matter,” she said.

Questions still to be answered include whether PM_2.5 pollutants could also be mutagenic, is the oncogenic pathway ubiquitous in tissue, which components of PM_2.5 might drive the effect, how long of an exposure is required to promote lung cancer, and why and how persons without cancer develop specific driver mutations such as EGFR, she said.

“This research is intriguing and exciting as it means that we can ask whether, in the future, it will be possible to use lung scans to look for precancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1B inhibitors,” said Tony Mok, MD, a lung cancer specialist at the Chinese University of Hong Kong, who was not involved in the study.

“We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find nonsmokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative,” he said in a statement.

The study was supported by Cancer Research UK, the Lung Cancer Research Foundations, Rosetrees Trust, the Mark Foundation for Cancer Research and the Ruth Strauss Foundation. Dr. Swanton disclosed grants/research support, honoraria, and stock ownership with multiple entities. Dr. Delaloge disclosed institutional financing and research funding from multiple companies. Dr. Mok disclosed stock ownership and honoraria with multiple companies.

PARIS – Air pollution has been recognized as a risk factor for lung cancer for about 2 decades, and investigators in the UK have now identified a potential mechanism whereby the air we breathe may trigger driver mutations already present in normal lung cells to cause cancer.

Think of it as “smoking gun–level” evidence that may explain why many nonsmokers still develop non–small cell lung cancer, said Charles Swanton, PhD, from the Francis Crick Institute and Cancer Research UK Chief Clinician, London.

“What this work shows is that air pollution is directly causing lung cancer but through a slightly unexpected pathway,” he said at a briefing prior to his presentation of the data in a presidential symposium held earlier this month in Paris at the European Society for Medical Oncology Congress 2022.

Importantly, he and his team also propose a mechanism for blocking the effects of air pollution with monoclonal antibodies directed against the inflammatory cytokine interleukein-1 beta.
 

Carcinogenesis explored

Lung cancer in never-smokers has a low mutational burden, with about 5- to 10-fold fewer mutations in a nonsmoker, compared with an ever smoker or current smoker, Dr. Swanton noted.

“The other thing to say about never-smokers is that they don’t have a clear environmental carcinogenic signature. So how do you square the circle? You’ve got the problem that you know that air pollution is associated with lung cancer – we don’t know if it causes it – but we also see that we’ve got no DNA mutations due to an environmental carcinogen,” he said during his symposium presentation.

The traditional model proposed to explain how carcinogens cause cancer holds that exposure to a carcinogen causes DNA mutations that lead to clonal expansion and tumor growth.

“But there are some major problems with this model,” Dr. Swanton said.

For example, normal skin contains a “patchwork of mutant clones,” but skin cancer is still uncommon, he said, and in studies in mice, 17 of 20 environmental carcinogens did not induce DNA mutations. He also noted that a common melanoma driver mutation, BRAF V600E, is not induced by exposure to a ultraviolet light.

“Any explanation for never-smoking lung cancer would have to fulfill three criteria: one, you have to explain why geographic variation exists; two, you have to prove causation; and three, you have to explain how cancers can be initiated without directly causing DNA mutations,” he said.

Normal lung tissues in nonsmoking adults can harbor pre-existing mutations, with the number of mutations increasing likely as a consequence of aging. In fact, more than 50% of normal lung biopsy tissues have been shown to harbor driver KRAS and/or EGFR mutations, Dr. Swanton said.

“In our research, these mutations alone only weakly potentiated cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, we saw more cancers and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harboring driver gene mutations. The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants while others don’t,” he said.
 

Geographical exposures

Looking at data on 447,932 participants in the UK Biobank, the investigators found that increasing exposure to ambient air particles smaller than 2.5 mcm (PM_2.5) was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM­­_2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.

And crucially, as Dr. Swanton and associates showed in mouse models, exposure of lung cells bearing somatic EGFR and KRAS mutations to PM2.5 causes recruitment of macrophages that in turn secrete IL-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.

Importantly, pollution-induced tumor formation can be blocked by antibodies directed against IL-1B, Dr. Swanton said.

He pointed to a 2017 study in The Lancet suggesting that anti-inflammatory therapy with the anti–IL-1 antibody canakinumab (Ilaris) could reduce incident lung cancer and lung cancer deaths.
 

‘Elegant first demonstration’

“This is a very meaningful demonstration, from epidemiological data to preclinical models of the role of PM_­2.5 air pollutants in the promotion of lung cancer, and it provides us with very important insights into the mechanism through which nonsmokers can get lung cancer,” commented Suzette Delaloge, MD, from the cancer interception program at Institut Goustave Roussy in Villejuif, France, the invited discussant.

“But beyond that, it also has a great impact on our vision of carcinogenesis, with this very elegant first demonstration of the alternative nonmutagenic, carcinogenetic promotion hypothesis for fine particulate matter,” she said.

Questions still to be answered include whether PM_2.5 pollutants could also be mutagenic, is the oncogenic pathway ubiquitous in tissue, which components of PM_2.5 might drive the effect, how long of an exposure is required to promote lung cancer, and why and how persons without cancer develop specific driver mutations such as EGFR, she said.

“This research is intriguing and exciting as it means that we can ask whether, in the future, it will be possible to use lung scans to look for precancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1B inhibitors,” said Tony Mok, MD, a lung cancer specialist at the Chinese University of Hong Kong, who was not involved in the study.

“We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find nonsmokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative,” he said in a statement.

The study was supported by Cancer Research UK, the Lung Cancer Research Foundations, Rosetrees Trust, the Mark Foundation for Cancer Research and the Ruth Strauss Foundation. Dr. Swanton disclosed grants/research support, honoraria, and stock ownership with multiple entities. Dr. Delaloge disclosed institutional financing and research funding from multiple companies. Dr. Mok disclosed stock ownership and honoraria with multiple companies.

PARIS – Air pollution has been recognized as a risk factor for lung cancer for about 2 decades, and investigators in the UK have now identified a potential mechanism whereby the air we breathe may trigger driver mutations already present in normal lung cells to cause cancer.

Think of it as “smoking gun–level” evidence that may explain why many nonsmokers still develop non–small cell lung cancer, said Charles Swanton, PhD, from the Francis Crick Institute and Cancer Research UK Chief Clinician, London.

“What this work shows is that air pollution is directly causing lung cancer but through a slightly unexpected pathway,” he said at a briefing prior to his presentation of the data in a presidential symposium held earlier this month in Paris at the European Society for Medical Oncology Congress 2022.

Importantly, he and his team also propose a mechanism for blocking the effects of air pollution with monoclonal antibodies directed against the inflammatory cytokine interleukein-1 beta.
 

Carcinogenesis explored

Lung cancer in never-smokers has a low mutational burden, with about 5- to 10-fold fewer mutations in a nonsmoker, compared with an ever smoker or current smoker, Dr. Swanton noted.

“The other thing to say about never-smokers is that they don’t have a clear environmental carcinogenic signature. So how do you square the circle? You’ve got the problem that you know that air pollution is associated with lung cancer – we don’t know if it causes it – but we also see that we’ve got no DNA mutations due to an environmental carcinogen,” he said during his symposium presentation.

The traditional model proposed to explain how carcinogens cause cancer holds that exposure to a carcinogen causes DNA mutations that lead to clonal expansion and tumor growth.

“But there are some major problems with this model,” Dr. Swanton said.

For example, normal skin contains a “patchwork of mutant clones,” but skin cancer is still uncommon, he said, and in studies in mice, 17 of 20 environmental carcinogens did not induce DNA mutations. He also noted that a common melanoma driver mutation, BRAF V600E, is not induced by exposure to a ultraviolet light.

“Any explanation for never-smoking lung cancer would have to fulfill three criteria: one, you have to explain why geographic variation exists; two, you have to prove causation; and three, you have to explain how cancers can be initiated without directly causing DNA mutations,” he said.

Normal lung tissues in nonsmoking adults can harbor pre-existing mutations, with the number of mutations increasing likely as a consequence of aging. In fact, more than 50% of normal lung biopsy tissues have been shown to harbor driver KRAS and/or EGFR mutations, Dr. Swanton said.

“In our research, these mutations alone only weakly potentiated cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, we saw more cancers and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harboring driver gene mutations. The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants while others don’t,” he said.
 

Geographical exposures

Looking at data on 447,932 participants in the UK Biobank, the investigators found that increasing exposure to ambient air particles smaller than 2.5 mcm (PM_2.5) was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM­­_2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.

And crucially, as Dr. Swanton and associates showed in mouse models, exposure of lung cells bearing somatic EGFR and KRAS mutations to PM2.5 causes recruitment of macrophages that in turn secrete IL-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.

Importantly, pollution-induced tumor formation can be blocked by antibodies directed against IL-1B, Dr. Swanton said.

He pointed to a 2017 study in The Lancet suggesting that anti-inflammatory therapy with the anti–IL-1 antibody canakinumab (Ilaris) could reduce incident lung cancer and lung cancer deaths.
 

‘Elegant first demonstration’

“This is a very meaningful demonstration, from epidemiological data to preclinical models of the role of PM_­2.5 air pollutants in the promotion of lung cancer, and it provides us with very important insights into the mechanism through which nonsmokers can get lung cancer,” commented Suzette Delaloge, MD, from the cancer interception program at Institut Goustave Roussy in Villejuif, France, the invited discussant.

“But beyond that, it also has a great impact on our vision of carcinogenesis, with this very elegant first demonstration of the alternative nonmutagenic, carcinogenetic promotion hypothesis for fine particulate matter,” she said.

Questions still to be answered include whether PM_2.5 pollutants could also be mutagenic, is the oncogenic pathway ubiquitous in tissue, which components of PM_2.5 might drive the effect, how long of an exposure is required to promote lung cancer, and why and how persons without cancer develop specific driver mutations such as EGFR, she said.

“This research is intriguing and exciting as it means that we can ask whether, in the future, it will be possible to use lung scans to look for precancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1B inhibitors,” said Tony Mok, MD, a lung cancer specialist at the Chinese University of Hong Kong, who was not involved in the study.

“We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find nonsmokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative,” he said in a statement.

The study was supported by Cancer Research UK, the Lung Cancer Research Foundations, Rosetrees Trust, the Mark Foundation for Cancer Research and the Ruth Strauss Foundation. Dr. Swanton disclosed grants/research support, honoraria, and stock ownership with multiple entities. Dr. Delaloge disclosed institutional financing and research funding from multiple companies. Dr. Mok disclosed stock ownership and honoraria with multiple companies.

Small cell lung cancer has traditionally been attributed almost exclusively to tobacco exposure, but some recent studies have suggested a higher than expected prevalence among nonsmokers. A new retrospective analysis suggests the disease has a different genomic profile among smokers than nonsmokers, indicating that the subgroups may have unique disease characteristics. Key differences included a lower frequency of TP53 gene mutations and a higher frequency of epidermal growth factor receptor (EGFR) alterations in never smokers.

About 6.9% of small cell lung cancer patients in the CASPIAN study were nonsmokers, as were 3.0% in the IMpower133 study.

“Given that the pathogenesis of small cell lung cancer is often tied to the damaging effects of tobacco, we hypothesized that small cell lung cancer in never-smokers would possess distinct molecular attributes. Our data does not provide any solid evidence for any treatment implications, though it does raise therapeutic questions which we believe deserve further exploration,” said Michael Oh, MD, during a presentation of the study results at the annual meeting of the European Society for Medical Oncology. Dr. Oh is a fellow at the University of California, Los Angeles.

The topic is important clinically, according to Antonio Passaro, MD, PhD, who served as a discussant during the session. He noted that small cell lung cancer in never-smokers is the seventh-most common cause of cancer-related mortality worldwide. In non–small cell lung cancer, rates of tobacco-associated disease have been decreasing, but there are increases in diagnoses among never smokers. Nonsmoking small cell lung cancer patients do not have better prognoses, and novel therapies and advances like immunotherapy and low-dose CT lung cancer screening disproportionately benefit current or former smokers.

Potential risk factors for never-smokers include environmental exposures like radon gas, cooking oil vapors, indoor and outdoor wood burning, and genetic and viral factors. “At the present time we do not have the knowledge to identify the most important factor in development of lung cancer in never-smoking [patients],” said Dr. Passaro, who is a medical oncologist at the European Institute of Oncology in Milan.

He added that the current study results are interesting but need much more follow-up, such as “longitudinal studies combining detailed clinical annotation with tissue and blood sampling. Here there is a need for collaborative efforts.” Key questions include the roles of the genomic landscape in normal lung tissue may play, the lung micro-environment, genetic factors, and environmental exposures.

One key possibility is air pollution. “We know that lung cancer in never-smokers is frequent in some countries, for example in Asian countries and it is more frequent in the United States than in Europe, but to find an explanation to this kind of data is difficult at the present time,” Dr. Passaro said.

The researchers retrospectively analyzed data from 608 current or former smokers and 54 never-smokers with small cell lung cancer, with the latter making up 8% of the total population. 70.4% of never-smokers and 55.1% of current or former smokers were female (P = .031). There was no significant between-group difference with respect to age at diagnosis or race.

Somatic mutations were similar to what has been found in previous studies for current or former smokers. 85.2% had changes in TP53, compared with just 59.3% of never-smokers (Q < .001). Changes to EGFR were more common in never-smokers, occurring in 25.9% versus 2.6% (Q < .001). PIK3CA alterations were also more common in never-smokers (14.8% vs. 3.6%; Q = 0.022). There was no significant difference between the two groups with respect to changes in RB1.

Never smokers had tumors with less immune cell infiltration (P = .008), including fewer CD4+ T cells, CD8+ T cells, and macrophages. Their tumor mutation burden was also lower (median, 2.59 vs. 4.99; P < .001).

Dr. Oh has no relevant financial disclosures. Dr. Passaro has consulted, advised, and received research funding from a wide range of pharmaceutical companies.

Small cell lung cancer has traditionally been attributed almost exclusively to tobacco exposure, but some recent studies have suggested a higher than expected prevalence among nonsmokers. A new retrospective analysis suggests the disease has a different genomic profile among smokers than nonsmokers, indicating that the subgroups may have unique disease characteristics. Key differences included a lower frequency of TP53 gene mutations and a higher frequency of epidermal growth factor receptor (EGFR) alterations in never smokers.

About 6.9% of small cell lung cancer patients in the CASPIAN study were nonsmokers, as were 3.0% in the IMpower133 study.

“Given that the pathogenesis of small cell lung cancer is often tied to the damaging effects of tobacco, we hypothesized that small cell lung cancer in never-smokers would possess distinct molecular attributes. Our data does not provide any solid evidence for any treatment implications, though it does raise therapeutic questions which we believe deserve further exploration,” said Michael Oh, MD, during a presentation of the study results at the annual meeting of the European Society for Medical Oncology. Dr. Oh is a fellow at the University of California, Los Angeles.

The topic is important clinically, according to Antonio Passaro, MD, PhD, who served as a discussant during the session. He noted that small cell lung cancer in never-smokers is the seventh-most common cause of cancer-related mortality worldwide. In non–small cell lung cancer, rates of tobacco-associated disease have been decreasing, but there are increases in diagnoses among never smokers. Nonsmoking small cell lung cancer patients do not have better prognoses, and novel therapies and advances like immunotherapy and low-dose CT lung cancer screening disproportionately benefit current or former smokers.

Potential risk factors for never-smokers include environmental exposures like radon gas, cooking oil vapors, indoor and outdoor wood burning, and genetic and viral factors. “At the present time we do not have the knowledge to identify the most important factor in development of lung cancer in never-smoking [patients],” said Dr. Passaro, who is a medical oncologist at the European Institute of Oncology in Milan.

He added that the current study results are interesting but need much more follow-up, such as “longitudinal studies combining detailed clinical annotation with tissue and blood sampling. Here there is a need for collaborative efforts.” Key questions include the roles of the genomic landscape in normal lung tissue may play, the lung micro-environment, genetic factors, and environmental exposures.

One key possibility is air pollution. “We know that lung cancer in never-smokers is frequent in some countries, for example in Asian countries and it is more frequent in the United States than in Europe, but to find an explanation to this kind of data is difficult at the present time,” Dr. Passaro said.

The researchers retrospectively analyzed data from 608 current or former smokers and 54 never-smokers with small cell lung cancer, with the latter making up 8% of the total population. 70.4% of never-smokers and 55.1% of current or former smokers were female (P = .031). There was no significant between-group difference with respect to age at diagnosis or race.

Somatic mutations were similar to what has been found in previous studies for current or former smokers. 85.2% had changes in TP53, compared with just 59.3% of never-smokers (Q < .001). Changes to EGFR were more common in never-smokers, occurring in 25.9% versus 2.6% (Q < .001). PIK3CA alterations were also more common in never-smokers (14.8% vs. 3.6%; Q = 0.022). There was no significant difference between the two groups with respect to changes in RB1.

Never smokers had tumors with less immune cell infiltration (P = .008), including fewer CD4+ T cells, CD8+ T cells, and macrophages. Their tumor mutation burden was also lower (median, 2.59 vs. 4.99; P < .001).

Dr. Oh has no relevant financial disclosures. Dr. Passaro has consulted, advised, and received research funding from a wide range of pharmaceutical companies.

Small cell lung cancer has traditionally been attributed almost exclusively to tobacco exposure, but some recent studies have suggested a higher than expected prevalence among nonsmokers. A new retrospective analysis suggests the disease has a different genomic profile among smokers than nonsmokers, indicating that the subgroups may have unique disease characteristics. Key differences included a lower frequency of TP53 gene mutations and a higher frequency of epidermal growth factor receptor (EGFR) alterations in never smokers.

About 6.9% of small cell lung cancer patients in the CASPIAN study were nonsmokers, as were 3.0% in the IMpower133 study.

“Given that the pathogenesis of small cell lung cancer is often tied to the damaging effects of tobacco, we hypothesized that small cell lung cancer in never-smokers would possess distinct molecular attributes. Our data does not provide any solid evidence for any treatment implications, though it does raise therapeutic questions which we believe deserve further exploration,” said Michael Oh, MD, during a presentation of the study results at the annual meeting of the European Society for Medical Oncology. Dr. Oh is a fellow at the University of California, Los Angeles.

The topic is important clinically, according to Antonio Passaro, MD, PhD, who served as a discussant during the session. He noted that small cell lung cancer in never-smokers is the seventh-most common cause of cancer-related mortality worldwide. In non–small cell lung cancer, rates of tobacco-associated disease have been decreasing, but there are increases in diagnoses among never smokers. Nonsmoking small cell lung cancer patients do not have better prognoses, and novel therapies and advances like immunotherapy and low-dose CT lung cancer screening disproportionately benefit current or former smokers.

Potential risk factors for never-smokers include environmental exposures like radon gas, cooking oil vapors, indoor and outdoor wood burning, and genetic and viral factors. “At the present time we do not have the knowledge to identify the most important factor in development of lung cancer in never-smoking [patients],” said Dr. Passaro, who is a medical oncologist at the European Institute of Oncology in Milan.

He added that the current study results are interesting but need much more follow-up, such as “longitudinal studies combining detailed clinical annotation with tissue and blood sampling. Here there is a need for collaborative efforts.” Key questions include the roles of the genomic landscape in normal lung tissue may play, the lung micro-environment, genetic factors, and environmental exposures.

One key possibility is air pollution. “We know that lung cancer in never-smokers is frequent in some countries, for example in Asian countries and it is more frequent in the United States than in Europe, but to find an explanation to this kind of data is difficult at the present time,” Dr. Passaro said.

The researchers retrospectively analyzed data from 608 current or former smokers and 54 never-smokers with small cell lung cancer, with the latter making up 8% of the total population. 70.4% of never-smokers and 55.1% of current or former smokers were female (P = .031). There was no significant between-group difference with respect to age at diagnosis or race.

Somatic mutations were similar to what has been found in previous studies for current or former smokers. 85.2% had changes in TP53, compared with just 59.3% of never-smokers (Q < .001). Changes to EGFR were more common in never-smokers, occurring in 25.9% versus 2.6% (Q < .001). PIK3CA alterations were also more common in never-smokers (14.8% vs. 3.6%; Q = 0.022). There was no significant difference between the two groups with respect to changes in RB1.

Never smokers had tumors with less immune cell infiltration (P = .008), including fewer CD4+ T cells, CD8+ T cells, and macrophages. Their tumor mutation burden was also lower (median, 2.59 vs. 4.99; P < .001).

Dr. Oh has no relevant financial disclosures. Dr. Passaro has consulted, advised, and received research funding from a wide range of pharmaceutical companies.