IASLC 2020

A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.

The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.

The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.

Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.

The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.

As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.

“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”

With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.

“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.

In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).

When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.

However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.

Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.

“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”

The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.

Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.

“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.

Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.

[email protected]

A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.

The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.

The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.

Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.

The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.

As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.

“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”

With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.

“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.

In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).

When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.

However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.

Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.

“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”

The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.

Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.

“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.

Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.

[email protected]

A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.

The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.

The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.

Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.

The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.

As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.

“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”

With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.

“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.

In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).

When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.

However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.

Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.

“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”

The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.

Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.

“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.

Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.

[email protected]

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

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

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

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

Longer-term survival with immunotherapy for patients with non–small cell lung cancer (NSCLC) is once again being applauded by experts in the field.

This time, the data come from trials that tested immunotherapy in the second-line setting for patients who had experienced disease progression with platinum-based chemotherapy. The latest 5-year follow-up from two landmark trials, one with pembrolizumab, the other with nivolumab, show that the survival benefit can persist for years after treatment is stopped.

“These are unprecedented data,” Fred R. Hirsch, MD, PhD, executive director of the Center for Thoracic Oncology at the Tisch Cancer Institute, New York, said in an interview. He was not involved in either trial and was approached for comment.
 

Pembrolizumab survival data

The new longer-term data on pembrolizumab come from the KEYNOTE-010 trial, which included more than 1,000 patients with advanced NSCLC who had previously undergone treatment with platinum-based chemotherapy. The patients were randomly assigned to receive either pembrolizumab or docetaxel for 2 years.

This is the latest update on data from this trial, which has been described as “really extraordinary.”

The 5-year overall survival rates were more than doubled in the pembrolizumab groups, compared with the docetaxel group, reported Roy Herbst, MD, PhD, department of medical oncology, Yale Comprehensive Cancer Center, New Haven, Conn.. He was presenting the new data at the recent World Conference on Lung Cancer 2020.

Overall results for patients with programmed death-ligand 1 (PD-L1) Tumor Proportion Score (TPS) expression greater than 1% show that 15.6% of the pembrolizumab group were still alive at 5 years versus 6.5% of the docetaxel group.

The results were even better among patients who had high PD-L1 TPS expression (>50%): in this subgroup, 25% of the patients who received pembrolizumab were still alive versus 8.2% of those who received docetaxel.

In addition, at 5 years, 9.4% of patients who received pembrolizumab were disease free versus 0.7% of the patients who received docetaxel, Dr. Herbst reported.

Dr. Hirsch commented that the 5-year survival rate of 25% among patients with high PD-L1 expression who underwent treatment with pembrolizumab is “great progress in lung cancer treatment, there is no doubt about it.”

He noted that the results also show that “numerically,” it matters whether patients have low PD-L1 expression. “We know from first-line studies that pembrolizumab monotherapy is effective in high PD-L1–expressing tumors, so these data fit very well,” he said.

At the meeting, Dr. Herbst summarized his presentation on pembrolizumab for patients with NSCLC who had previously undergone treatment, saying that, “with 5 years of follow-up, we continue to see a clinically meaningful improvement in overall survival and PFS [progression-free survival].

“Pembrolizumab monotherapy is a standard of care in patients with immunotherapy-naive or previously treated PD-L1–positive advanced non–small cell lung cancer,” Herbst stated.

Dr. Hirsch was largely in agreement. He believes that, for patients with a PD-L1 TPS of at least 50%, the standard of care “is practically pembrolizumab monotherapy, unless there are certain circumstances where you would add chemotherapy,” such as for patients with a high tumor volume, “where you want to see a very quick response.”

Dr. Hirsch pointed out, however, that currently most patients with high PD-L1–expressing tumors are given pembrolizumab in the first line, which begs the question as to what to give those who experience disease progression after immunotherapy.

“That is an open space,” he said. “There is a lot of studies going on in what we call the immunotherapy-refractory patients.

“We don’t have clear guidance for clinical practice yet,” he commented. He noted that there are several options: “Do you continue with chemotherapy? Do you continue with chemotherapy plus another immunotherapy? Do you switch to another immunotherapy?”

Commenting on Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said the results were “very exciting.”

However, he wondered whether the results suggest that patients with high PD-L1 expression “may be able to stop” receiving pembrolizumab, whereas those with disease of lower expression “may need longer therapy.”

H. Jack West, MD, medical director of the thoracic oncology program, Swedish Cancer Institute, Seattle, said on Twitter that, to him, the “most impressive” aspect was the “new insight about patients stopping pembro after 2 years but still having two-thirds with sustained response.”

He added that he would “love to learn which patients can stop therapy and when, or whether we can do infrequent maintenance IO [immunotherapy].”

 

Nivolumab survival data

The data on nivolumab come from a pooled analysis of 5-year data on 854 patients from CheckMate 057 and CheckMate 017. The analysis was published in the Journal of Clinical Oncology on Jan. 15, 2021.

Both of these trials compared nivolumab with docetaxel for patients with NSCLC who had experienced disease progression with platinum-based chemotherapy.

The pooled analysis showed that the 5-year overall survival rate was more than fivefold greater with nivolumab than with docetaxel, at 13.4% versus 2.6%.

Moreover, more than 80% of patients who had not experienced progression with the immunotherapy at 2 years were still alive at 5 years. The percentage rose to more than 90% among those who had not experienced progression at 3 years.

Lead author Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, and colleagues said the results “demonstrate that nivolumab can provide long-term survival benefit with durable responses and a tolerable safety profile in patients with previously treated, advanced NSCLC.

“Furthermore, some patients appear to maintain prolonged disease control even after stopping systemic therapy,” they noted.

Dr. Hirsch commented that, although the survival rates with nivolumab were slightly lower than reported with pembrolizumab in KEYNOTE-010, they could still be “within the range.” He added that “I wouldn’t conclude that pembrolizumab is better than nivolumab.”

Many factors may account for these differences, he suggested, including differences in the patient populations or simply differences in the numbers of patients included.

For him, the “main point” of the new data from both trials is that immunotherapy has shown “tremendous progress, compared to chemotherapy.”

KEYNOTE-010 was sponsored by Merck Sharp & Dohme. CheckMate 017 and CheckMate057 were sponsored by Bristol-Myers Squibb. Dr. Herbst has relationships with Jun Shi Pharmaceuticals, AstraZeneca, Genentech, Merck, Pfizer, AbbVie, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Heat Biologics, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, Tesaro, Neon Therapeutics, Infinity Pharmaceuticals, Armo Biosciences, Genmab, Halozyme, and Tocagen. Dr. Brahmer has relationships with Roche/Genentech, Bristol-Myers Squibb, Lilly, Celgene, Syndax, Janssen Oncology, Merck, Amgen, Genentech, AstraZeneca, Incyte, Spectrum Pharmaceuticals, Revolution, and Roche/Genentech.

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

New research suggests that proposed lung cancer screening guidelines could inadvertently increase racial and ethnic disparities, but adding in a risk prediction model could reduce some of these disparities by identifying people with high predicted benefit, regardless of race or ethnicity.

The draft United States Preventive Services Task Force (USPSTF) 2020 guidelines recommend annual lung cancer screening for individuals aged 50-80 who currently smoke or quit in the last 15 years, and who have a smoking history equivalent to at least one pack of cigarettes per day for 20 years or more.

This expands the age range and smoking history requirement compared to the 2013 USPSTF recommendations in an attempt to partially ameliorate racial disparities in screening eligibility. The 2013 guidelines recommend screening ever-smokers aged 55-80 with 30 or more pack-years and 15 or fewer quit-years.

However, neither the 2013 nor the 2020 USPSTF recommendations consider the higher risk of lung cancer and younger ages at diagnosis among African Americans, despite their smoking less than Whites, according to Rebecca Landy, PhD, of the National Cancer Institute in Bethesda, Md.

“For the same age and smoking history as Whites, minorities have substantially different lung cancer risk,” Dr. Landy said. “Incorporating individualized prediction models into USPSTF guidelines may reduce racial/ethnic disparities in lung cancer screening eligibility.”

Dr. Landy and colleagues set out to test that theory, and she presented the results at the 2020 World Congress on Lung Cancer (Abstract 3564), which was rescheduled for January 2021. The results were published in the Journal of the National Cancer Institute.
 

Study details

Dr. Landy and colleagues modeled the performance of National Lung Screening Trial–like screening (three annual CT screens, 5 years of follow-up) among three cohorts of ever-smokers aged 50-80 using the 2015 National Health Interview Survey.

One group was eligible by USPSTF 2013 guidelines, another by draft USPSTF 2020 guidelines, and yet another by augmenting the USPSTF 2020 guidelines using risk prediction to include individuals with 12 or more days of life gained according to the Life-Years From Screening–CT (LYFS-CT) model.

“Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung cancer deaths prevented, proportion of gainable life-years gained, and screening effectiveness, as well as the relative disparities in lung cancer deaths prevented and life-years gained,” Dr. Landy said.
 

Results

Under the 2013 guidelines, 8 million ever-smokers were eligible. The disparities in lung cancer death sensitivity, compared to Whites, were 15% for African Americans, 15% for Asian Americans, and 24% for Hispanic Americans. Disparities for life-year gained sensitivity were 15%, 13%, and 24%, respectively.

Under the 2020 draft guidelines, 14.5 million ever-smokers were eligible, but racial/ethnic disparities persisted. Disparities in lung cancer death sensitivity were 13% for African Americans, 19% for Asian Americans, and 27% for Hispanic Americans. Disparities for life-year gained sensitivity were 16%, 19%, and 27%, respectively.

Using the LYFS-CT predictive-risk model added an additional 3.5 million people and “nearly eliminated” disparities for African Americans, Dr. Landy noted. However, disparities persisted for Asian Americans and Hispanic Americans.

Disparities in lung cancer death sensitivity were 0% for African Americans, 19% for Asian Americans, and 23% for Hispanic Americans. Disparities for life-year gained sensitivity were 1%, 19%, and 24%, respectively.
 

More and widening disparity

The results showed that augmenting USPSTF criteria to include high-benefit people selected significantly more African Americans than Whites and could therefore reduce or even eliminate disparities between Whites and African Americans.

“The 2020 USPSTF draft recommendations would make 6.5 million more people eligible to be screened, in addition to the 8 million from the 2013 criteria,” said Gerard Silvestri, MD, of the Medical University of South Carolina, Charleston, who was not involved in this study.

“But there will be more White people than African American people added, and the disparity between them may widen. Using the risk prediction model outlined in this well-researched study could close the gap in disparity. It’s important to identify individual risk and life expectancy.”

Dr. Silvestri pointed out that, compared to Whites, African Americans develop lung cancer at an earlier age with fewer pack-years history of smoking and have worse outcomes.

“We can’t just focus on one aspect of disparity,” he said. “African Americans are much less likely to be insured or to identify a primary care provider for integrated care. We know that screening works. The 2020 USPSTF draft recommendations will enlarge the pool of eligible African Americans and reduce disparities if the other part of the equation holds; that is, they get access to care and screening.”

This study was funded by the National Institutes of Health/National Cancer Institute. Dr. Landy and Dr. Silvestri have no disclosures.

New research suggests that proposed lung cancer screening guidelines could inadvertently increase racial and ethnic disparities, but adding in a risk prediction model could reduce some of these disparities by identifying people with high predicted benefit, regardless of race or ethnicity.

The draft United States Preventive Services Task Force (USPSTF) 2020 guidelines recommend annual lung cancer screening for individuals aged 50-80 who currently smoke or quit in the last 15 years, and who have a smoking history equivalent to at least one pack of cigarettes per day for 20 years or more.

This expands the age range and smoking history requirement compared to the 2013 USPSTF recommendations in an attempt to partially ameliorate racial disparities in screening eligibility. The 2013 guidelines recommend screening ever-smokers aged 55-80 with 30 or more pack-years and 15 or fewer quit-years.

However, neither the 2013 nor the 2020 USPSTF recommendations consider the higher risk of lung cancer and younger ages at diagnosis among African Americans, despite their smoking less than Whites, according to Rebecca Landy, PhD, of the National Cancer Institute in Bethesda, Md.

“For the same age and smoking history as Whites, minorities have substantially different lung cancer risk,” Dr. Landy said. “Incorporating individualized prediction models into USPSTF guidelines may reduce racial/ethnic disparities in lung cancer screening eligibility.”

Dr. Landy and colleagues set out to test that theory, and she presented the results at the 2020 World Congress on Lung Cancer (Abstract 3564), which was rescheduled for January 2021. The results were published in the Journal of the National Cancer Institute.
 

Study details

Dr. Landy and colleagues modeled the performance of National Lung Screening Trial–like screening (three annual CT screens, 5 years of follow-up) among three cohorts of ever-smokers aged 50-80 using the 2015 National Health Interview Survey.

One group was eligible by USPSTF 2013 guidelines, another by draft USPSTF 2020 guidelines, and yet another by augmenting the USPSTF 2020 guidelines using risk prediction to include individuals with 12 or more days of life gained according to the Life-Years From Screening–CT (LYFS-CT) model.

“Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung cancer deaths prevented, proportion of gainable life-years gained, and screening effectiveness, as well as the relative disparities in lung cancer deaths prevented and life-years gained,” Dr. Landy said.
 

Results

Under the 2013 guidelines, 8 million ever-smokers were eligible. The disparities in lung cancer death sensitivity, compared to Whites, were 15% for African Americans, 15% for Asian Americans, and 24% for Hispanic Americans. Disparities for life-year gained sensitivity were 15%, 13%, and 24%, respectively.

Under the 2020 draft guidelines, 14.5 million ever-smokers were eligible, but racial/ethnic disparities persisted. Disparities in lung cancer death sensitivity were 13% for African Americans, 19% for Asian Americans, and 27% for Hispanic Americans. Disparities for life-year gained sensitivity were 16%, 19%, and 27%, respectively.

Using the LYFS-CT predictive-risk model added an additional 3.5 million people and “nearly eliminated” disparities for African Americans, Dr. Landy noted. However, disparities persisted for Asian Americans and Hispanic Americans.

Disparities in lung cancer death sensitivity were 0% for African Americans, 19% for Asian Americans, and 23% for Hispanic Americans. Disparities for life-year gained sensitivity were 1%, 19%, and 24%, respectively.
 

More and widening disparity

The results showed that augmenting USPSTF criteria to include high-benefit people selected significantly more African Americans than Whites and could therefore reduce or even eliminate disparities between Whites and African Americans.

“The 2020 USPSTF draft recommendations would make 6.5 million more people eligible to be screened, in addition to the 8 million from the 2013 criteria,” said Gerard Silvestri, MD, of the Medical University of South Carolina, Charleston, who was not involved in this study.

“But there will be more White people than African American people added, and the disparity between them may widen. Using the risk prediction model outlined in this well-researched study could close the gap in disparity. It’s important to identify individual risk and life expectancy.”

Dr. Silvestri pointed out that, compared to Whites, African Americans develop lung cancer at an earlier age with fewer pack-years history of smoking and have worse outcomes.

“We can’t just focus on one aspect of disparity,” he said. “African Americans are much less likely to be insured or to identify a primary care provider for integrated care. We know that screening works. The 2020 USPSTF draft recommendations will enlarge the pool of eligible African Americans and reduce disparities if the other part of the equation holds; that is, they get access to care and screening.”

This study was funded by the National Institutes of Health/National Cancer Institute. Dr. Landy and Dr. Silvestri have no disclosures.

New research suggests that proposed lung cancer screening guidelines could inadvertently increase racial and ethnic disparities, but adding in a risk prediction model could reduce some of these disparities by identifying people with high predicted benefit, regardless of race or ethnicity.

The draft United States Preventive Services Task Force (USPSTF) 2020 guidelines recommend annual lung cancer screening for individuals aged 50-80 who currently smoke or quit in the last 15 years, and who have a smoking history equivalent to at least one pack of cigarettes per day for 20 years or more.

This expands the age range and smoking history requirement compared to the 2013 USPSTF recommendations in an attempt to partially ameliorate racial disparities in screening eligibility. The 2013 guidelines recommend screening ever-smokers aged 55-80 with 30 or more pack-years and 15 or fewer quit-years.

However, neither the 2013 nor the 2020 USPSTF recommendations consider the higher risk of lung cancer and younger ages at diagnosis among African Americans, despite their smoking less than Whites, according to Rebecca Landy, PhD, of the National Cancer Institute in Bethesda, Md.

“For the same age and smoking history as Whites, minorities have substantially different lung cancer risk,” Dr. Landy said. “Incorporating individualized prediction models into USPSTF guidelines may reduce racial/ethnic disparities in lung cancer screening eligibility.”

Dr. Landy and colleagues set out to test that theory, and she presented the results at the 2020 World Congress on Lung Cancer (Abstract 3564), which was rescheduled for January 2021. The results were published in the Journal of the National Cancer Institute.
 

Study details

Dr. Landy and colleagues modeled the performance of National Lung Screening Trial–like screening (three annual CT screens, 5 years of follow-up) among three cohorts of ever-smokers aged 50-80 using the 2015 National Health Interview Survey.

One group was eligible by USPSTF 2013 guidelines, another by draft USPSTF 2020 guidelines, and yet another by augmenting the USPSTF 2020 guidelines using risk prediction to include individuals with 12 or more days of life gained according to the Life-Years From Screening–CT (LYFS-CT) model.

“Among each race/ethnicity, we calculated the number eligible for screening, proportion of preventable lung cancer deaths prevented, proportion of gainable life-years gained, and screening effectiveness, as well as the relative disparities in lung cancer deaths prevented and life-years gained,” Dr. Landy said.
 

Results

Under the 2013 guidelines, 8 million ever-smokers were eligible. The disparities in lung cancer death sensitivity, compared to Whites, were 15% for African Americans, 15% for Asian Americans, and 24% for Hispanic Americans. Disparities for life-year gained sensitivity were 15%, 13%, and 24%, respectively.

Under the 2020 draft guidelines, 14.5 million ever-smokers were eligible, but racial/ethnic disparities persisted. Disparities in lung cancer death sensitivity were 13% for African Americans, 19% for Asian Americans, and 27% for Hispanic Americans. Disparities for life-year gained sensitivity were 16%, 19%, and 27%, respectively.

Using the LYFS-CT predictive-risk model added an additional 3.5 million people and “nearly eliminated” disparities for African Americans, Dr. Landy noted. However, disparities persisted for Asian Americans and Hispanic Americans.

Disparities in lung cancer death sensitivity were 0% for African Americans, 19% for Asian Americans, and 23% for Hispanic Americans. Disparities for life-year gained sensitivity were 1%, 19%, and 24%, respectively.
 

More and widening disparity

The results showed that augmenting USPSTF criteria to include high-benefit people selected significantly more African Americans than Whites and could therefore reduce or even eliminate disparities between Whites and African Americans.

“The 2020 USPSTF draft recommendations would make 6.5 million more people eligible to be screened, in addition to the 8 million from the 2013 criteria,” said Gerard Silvestri, MD, of the Medical University of South Carolina, Charleston, who was not involved in this study.

“But there will be more White people than African American people added, and the disparity between them may widen. Using the risk prediction model outlined in this well-researched study could close the gap in disparity. It’s important to identify individual risk and life expectancy.”

Dr. Silvestri pointed out that, compared to Whites, African Americans develop lung cancer at an earlier age with fewer pack-years history of smoking and have worse outcomes.

“We can’t just focus on one aspect of disparity,” he said. “African Americans are much less likely to be insured or to identify a primary care provider for integrated care. We know that screening works. The 2020 USPSTF draft recommendations will enlarge the pool of eligible African Americans and reduce disparities if the other part of the equation holds; that is, they get access to care and screening.”

This study was funded by the National Institutes of Health/National Cancer Institute. Dr. Landy and Dr. Silvestri have no disclosures.

Tailoring adjuvant chemotherapy based on the expression of two molecular markers did not confer a survival advantage in patients with completely resected stage II-III non–small cell lung cancer (NSCLC) in a phase 3 trial.

The patients were randomized to receive investigator’s choice of platinum-based chemotherapy or treatment tailored according to messenger RNA (mRNA) expression of two molecular markers – excision repair cross complementation 1 (ERCC1) and thymidylate synthase (TS).

There was no significant difference in overall survival or recurrence-free survival between the treatment approaches. However, toxicity was less common among patients who received customized treatment.

These results, from the phase 3 ITACA trial, were presented at the 2020 World Conference on Lung Cancer (Abstract 1820), which was rescheduled to January 2021.

“There is a clear need to define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy,” said presenter Silvia Novello, MD, PhD, of the University of Turin in Italy. “mRNA expression of different genes has been correlated with the sensitivity or resistance to specific anticancer agents.”

With this in mind, Dr. Novello and colleagues conducted the ITACA trial. The researchers’ primary goal was to determine whether an adjuvant pharmacogenomic-driven approach was able to improve overall survival in completely resected NSCLC.
 

Patients and treatment

The researchers randomized 773 NSCLC patients within 5-8 weeks after radical surgery. Genomic analyses were performed soon after surgery, and patients were randomly assigned to investigator’s choice of platinum-based chemotherapy or to tailored treatments defined by mRNA levels of ERCC1 and TS.

Patients with high ERCC1 mRNA expression who were randomized to tailored treatment received single-agent docetaxel if their TS level was high or pemetrexed monotherapy if their TS level was low.

Patients with low ERCC1 mRNA expression who were randomized to tailored treatment received cisplatin-gemcitabine if their TS level was high or cisplatin-pemetrexed if their TS was low.

The most frequent doublets used in control patients were cisplatin-gemcitabine and cisplatin-vinorelbine.

The demographic characteristics of the 384 patients randomized to tailored therapy and the 389 control subjects were well-balanced, Dr. Novello said. Two-thirds of patients had stage II disease, 11% were never smokers, and the vast majority had a lobectomy as the resection method.
 

Results

At a median follow-up of 28.2 months, the median overall survival was 96.4 months in the tailored therapy arm and 83.5 months in the control arm. The median recurrence-free survival was 64.4 months and 41.5 months, respectively.

“Adjuvant chemotherapy customization based on the primary tumor tissue mRNA expression of ERCC1 and TS did not significantly improve overall survival or recurrence-free survival,” Dr. Novello said. “There was a non–statistically significant trend for overall survival favoring the customized arm.”

Dr. Novello noted that, when the final analysis was performed, the study was underpowered, as only 46% of expected events were collected. Assuming the same hazard ratio point estimate and that the expected 336 events were collected, the hazard ratio estimate would be 0.76 (P = .012).

Grade 3/4 toxicities occurred in 32.6% of patients in the tailored therapy arm and 45.9% of those in the control arm (P < .001).

“It is important to underline that the treatment customization significantly improved the toxicity profile without compromising the efficacy,” Dr. Novello said.

She added that “more comprehensive and high-throughput diagnostic techniques will be needed in order to tailor adjuvant chemotherapy, with or without immunotherapy, in completely resected NSCLC.”

“The ITACA study is the largest adjuvant study tailored to ERCC1/TS status, and the results have been long-awaited,” said Tetsuya Mitsudomi, MD, a professor at Kindai University in Japan and president of the International Association for the Study of Lung Cancer.

“This trial should be praised for the mandated genomic analysis that was accomplished within a reasonably short time frame before random assignment. In addition, this trial confirmed that there is no biomarker strong enough to predict the efficacy of cytotoxic chemotherapy. However, the concept of customizing adjuvant therapy according to the genomic status of patients’ tumors is valid, leading to the recent demonstration in the ADAURA study of the superiority of osimertinib in delaying the postoperative recurrence of disease in patients with EGFR-mutated NSCLC.”

The ITACA study was funded by University of Turin and Eli Lilly. Dr. Novello disclosed relationships with Eli Lilly, Amgen, AstraZeneca, Bohringer Ingelheim, Beigene, Pfizer, Roche, Merck, Bristol-Myers Squibb, Takeda, and Sanofi. Dr. Mitsudomi disclosed relationships with Eli Lilly, AstraZeneca, Boehringer-Ingelheim, Chugai, Pfizer, Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis, ThermoFisher, Guardant, Eisai, Amgen, and Johnson & Johnson.

Tailoring adjuvant chemotherapy based on the expression of two molecular markers did not confer a survival advantage in patients with completely resected stage II-III non–small cell lung cancer (NSCLC) in a phase 3 trial.

The patients were randomized to receive investigator’s choice of platinum-based chemotherapy or treatment tailored according to messenger RNA (mRNA) expression of two molecular markers – excision repair cross complementation 1 (ERCC1) and thymidylate synthase (TS).

There was no significant difference in overall survival or recurrence-free survival between the treatment approaches. However, toxicity was less common among patients who received customized treatment.

These results, from the phase 3 ITACA trial, were presented at the 2020 World Conference on Lung Cancer (Abstract 1820), which was rescheduled to January 2021.

“There is a clear need to define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy,” said presenter Silvia Novello, MD, PhD, of the University of Turin in Italy. “mRNA expression of different genes has been correlated with the sensitivity or resistance to specific anticancer agents.”

With this in mind, Dr. Novello and colleagues conducted the ITACA trial. The researchers’ primary goal was to determine whether an adjuvant pharmacogenomic-driven approach was able to improve overall survival in completely resected NSCLC.
 

Patients and treatment

The researchers randomized 773 NSCLC patients within 5-8 weeks after radical surgery. Genomic analyses were performed soon after surgery, and patients were randomly assigned to investigator’s choice of platinum-based chemotherapy or to tailored treatments defined by mRNA levels of ERCC1 and TS.

Patients with high ERCC1 mRNA expression who were randomized to tailored treatment received single-agent docetaxel if their TS level was high or pemetrexed monotherapy if their TS level was low.

Patients with low ERCC1 mRNA expression who were randomized to tailored treatment received cisplatin-gemcitabine if their TS level was high or cisplatin-pemetrexed if their TS was low.

The most frequent doublets used in control patients were cisplatin-gemcitabine and cisplatin-vinorelbine.

The demographic characteristics of the 384 patients randomized to tailored therapy and the 389 control subjects were well-balanced, Dr. Novello said. Two-thirds of patients had stage II disease, 11% were never smokers, and the vast majority had a lobectomy as the resection method.
 

Results

At a median follow-up of 28.2 months, the median overall survival was 96.4 months in the tailored therapy arm and 83.5 months in the control arm. The median recurrence-free survival was 64.4 months and 41.5 months, respectively.

“Adjuvant chemotherapy customization based on the primary tumor tissue mRNA expression of ERCC1 and TS did not significantly improve overall survival or recurrence-free survival,” Dr. Novello said. “There was a non–statistically significant trend for overall survival favoring the customized arm.”

Dr. Novello noted that, when the final analysis was performed, the study was underpowered, as only 46% of expected events were collected. Assuming the same hazard ratio point estimate and that the expected 336 events were collected, the hazard ratio estimate would be 0.76 (P = .012).

Grade 3/4 toxicities occurred in 32.6% of patients in the tailored therapy arm and 45.9% of those in the control arm (P < .001).

“It is important to underline that the treatment customization significantly improved the toxicity profile without compromising the efficacy,” Dr. Novello said.

She added that “more comprehensive and high-throughput diagnostic techniques will be needed in order to tailor adjuvant chemotherapy, with or without immunotherapy, in completely resected NSCLC.”

“The ITACA study is the largest adjuvant study tailored to ERCC1/TS status, and the results have been long-awaited,” said Tetsuya Mitsudomi, MD, a professor at Kindai University in Japan and president of the International Association for the Study of Lung Cancer.

“This trial should be praised for the mandated genomic analysis that was accomplished within a reasonably short time frame before random assignment. In addition, this trial confirmed that there is no biomarker strong enough to predict the efficacy of cytotoxic chemotherapy. However, the concept of customizing adjuvant therapy according to the genomic status of patients’ tumors is valid, leading to the recent demonstration in the ADAURA study of the superiority of osimertinib in delaying the postoperative recurrence of disease in patients with EGFR-mutated NSCLC.”

The ITACA study was funded by University of Turin and Eli Lilly. Dr. Novello disclosed relationships with Eli Lilly, Amgen, AstraZeneca, Bohringer Ingelheim, Beigene, Pfizer, Roche, Merck, Bristol-Myers Squibb, Takeda, and Sanofi. Dr. Mitsudomi disclosed relationships with Eli Lilly, AstraZeneca, Boehringer-Ingelheim, Chugai, Pfizer, Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis, ThermoFisher, Guardant, Eisai, Amgen, and Johnson & Johnson.

Tailoring adjuvant chemotherapy based on the expression of two molecular markers did not confer a survival advantage in patients with completely resected stage II-III non–small cell lung cancer (NSCLC) in a phase 3 trial.

The patients were randomized to receive investigator’s choice of platinum-based chemotherapy or treatment tailored according to messenger RNA (mRNA) expression of two molecular markers – excision repair cross complementation 1 (ERCC1) and thymidylate synthase (TS).

There was no significant difference in overall survival or recurrence-free survival between the treatment approaches. However, toxicity was less common among patients who received customized treatment.

These results, from the phase 3 ITACA trial, were presented at the 2020 World Conference on Lung Cancer (Abstract 1820), which was rescheduled to January 2021.

“There is a clear need to define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy,” said presenter Silvia Novello, MD, PhD, of the University of Turin in Italy. “mRNA expression of different genes has been correlated with the sensitivity or resistance to specific anticancer agents.”

With this in mind, Dr. Novello and colleagues conducted the ITACA trial. The researchers’ primary goal was to determine whether an adjuvant pharmacogenomic-driven approach was able to improve overall survival in completely resected NSCLC.
 

Patients and treatment

The researchers randomized 773 NSCLC patients within 5-8 weeks after radical surgery. Genomic analyses were performed soon after surgery, and patients were randomly assigned to investigator’s choice of platinum-based chemotherapy or to tailored treatments defined by mRNA levels of ERCC1 and TS.

Patients with high ERCC1 mRNA expression who were randomized to tailored treatment received single-agent docetaxel if their TS level was high or pemetrexed monotherapy if their TS level was low.

Patients with low ERCC1 mRNA expression who were randomized to tailored treatment received cisplatin-gemcitabine if their TS level was high or cisplatin-pemetrexed if their TS was low.

The most frequent doublets used in control patients were cisplatin-gemcitabine and cisplatin-vinorelbine.

The demographic characteristics of the 384 patients randomized to tailored therapy and the 389 control subjects were well-balanced, Dr. Novello said. Two-thirds of patients had stage II disease, 11% were never smokers, and the vast majority had a lobectomy as the resection method.
 

Results

At a median follow-up of 28.2 months, the median overall survival was 96.4 months in the tailored therapy arm and 83.5 months in the control arm. The median recurrence-free survival was 64.4 months and 41.5 months, respectively.

“Adjuvant chemotherapy customization based on the primary tumor tissue mRNA expression of ERCC1 and TS did not significantly improve overall survival or recurrence-free survival,” Dr. Novello said. “There was a non–statistically significant trend for overall survival favoring the customized arm.”

Dr. Novello noted that, when the final analysis was performed, the study was underpowered, as only 46% of expected events were collected. Assuming the same hazard ratio point estimate and that the expected 336 events were collected, the hazard ratio estimate would be 0.76 (P = .012).

Grade 3/4 toxicities occurred in 32.6% of patients in the tailored therapy arm and 45.9% of those in the control arm (P < .001).

“It is important to underline that the treatment customization significantly improved the toxicity profile without compromising the efficacy,” Dr. Novello said.

She added that “more comprehensive and high-throughput diagnostic techniques will be needed in order to tailor adjuvant chemotherapy, with or without immunotherapy, in completely resected NSCLC.”

“The ITACA study is the largest adjuvant study tailored to ERCC1/TS status, and the results have been long-awaited,” said Tetsuya Mitsudomi, MD, a professor at Kindai University in Japan and president of the International Association for the Study of Lung Cancer.

“This trial should be praised for the mandated genomic analysis that was accomplished within a reasonably short time frame before random assignment. In addition, this trial confirmed that there is no biomarker strong enough to predict the efficacy of cytotoxic chemotherapy. However, the concept of customizing adjuvant therapy according to the genomic status of patients’ tumors is valid, leading to the recent demonstration in the ADAURA study of the superiority of osimertinib in delaying the postoperative recurrence of disease in patients with EGFR-mutated NSCLC.”

The ITACA study was funded by University of Turin and Eli Lilly. Dr. Novello disclosed relationships with Eli Lilly, Amgen, AstraZeneca, Bohringer Ingelheim, Beigene, Pfizer, Roche, Merck, Bristol-Myers Squibb, Takeda, and Sanofi. Dr. Mitsudomi disclosed relationships with Eli Lilly, AstraZeneca, Boehringer-Ingelheim, Chugai, Pfizer, Merck, Ono Pharmaceutical, Bristol-Myers Squibb, Novartis, ThermoFisher, Guardant, Eisai, Amgen, and Johnson & Johnson.

Neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients with stage IB-IIIB lung cancer and produced a 21% major pathologic response rate, according to the primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study.

Small pilot studies previously suggested that preoperative immune checkpoint inhibitor (ICI) therapy may benefit patients with resectable non–small cell lung cancer (NSCLC).

The LCMC3 study is “unique” because it is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, and it’s “a landmark study” because it validated results from smaller trials and can serve as a benchmark for future ones, said Jay M. Lee, MD, of the University of California, Los Angeles.

Dr. Lee presented results from LCMC3 at the 2020 World Congress on Lung Cancer (Abstract PS01.05), which was rescheduled for January 2021.

The study included 181 patients, median age 65 years, with stage IB-IIIB NSCLC. The vast majority (90%) of patients were current/former smokers, and two-thirds had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB, 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

Patients received 1,200 mg of neoadjuvant atezolizumab intravenously every 3 weeks for two cycles followed by resection between 30 and 50 days from the first cycle. Patients who benefited from the therapy continued adjuvant atezolizumab for 12 months.

The primary endpoint was major pathological response, defined as no more than 10% viable tumor cells at surgery, in patients without epidermal growth factor receptor or anaplastic lymphoma kinase mutations.
 

Results

Following atezolizumab treatment, 43% of patients were down-staged, and 19% were up-staged. Some degree of pathological regression was observed in all but 3 of the 159 patients who underwent resection.

Among the 144 patients included in the efficacy analysis, the major pathological response rate was 21%, with 7% of patients achieving a complete pathological response.

“We demonstrated that more than half of patients resected with a minimally invasive operation. Remarkably, only 15% required thoracotomy. The 92% complete resection rate is comparable, if not superior to, preoperative chemotherapy trials,” Dr. Lee said.

The majority (88%) of patients underwent surgical resection within a 20-day protocol window. The median time from end of neoadjuvant therapy to surgery was 22 days.

“Historically, the neoadjuvant chemotherapy window is much later for surgery, 3 weeks from neoadjuvant therapy, and that can be stretched to up to 56 days,” Dr. Lee said.

In an exploratory analysis, the 1.5-year overall survival rate was 91% for stage I and II disease and 87% for stage III disease. The survival in both cohorts was superior to that expected historically, Dr. Lee noted.

Intraoperative complications were rare (3%). Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen.

One patient died following surgery after the first 30 days, which was deemed unrelated to treatment. Another patient died between 30 and 90 days from treatment-related pneumonitis.

“The LCMC3 study successfully met its primary endpoint of achieving major pathological response,” Dr. Lee concluded. “Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window and with a short time frame from completion of atezolizumab and with a correspondingly high complete resection rate.”

The study’s results suggest that “neoadjuvant atezolizumab monotherapy is effective, well tolerated, and surgically acceptable,” said study discussant Shinichi Toyooka, MD, of Okayama (Japan) University Hospital.

“I would consider single-agent ICI neoadjuvant therapy for patients with early-stage disease and poor performance status, and an ICI plus chemotherapy for more advanced resectable cases, like locally advanced disease,” Dr. Toyooka said.

The LCMC3 study is sponsored by Genentech. Dr. Lee disclosed relationships with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis. Dr. Toyooka disclosed relationships with AstraZeneca, Chugai, Taiho Pharmaceutical Group, and Ono Pharmaceutical.

Neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients with stage IB-IIIB lung cancer and produced a 21% major pathologic response rate, according to the primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study.

Small pilot studies previously suggested that preoperative immune checkpoint inhibitor (ICI) therapy may benefit patients with resectable non–small cell lung cancer (NSCLC).

The LCMC3 study is “unique” because it is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, and it’s “a landmark study” because it validated results from smaller trials and can serve as a benchmark for future ones, said Jay M. Lee, MD, of the University of California, Los Angeles.

Dr. Lee presented results from LCMC3 at the 2020 World Congress on Lung Cancer (Abstract PS01.05), which was rescheduled for January 2021.

The study included 181 patients, median age 65 years, with stage IB-IIIB NSCLC. The vast majority (90%) of patients were current/former smokers, and two-thirds had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB, 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

Patients received 1,200 mg of neoadjuvant atezolizumab intravenously every 3 weeks for two cycles followed by resection between 30 and 50 days from the first cycle. Patients who benefited from the therapy continued adjuvant atezolizumab for 12 months.

The primary endpoint was major pathological response, defined as no more than 10% viable tumor cells at surgery, in patients without epidermal growth factor receptor or anaplastic lymphoma kinase mutations.
 

Results

Following atezolizumab treatment, 43% of patients were down-staged, and 19% were up-staged. Some degree of pathological regression was observed in all but 3 of the 159 patients who underwent resection.

Among the 144 patients included in the efficacy analysis, the major pathological response rate was 21%, with 7% of patients achieving a complete pathological response.

“We demonstrated that more than half of patients resected with a minimally invasive operation. Remarkably, only 15% required thoracotomy. The 92% complete resection rate is comparable, if not superior to, preoperative chemotherapy trials,” Dr. Lee said.

The majority (88%) of patients underwent surgical resection within a 20-day protocol window. The median time from end of neoadjuvant therapy to surgery was 22 days.

“Historically, the neoadjuvant chemotherapy window is much later for surgery, 3 weeks from neoadjuvant therapy, and that can be stretched to up to 56 days,” Dr. Lee said.

In an exploratory analysis, the 1.5-year overall survival rate was 91% for stage I and II disease and 87% for stage III disease. The survival in both cohorts was superior to that expected historically, Dr. Lee noted.

Intraoperative complications were rare (3%). Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen.

One patient died following surgery after the first 30 days, which was deemed unrelated to treatment. Another patient died between 30 and 90 days from treatment-related pneumonitis.

“The LCMC3 study successfully met its primary endpoint of achieving major pathological response,” Dr. Lee concluded. “Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window and with a short time frame from completion of atezolizumab and with a correspondingly high complete resection rate.”

The study’s results suggest that “neoadjuvant atezolizumab monotherapy is effective, well tolerated, and surgically acceptable,” said study discussant Shinichi Toyooka, MD, of Okayama (Japan) University Hospital.

“I would consider single-agent ICI neoadjuvant therapy for patients with early-stage disease and poor performance status, and an ICI plus chemotherapy for more advanced resectable cases, like locally advanced disease,” Dr. Toyooka said.

The LCMC3 study is sponsored by Genentech. Dr. Lee disclosed relationships with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis. Dr. Toyooka disclosed relationships with AstraZeneca, Chugai, Taiho Pharmaceutical Group, and Ono Pharmaceutical.

Neoadjuvant atezolizumab prior to lung cancer surgery was well tolerated by patients with stage IB-IIIB lung cancer and produced a 21% major pathologic response rate, according to the primary analysis of the Lung Cancer Mutation Consortium (LCMC) 3 study.

Small pilot studies previously suggested that preoperative immune checkpoint inhibitor (ICI) therapy may benefit patients with resectable non–small cell lung cancer (NSCLC).

The LCMC3 study is “unique” because it is the largest monotherapy trial of checkpoint inhibition in resectable NSCLC, and it’s “a landmark study” because it validated results from smaller trials and can serve as a benchmark for future ones, said Jay M. Lee, MD, of the University of California, Los Angeles.

Dr. Lee presented results from LCMC3 at the 2020 World Congress on Lung Cancer (Abstract PS01.05), which was rescheduled for January 2021.

The study included 181 patients, median age 65 years, with stage IB-IIIB NSCLC. The vast majority (90%) of patients were current/former smokers, and two-thirds had a nonsquamous histology. Patients were categorized in the following stages: 17 patients were staged at IB, 20 were IIA, 55 were IIB, 72 were IIIA, and 17 were IIIB.

Patients received 1,200 mg of neoadjuvant atezolizumab intravenously every 3 weeks for two cycles followed by resection between 30 and 50 days from the first cycle. Patients who benefited from the therapy continued adjuvant atezolizumab for 12 months.

The primary endpoint was major pathological response, defined as no more than 10% viable tumor cells at surgery, in patients without epidermal growth factor receptor or anaplastic lymphoma kinase mutations.
 

Results

Following atezolizumab treatment, 43% of patients were down-staged, and 19% were up-staged. Some degree of pathological regression was observed in all but 3 of the 159 patients who underwent resection.

Among the 144 patients included in the efficacy analysis, the major pathological response rate was 21%, with 7% of patients achieving a complete pathological response.

“We demonstrated that more than half of patients resected with a minimally invasive operation. Remarkably, only 15% required thoracotomy. The 92% complete resection rate is comparable, if not superior to, preoperative chemotherapy trials,” Dr. Lee said.

The majority (88%) of patients underwent surgical resection within a 20-day protocol window. The median time from end of neoadjuvant therapy to surgery was 22 days.

“Historically, the neoadjuvant chemotherapy window is much later for surgery, 3 weeks from neoadjuvant therapy, and that can be stretched to up to 56 days,” Dr. Lee said.

In an exploratory analysis, the 1.5-year overall survival rate was 91% for stage I and II disease and 87% for stage III disease. The survival in both cohorts was superior to that expected historically, Dr. Lee noted.

Intraoperative complications were rare (3%). Postoperative adverse reactions correlated with fewer viable tumor cells in the resected specimen.

One patient died following surgery after the first 30 days, which was deemed unrelated to treatment. Another patient died between 30 and 90 days from treatment-related pneumonitis.

“The LCMC3 study successfully met its primary endpoint of achieving major pathological response,” Dr. Lee concluded. “Neoadjuvant atezolizumab monotherapy was well tolerated, and resection was performed with low perioperative morbidity and mortality, usually within a narrow protocol window and with a short time frame from completion of atezolizumab and with a correspondingly high complete resection rate.”

The study’s results suggest that “neoadjuvant atezolizumab monotherapy is effective, well tolerated, and surgically acceptable,” said study discussant Shinichi Toyooka, MD, of Okayama (Japan) University Hospital.

“I would consider single-agent ICI neoadjuvant therapy for patients with early-stage disease and poor performance status, and an ICI plus chemotherapy for more advanced resectable cases, like locally advanced disease,” Dr. Toyooka said.

The LCMC3 study is sponsored by Genentech. Dr. Lee disclosed relationships with Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Merck, and Novartis. Dr. Toyooka disclosed relationships with AstraZeneca, Chugai, Taiho Pharmaceutical Group, and Ono Pharmaceutical.

The KRAS inhibitor sotorasib provides durable clinical benefit in heavily pretreated patients with non–small cell lung cancer (NSCLC) harboring KRAS p.G12C mutations, results of a phase 2 trial suggest.

“This is a historic milestone in lung cancer therapy. After 4 decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” said Bob T. Li, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Li reported results with sotorasib in NSCLC, from the phase 2 part of the CodeBreaK 100 trial, at the 2020 World Conference on Lung Cancer (Abstract PS01.07), which was rescheduled for January 2021.

“It’s an absolutely remarkable study,” said Dean A. Fennell, MBBS, PhD, of the University of Leicester and University Hospitals of Leicester NHS Trust in the United Kingdom.

“The ‘un-druggability’ of KRAS has been something of a challenge for decades. To see results like this from Dr. Li is absolutely fabulous and will lead to a new stratification option.”
 

Rationale and study details

Dr. Li noted that the KRAS p.G12C mutation is a key oncogenic driver, occurring in about 13% of lung adenocarcinomas.

Sotorasib is a first-in-class, highly selective, irreversible KRASG12C inhibitor. It showed durable clinical benefit in 59 NSCLC patients enrolled in the phase 1 part of the CodeBreaK 100 trial (N Engl J Med 2020;383:1207-17). One-third of the patients had an objective response across all doses tested. The median duration of response was 10.9 months, and the median progression-free survival was 6.3 months.

The phase 2 part of CodeBreaK 100 included 126 patients from 11 countries in North America, Europe, and Asia-Pacific. Their median age was 63.5 years (range, 37-80 years), and 92.9% were current or former smokers.

Patients had locally advanced or metastatic NSCLC and a centrally confirmed KRAS p.G12C mutation. They had progressed after three or fewer prior lines of therapy.

Patients received oral sotorasib at 960 mg daily until disease progression. They were followed for a median of 12.2 months. An independent blinded central review found that 124 patients had at least one measurable lesion at baseline and were therefore evaluable for efficacy.

Phase 2 results

Sotorasib “demonstrated early, deep, and durable responses,” Dr. Li said.

In all, 46 patients had a confirmed response – 3 complete responses and 43 partial responses – for an objective response rate of 37.1%.

The median time to objective response was 1.4 months, the median duration of response was 10 months, and 43% of responders were still on treatment without progression at the data cutoff.

“Tumor response to sotorasib was observed across a range of biomarker subgroups, including patients with negative or low PD-L1 expression level and those with mutant STK11,” Dr. Li said.

The disease control rate was 80.6%, and tumors shrank by an average of about 60%. The median progression-free survival was 6.8 months.

Treatment-related adverse events (TRAEs) were acceptable, with no surprises compared to phase 1 results, Dr. Li said.

TRAEs of any grade occurred in 69.8% of patients and led to discontinuation in 7.1%. TRAEs led to dose modification in 22.2% of patients.

Grade 3 TRAEs were reported in 19.8% of patients, including alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), diarrhea (4.0%), and blood alkaline phosphatase increase (0.8%).

“Sotorasib was well tolerated, with no deaths attributed to treatment and low incidence of grade 3 or 4 TRAEs, treatment discontinuation, and dose modification,” Dr. Li said.

A phase 3 trial of sotorasib compared with second-line docetaxel is now enrolling patients.

The phase 1/2 CodeBreaK 100 trial was funded by Amgen. Dr. Li disclosed relationships with Amgen and many other companies. Dr. Fennell disclosed relationships with AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Merck, Roche, Astex Therapeutics, Bayer, Lab21, Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

The KRAS inhibitor sotorasib provides durable clinical benefit in heavily pretreated patients with non–small cell lung cancer (NSCLC) harboring KRAS p.G12C mutations, results of a phase 2 trial suggest.

“This is a historic milestone in lung cancer therapy. After 4 decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” said Bob T. Li, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Li reported results with sotorasib in NSCLC, from the phase 2 part of the CodeBreaK 100 trial, at the 2020 World Conference on Lung Cancer (Abstract PS01.07), which was rescheduled for January 2021.

“It’s an absolutely remarkable study,” said Dean A. Fennell, MBBS, PhD, of the University of Leicester and University Hospitals of Leicester NHS Trust in the United Kingdom.

“The ‘un-druggability’ of KRAS has been something of a challenge for decades. To see results like this from Dr. Li is absolutely fabulous and will lead to a new stratification option.”
 

Rationale and study details

Dr. Li noted that the KRAS p.G12C mutation is a key oncogenic driver, occurring in about 13% of lung adenocarcinomas.

Sotorasib is a first-in-class, highly selective, irreversible KRASG12C inhibitor. It showed durable clinical benefit in 59 NSCLC patients enrolled in the phase 1 part of the CodeBreaK 100 trial (N Engl J Med 2020;383:1207-17). One-third of the patients had an objective response across all doses tested. The median duration of response was 10.9 months, and the median progression-free survival was 6.3 months.

The phase 2 part of CodeBreaK 100 included 126 patients from 11 countries in North America, Europe, and Asia-Pacific. Their median age was 63.5 years (range, 37-80 years), and 92.9% were current or former smokers.

Patients had locally advanced or metastatic NSCLC and a centrally confirmed KRAS p.G12C mutation. They had progressed after three or fewer prior lines of therapy.

Patients received oral sotorasib at 960 mg daily until disease progression. They were followed for a median of 12.2 months. An independent blinded central review found that 124 patients had at least one measurable lesion at baseline and were therefore evaluable for efficacy.

Phase 2 results

Sotorasib “demonstrated early, deep, and durable responses,” Dr. Li said.

In all, 46 patients had a confirmed response – 3 complete responses and 43 partial responses – for an objective response rate of 37.1%.

The median time to objective response was 1.4 months, the median duration of response was 10 months, and 43% of responders were still on treatment without progression at the data cutoff.

“Tumor response to sotorasib was observed across a range of biomarker subgroups, including patients with negative or low PD-L1 expression level and those with mutant STK11,” Dr. Li said.

The disease control rate was 80.6%, and tumors shrank by an average of about 60%. The median progression-free survival was 6.8 months.

Treatment-related adverse events (TRAEs) were acceptable, with no surprises compared to phase 1 results, Dr. Li said.

TRAEs of any grade occurred in 69.8% of patients and led to discontinuation in 7.1%. TRAEs led to dose modification in 22.2% of patients.

Grade 3 TRAEs were reported in 19.8% of patients, including alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), diarrhea (4.0%), and blood alkaline phosphatase increase (0.8%).

“Sotorasib was well tolerated, with no deaths attributed to treatment and low incidence of grade 3 or 4 TRAEs, treatment discontinuation, and dose modification,” Dr. Li said.

A phase 3 trial of sotorasib compared with second-line docetaxel is now enrolling patients.

The phase 1/2 CodeBreaK 100 trial was funded by Amgen. Dr. Li disclosed relationships with Amgen and many other companies. Dr. Fennell disclosed relationships with AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Merck, Roche, Astex Therapeutics, Bayer, Lab21, Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

The KRAS inhibitor sotorasib provides durable clinical benefit in heavily pretreated patients with non–small cell lung cancer (NSCLC) harboring KRAS p.G12C mutations, results of a phase 2 trial suggest.

“This is a historic milestone in lung cancer therapy. After 4 decades of scientific efforts in targeting KRAS, sotorasib has potential to be the first targeted treatment option for this patient population with a high unmet need,” said Bob T. Li, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Li reported results with sotorasib in NSCLC, from the phase 2 part of the CodeBreaK 100 trial, at the 2020 World Conference on Lung Cancer (Abstract PS01.07), which was rescheduled for January 2021.

“It’s an absolutely remarkable study,” said Dean A. Fennell, MBBS, PhD, of the University of Leicester and University Hospitals of Leicester NHS Trust in the United Kingdom.

“The ‘un-druggability’ of KRAS has been something of a challenge for decades. To see results like this from Dr. Li is absolutely fabulous and will lead to a new stratification option.”
 

Rationale and study details

Dr. Li noted that the KRAS p.G12C mutation is a key oncogenic driver, occurring in about 13% of lung adenocarcinomas.

Sotorasib is a first-in-class, highly selective, irreversible KRASG12C inhibitor. It showed durable clinical benefit in 59 NSCLC patients enrolled in the phase 1 part of the CodeBreaK 100 trial (N Engl J Med 2020;383:1207-17). One-third of the patients had an objective response across all doses tested. The median duration of response was 10.9 months, and the median progression-free survival was 6.3 months.

The phase 2 part of CodeBreaK 100 included 126 patients from 11 countries in North America, Europe, and Asia-Pacific. Their median age was 63.5 years (range, 37-80 years), and 92.9% were current or former smokers.

Patients had locally advanced or metastatic NSCLC and a centrally confirmed KRAS p.G12C mutation. They had progressed after three or fewer prior lines of therapy.

Patients received oral sotorasib at 960 mg daily until disease progression. They were followed for a median of 12.2 months. An independent blinded central review found that 124 patients had at least one measurable lesion at baseline and were therefore evaluable for efficacy.

Phase 2 results

Sotorasib “demonstrated early, deep, and durable responses,” Dr. Li said.

In all, 46 patients had a confirmed response – 3 complete responses and 43 partial responses – for an objective response rate of 37.1%.

The median time to objective response was 1.4 months, the median duration of response was 10 months, and 43% of responders were still on treatment without progression at the data cutoff.

“Tumor response to sotorasib was observed across a range of biomarker subgroups, including patients with negative or low PD-L1 expression level and those with mutant STK11,” Dr. Li said.

The disease control rate was 80.6%, and tumors shrank by an average of about 60%. The median progression-free survival was 6.8 months.

Treatment-related adverse events (TRAEs) were acceptable, with no surprises compared to phase 1 results, Dr. Li said.

TRAEs of any grade occurred in 69.8% of patients and led to discontinuation in 7.1%. TRAEs led to dose modification in 22.2% of patients.

Grade 3 TRAEs were reported in 19.8% of patients, including alanine aminotransferase increase (6.3%), aspartate aminotransferase increase (5.6%), diarrhea (4.0%), and blood alkaline phosphatase increase (0.8%).

“Sotorasib was well tolerated, with no deaths attributed to treatment and low incidence of grade 3 or 4 TRAEs, treatment discontinuation, and dose modification,” Dr. Li said.

A phase 3 trial of sotorasib compared with second-line docetaxel is now enrolling patients.

The phase 1/2 CodeBreaK 100 trial was funded by Amgen. Dr. Li disclosed relationships with Amgen and many other companies. Dr. Fennell disclosed relationships with AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Merck, Roche, Astex Therapeutics, Bayer, Lab21, Atara Biotherapeutics, Boehringer Ingelheim, and Inventiva.

A third of patients with COVID-19 and thoracic malignancies die, according to updated results from the TERAVOLT registry.

The risk of death was similar across racial and ethnic groups. Factors associated with an increased risk of death were male sex, older age, worse performance scores, and four or more metastatic sites.

“Death rates remain high at 33%, underscoring the importance of COVID-19 vaccination in patients with thoracic cancers, when available,” said Umit Tapan, MD, of Boston University.

Dr. Tapan presented the TERAVOLT update at the 2020 World Congress on Lung Cancer (Abstract P09.18), which was rescheduled for January 2021.

The TERAVOLT registry is a multicenter, observational study with a cross-sectional component and a longitudinal cohort component.

The registry includes patients who have thoracic cancers – non–small cell lung cancer (NSCLC), small cell lung cancer, mesothelioma, thymic epithelial tumors, and other pulmonary neuroendocrine neoplasms – and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms.

Clinical data were extracted from medical records of consecutive patients from Jan. 1, 2020, and will be collected until the end of pandemic, as declared by the World Health Organization. Data collected include demographics, oncologic history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes.

“The overarching goals of this consortium are to provide data for guidance to oncology professionals on managing patients with thoracic malignancies while understanding the risk factors for morbidity and mortality from this novel virus,” Dr. Tapan said.

Data from TERAVOLT were previously presented at AACR, ASCO, and ESMO last year, as well as published in The Lancet Oncology.

Updated results

Dr. Tapan presented data on 1,011 patients from 120 centers in 19 countries. The patients’ median age was 68 years (range, 28-95 years), and more than half were male (58%). Most patients (72%) were White, 20% were Hispanic/Latino, and 8% were Black/African American.

Most patients had NSCLC (82%), and most had stage IV disease (68%). Patients had received a median of one prior line of therapy.

As in earlier reports of TERAVOLT data, the mortality rate was 33%.

In a multivariate analysis, the following characteristics were associated with an increased risk of death:

• Male sex (odds ratio, 1.4).
• Older age (per 10 years; OR, 1.21).
• Performance score of 1 (OR, 1.73), 2 (OR, 4.74), and 3/4 (OR, 10.7).
• Four or more metastatic sites (OR, 3.05).

The following characteristics were associated with an increased risk of hospitalization in a multivariate analysis:

• Male sex (OR, 1.67).
• Older age (per 10 years; OR, 1.24).
• Performance score of 2 (OR, 4.47) and 3/4 (OR, 9.63).
• Four or more metastatic sites (OR, 4.0).
• Thymic carcinoma (OR, 3.58).
• Receiving radiation (OR, 2.1).

Race and ethnicity did not seem to affect the risk of death or hospitalization, “but we plan to conduct further analysis,” Dr. Tapan said.

Roxana Reyes, MD, of Hospital Clínic de Barcelona, said her hospital sees patients with lung cancer at high risk for COVID-19, but there is no screening program in place.

“We use medical consultations to focus on early diagnosis. We treat COVID-19 complications but lose a lot of patients. There is an opportunity to be found to find these patients sooner,” Dr. Reyes said.

She noted that COVID-19 will likely last a long time, and therefore “we have to protect against it and continue to diagnose lung cancer at earlier stages.”

Dr. Reyes disclosed relationships with Roche, Bristol-Myers Squibb, and Merck Sharp & Dohme. Dr. Tapan has no relevant disclosures. The TERAVOLT registry is funded, in part, by the International Association for the Study of Lung Cancer.

A third of patients with COVID-19 and thoracic malignancies die, according to updated results from the TERAVOLT registry.

The risk of death was similar across racial and ethnic groups. Factors associated with an increased risk of death were male sex, older age, worse performance scores, and four or more metastatic sites.

“Death rates remain high at 33%, underscoring the importance of COVID-19 vaccination in patients with thoracic cancers, when available,” said Umit Tapan, MD, of Boston University.

Dr. Tapan presented the TERAVOLT update at the 2020 World Congress on Lung Cancer (Abstract P09.18), which was rescheduled for January 2021.

The TERAVOLT registry is a multicenter, observational study with a cross-sectional component and a longitudinal cohort component.

The registry includes patients who have thoracic cancers – non–small cell lung cancer (NSCLC), small cell lung cancer, mesothelioma, thymic epithelial tumors, and other pulmonary neuroendocrine neoplasms – and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms.

Clinical data were extracted from medical records of consecutive patients from Jan. 1, 2020, and will be collected until the end of pandemic, as declared by the World Health Organization. Data collected include demographics, oncologic history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes.

“The overarching goals of this consortium are to provide data for guidance to oncology professionals on managing patients with thoracic malignancies while understanding the risk factors for morbidity and mortality from this novel virus,” Dr. Tapan said.

Data from TERAVOLT were previously presented at AACR, ASCO, and ESMO last year, as well as published in The Lancet Oncology.

Updated results

Dr. Tapan presented data on 1,011 patients from 120 centers in 19 countries. The patients’ median age was 68 years (range, 28-95 years), and more than half were male (58%). Most patients (72%) were White, 20% were Hispanic/Latino, and 8% were Black/African American.

Most patients had NSCLC (82%), and most had stage IV disease (68%). Patients had received a median of one prior line of therapy.

As in earlier reports of TERAVOLT data, the mortality rate was 33%.

In a multivariate analysis, the following characteristics were associated with an increased risk of death:

• Male sex (odds ratio, 1.4).
• Older age (per 10 years; OR, 1.21).
• Performance score of 1 (OR, 1.73), 2 (OR, 4.74), and 3/4 (OR, 10.7).
• Four or more metastatic sites (OR, 3.05).

The following characteristics were associated with an increased risk of hospitalization in a multivariate analysis:

• Male sex (OR, 1.67).
• Older age (per 10 years; OR, 1.24).
• Performance score of 2 (OR, 4.47) and 3/4 (OR, 9.63).
• Four or more metastatic sites (OR, 4.0).
• Thymic carcinoma (OR, 3.58).
• Receiving radiation (OR, 2.1).

Race and ethnicity did not seem to affect the risk of death or hospitalization, “but we plan to conduct further analysis,” Dr. Tapan said.

Roxana Reyes, MD, of Hospital Clínic de Barcelona, said her hospital sees patients with lung cancer at high risk for COVID-19, but there is no screening program in place.

“We use medical consultations to focus on early diagnosis. We treat COVID-19 complications but lose a lot of patients. There is an opportunity to be found to find these patients sooner,” Dr. Reyes said.

She noted that COVID-19 will likely last a long time, and therefore “we have to protect against it and continue to diagnose lung cancer at earlier stages.”

Dr. Reyes disclosed relationships with Roche, Bristol-Myers Squibb, and Merck Sharp & Dohme. Dr. Tapan has no relevant disclosures. The TERAVOLT registry is funded, in part, by the International Association for the Study of Lung Cancer.

A third of patients with COVID-19 and thoracic malignancies die, according to updated results from the TERAVOLT registry.

The risk of death was similar across racial and ethnic groups. Factors associated with an increased risk of death were male sex, older age, worse performance scores, and four or more metastatic sites.

“Death rates remain high at 33%, underscoring the importance of COVID-19 vaccination in patients with thoracic cancers, when available,” said Umit Tapan, MD, of Boston University.

Dr. Tapan presented the TERAVOLT update at the 2020 World Congress on Lung Cancer (Abstract P09.18), which was rescheduled for January 2021.

The TERAVOLT registry is a multicenter, observational study with a cross-sectional component and a longitudinal cohort component.

The registry includes patients who have thoracic cancers – non–small cell lung cancer (NSCLC), small cell lung cancer, mesothelioma, thymic epithelial tumors, and other pulmonary neuroendocrine neoplasms – and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms.

Clinical data were extracted from medical records of consecutive patients from Jan. 1, 2020, and will be collected until the end of pandemic, as declared by the World Health Organization. Data collected include demographics, oncologic history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes.

“The overarching goals of this consortium are to provide data for guidance to oncology professionals on managing patients with thoracic malignancies while understanding the risk factors for morbidity and mortality from this novel virus,” Dr. Tapan said.

Data from TERAVOLT were previously presented at AACR, ASCO, and ESMO last year, as well as published in The Lancet Oncology.

Updated results

Dr. Tapan presented data on 1,011 patients from 120 centers in 19 countries. The patients’ median age was 68 years (range, 28-95 years), and more than half were male (58%). Most patients (72%) were White, 20% were Hispanic/Latino, and 8% were Black/African American.

Most patients had NSCLC (82%), and most had stage IV disease (68%). Patients had received a median of one prior line of therapy.

As in earlier reports of TERAVOLT data, the mortality rate was 33%.

In a multivariate analysis, the following characteristics were associated with an increased risk of death:

• Male sex (odds ratio, 1.4).
• Older age (per 10 years; OR, 1.21).
• Performance score of 1 (OR, 1.73), 2 (OR, 4.74), and 3/4 (OR, 10.7).
• Four or more metastatic sites (OR, 3.05).

The following characteristics were associated with an increased risk of hospitalization in a multivariate analysis:

• Male sex (OR, 1.67).
• Older age (per 10 years; OR, 1.24).
• Performance score of 2 (OR, 4.47) and 3/4 (OR, 9.63).
• Four or more metastatic sites (OR, 4.0).
• Thymic carcinoma (OR, 3.58).
• Receiving radiation (OR, 2.1).

Race and ethnicity did not seem to affect the risk of death or hospitalization, “but we plan to conduct further analysis,” Dr. Tapan said.

Roxana Reyes, MD, of Hospital Clínic de Barcelona, said her hospital sees patients with lung cancer at high risk for COVID-19, but there is no screening program in place.

“We use medical consultations to focus on early diagnosis. We treat COVID-19 complications but lose a lot of patients. There is an opportunity to be found to find these patients sooner,” Dr. Reyes said.

She noted that COVID-19 will likely last a long time, and therefore “we have to protect against it and continue to diagnose lung cancer at earlier stages.”

Dr. Reyes disclosed relationships with Roche, Bristol-Myers Squibb, and Merck Sharp & Dohme. Dr. Tapan has no relevant disclosures. The TERAVOLT registry is funded, in part, by the International Association for the Study of Lung Cancer.

In the first ever placebo-controlled phase 3 trial in patients with relapsed mesothelioma, immunotherapy with nivolumab significantly improved both overall survival (OS) and progression-free survival (PFS).

The CONFIRM trial involved 330 previously treated patients with mesothelioma who were randomly assigned to nivolumab or placebo for 1 year or until progression or unacceptable toxicity.

Although recruitment to the study was stopped early because of the COVID-19 pandemic, enough data accrued to show that nivolumab improved overall survival by 28% over placebo, and increased PFS by 39%.

“Nivolumab was deemed a safe and effective treatment and should be considered a new treatment option for patients with relapsed mesothelioma,” said principal investigator Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester (England).

He presented the results at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021.

Rina Hui, MD, PhD, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, who was not involved in the study, said that these results had been a “long time coming.”

CONFIRM has added “important, encouraging data on immunotherapy in the salvage setting,” Dr. Hui said, noting that two-thirds of patients had received two or more prior lines of therapy.

Dr. Fennel noted that “a significant clinical benefit was observed in the epithelioid subtype” of the disease but not in patients with nonepithelioid disease.

However, there was “no evidence” to support programmed death–ligand 1 (PD-L1) expression as predictive of outcomes, he added, which does appear to be the case in some trials on lung cancer and other tumors.

Commenting on these observations, Dr. Hui said that PD-L1 as a predictive biomarker in mesothelioma has been “controversial,” and she emphasized that the results from CONFIRM indicate “no evidence of PD-L1 being predictive.”

However, Dr. Hui questioned the other observation that clinical benefit appeared to be seen only in the epithelioid subtype.

She emphasized that nonepithelioid disease is known to be a “more aggressive, chemoresistant subtype ... with a steep decline in the survival curves.

“Therefore, a lot of patients would not have made it to a subsequent-line clinical trial, explaining why there were only 12% in the CONFIRM study,” and so the sample size may be “too small to detect a difference in outcome,” Dr. Hui said.

Consequently, Dr. Hui said she “would not deny patients with nonepithelioid histology from considering nivolumab in the salvage setting.”

She argued that there was “no clear predictive biomarker for patient selection” emerging from the CONFIRM data.

She agreed that, in patients with mesothelioma who have progressed following platinum/pemetrexed-based chemotherapy as in the first line, “monotherapy nivolumab now can be considered as a treatment option in the second- ... or third-line setting, after second-line chemotherapy”.

However, outstanding questions remain, including whether nivolumab “provides better outcomes than second-line single agent chemotherapy or second-line gemcitabine with the [vascular endothelial growth factor receptor] inhibitor ramucirumab.”

It may also be that nivolumab plus ipilimumab might be superior to nivolumab alone in the salvage setting.

But a more fundamental question is what should be considered for salvage therapy if nivolumab and ipilimumab have already been used in the first-line setting, Dr. Hui said.

Results of first-line immunotherapy combination trials are “eagerly awaited ... to determine and develop other salvage treatments,” she commented.

Responding on Twitter, Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust in Royal Tunbridge Wells, England, echoed these comments, saying that the results were “very exciting,” but he also “can’t wait to see the first-line chemo–immunotherapy data.”

Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, commented on Twitter that there was “not a lot of safety data” in the presentation and awaits their eventual publication.

He added that it is “good to have a positive trial” in relapsed mesothelioma, “though the first-line studies will decrease the eventual impact as immunotherapy becomes involved earlier in treatment.”

 

Details of the CONFIRM results 

Relapsed mesothelioma is an “unmet need,” and, until now, “there have been no phase 3 trials which have demonstrated improved overall survival,” Dr. Fennell said in his presentation.

However, three phase 2 trials have shown that immune checkpoint targeting via PD-1 has shown useful clinical activity as a monotherapy in the relapsed setting, and one of these trials has led to approval of nivolumab in Japan for this indication.

CONFIRM was an investigator-initiated phase 3 trial in patients with relapsed mesothelioma who had received more than one prior line of therapy and had a good performance status.

Recruitment began in April 2017, and the “target sample size was 336 patients,” Dr. Fennell said, but the trial was “halted at 332 patients (in March 2020) due to the peaking of the COVID-19 pandemic in the U.K.”

“However, at the time, it was felt there were sufficient events” to justify the current analysis of the coprimary endpoints of PFS and OS, despite the latter being 59 events short of the target of 291.

Dr. Fennell said that baseline characteristics were “generally well balanced” between the nivolumab (n = 221) and placebo (n = 111) arms.

However, there were more patients with a PD-L1 tumor proportion score (TPS) of at least 1% among the patients given nivolumab, at 37% versus 29% in the placebo arm.

After a median follow-up of 17.1 months in the nivolumab arm and 14.2 months in the placebo group, overall survival was significantly longer with the active treatment, at 9.2 months versus 6.6 months with placebo (hazard ratio, 0.72; P = .018).

The proportion of patients alive at 12 months was 39.5% in the nivolumab group and 26.9% in patients given placebo. Investigator-assessed PFS was also significantly longer with nivolumab, at 3.0 months versus 1.8 months with placebo (HR, 0.61; P < .001).

The proportion of patients disease free at 12 months was 14.5% with active treatment versus 4.9% months with the placebo.

“The role for PD-L1 as a potential biomarker was assessed,” Dr. Fennell said, using the Dako 22C3 antibody, with 150 nivolumab and 84 placebo patients divided into those with a TPS <1% or ≥1%.

He noted that PD-L1 expression in the tumor “did not predict survival for patients in the CONFIRM trial,” with neither PD-L1 positive nor PD-L1 negative patients demonstrating a significant improvement in overall survival with nivolumab vs placebo.

“For histology, epithelioid mesothelioma patients benefited from nivolumab,” Dr. Fennell continued, with a hazard ratio for death of 0.71 versus placebo (P = .021). “However, for the nonepithelioid subgroup, in this immature survival analysis ... the P value was not significant,” but this was a small subgroup of patients (12% in both nivolumab and placebo groups).

The safety analysis revealed that the proportion of patients with any serious adverse events, of any grade or grade 3 or higher, was almost identical between the active and placebo arms, Dr. Fennel reported. There were five deaths (3.6%) related to a serious adverse event in the nivolumab arm and four (5.3%) in the placebo group.

This research was funded by the Stand Up to Cancer campaign for Cancer Research UK, supported by Cancer Research UK core funding at the Southampton Clinical Trials Unit, and investigator-initiated support from Bristol-Myers Squibb for free drug labeling and distribution and funding for RECIST reporting. Dr. Fennell reported relationships with Astex Therapeutics, AstraZeneca, Atara Biotherapeutics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Inventiva, Lab 21, Merck, and Roche. Dr. Hui reported relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, and Seagen.

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

In the first ever placebo-controlled phase 3 trial in patients with relapsed mesothelioma, immunotherapy with nivolumab significantly improved both overall survival (OS) and progression-free survival (PFS).

The CONFIRM trial involved 330 previously treated patients with mesothelioma who were randomly assigned to nivolumab or placebo for 1 year or until progression or unacceptable toxicity.

Although recruitment to the study was stopped early because of the COVID-19 pandemic, enough data accrued to show that nivolumab improved overall survival by 28% over placebo, and increased PFS by 39%.

“Nivolumab was deemed a safe and effective treatment and should be considered a new treatment option for patients with relapsed mesothelioma,” said principal investigator Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester (England).

He presented the results at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021.

Rina Hui, MD, PhD, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, who was not involved in the study, said that these results had been a “long time coming.”

CONFIRM has added “important, encouraging data on immunotherapy in the salvage setting,” Dr. Hui said, noting that two-thirds of patients had received two or more prior lines of therapy.

Dr. Fennel noted that “a significant clinical benefit was observed in the epithelioid subtype” of the disease but not in patients with nonepithelioid disease.

However, there was “no evidence” to support programmed death–ligand 1 (PD-L1) expression as predictive of outcomes, he added, which does appear to be the case in some trials on lung cancer and other tumors.

Commenting on these observations, Dr. Hui said that PD-L1 as a predictive biomarker in mesothelioma has been “controversial,” and she emphasized that the results from CONFIRM indicate “no evidence of PD-L1 being predictive.”

However, Dr. Hui questioned the other observation that clinical benefit appeared to be seen only in the epithelioid subtype.

She emphasized that nonepithelioid disease is known to be a “more aggressive, chemoresistant subtype ... with a steep decline in the survival curves.

“Therefore, a lot of patients would not have made it to a subsequent-line clinical trial, explaining why there were only 12% in the CONFIRM study,” and so the sample size may be “too small to detect a difference in outcome,” Dr. Hui said.

Consequently, Dr. Hui said she “would not deny patients with nonepithelioid histology from considering nivolumab in the salvage setting.”

She argued that there was “no clear predictive biomarker for patient selection” emerging from the CONFIRM data.

She agreed that, in patients with mesothelioma who have progressed following platinum/pemetrexed-based chemotherapy as in the first line, “monotherapy nivolumab now can be considered as a treatment option in the second- ... or third-line setting, after second-line chemotherapy”.

However, outstanding questions remain, including whether nivolumab “provides better outcomes than second-line single agent chemotherapy or second-line gemcitabine with the [vascular endothelial growth factor receptor] inhibitor ramucirumab.”

It may also be that nivolumab plus ipilimumab might be superior to nivolumab alone in the salvage setting.

But a more fundamental question is what should be considered for salvage therapy if nivolumab and ipilimumab have already been used in the first-line setting, Dr. Hui said.

Results of first-line immunotherapy combination trials are “eagerly awaited ... to determine and develop other salvage treatments,” she commented.

Responding on Twitter, Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust in Royal Tunbridge Wells, England, echoed these comments, saying that the results were “very exciting,” but he also “can’t wait to see the first-line chemo–immunotherapy data.”

Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, commented on Twitter that there was “not a lot of safety data” in the presentation and awaits their eventual publication.

He added that it is “good to have a positive trial” in relapsed mesothelioma, “though the first-line studies will decrease the eventual impact as immunotherapy becomes involved earlier in treatment.”

 

Details of the CONFIRM results 

Relapsed mesothelioma is an “unmet need,” and, until now, “there have been no phase 3 trials which have demonstrated improved overall survival,” Dr. Fennell said in his presentation.

However, three phase 2 trials have shown that immune checkpoint targeting via PD-1 has shown useful clinical activity as a monotherapy in the relapsed setting, and one of these trials has led to approval of nivolumab in Japan for this indication.

CONFIRM was an investigator-initiated phase 3 trial in patients with relapsed mesothelioma who had received more than one prior line of therapy and had a good performance status.

Recruitment began in April 2017, and the “target sample size was 336 patients,” Dr. Fennell said, but the trial was “halted at 332 patients (in March 2020) due to the peaking of the COVID-19 pandemic in the U.K.”

“However, at the time, it was felt there were sufficient events” to justify the current analysis of the coprimary endpoints of PFS and OS, despite the latter being 59 events short of the target of 291.

Dr. Fennell said that baseline characteristics were “generally well balanced” between the nivolumab (n = 221) and placebo (n = 111) arms.

However, there were more patients with a PD-L1 tumor proportion score (TPS) of at least 1% among the patients given nivolumab, at 37% versus 29% in the placebo arm.

After a median follow-up of 17.1 months in the nivolumab arm and 14.2 months in the placebo group, overall survival was significantly longer with the active treatment, at 9.2 months versus 6.6 months with placebo (hazard ratio, 0.72; P = .018).

The proportion of patients alive at 12 months was 39.5% in the nivolumab group and 26.9% in patients given placebo. Investigator-assessed PFS was also significantly longer with nivolumab, at 3.0 months versus 1.8 months with placebo (HR, 0.61; P < .001).

The proportion of patients disease free at 12 months was 14.5% with active treatment versus 4.9% months with the placebo.

“The role for PD-L1 as a potential biomarker was assessed,” Dr. Fennell said, using the Dako 22C3 antibody, with 150 nivolumab and 84 placebo patients divided into those with a TPS <1% or ≥1%.

He noted that PD-L1 expression in the tumor “did not predict survival for patients in the CONFIRM trial,” with neither PD-L1 positive nor PD-L1 negative patients demonstrating a significant improvement in overall survival with nivolumab vs placebo.

“For histology, epithelioid mesothelioma patients benefited from nivolumab,” Dr. Fennell continued, with a hazard ratio for death of 0.71 versus placebo (P = .021). “However, for the nonepithelioid subgroup, in this immature survival analysis ... the P value was not significant,” but this was a small subgroup of patients (12% in both nivolumab and placebo groups).

The safety analysis revealed that the proportion of patients with any serious adverse events, of any grade or grade 3 or higher, was almost identical between the active and placebo arms, Dr. Fennel reported. There were five deaths (3.6%) related to a serious adverse event in the nivolumab arm and four (5.3%) in the placebo group.

This research was funded by the Stand Up to Cancer campaign for Cancer Research UK, supported by Cancer Research UK core funding at the Southampton Clinical Trials Unit, and investigator-initiated support from Bristol-Myers Squibb for free drug labeling and distribution and funding for RECIST reporting. Dr. Fennell reported relationships with Astex Therapeutics, AstraZeneca, Atara Biotherapeutics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Inventiva, Lab 21, Merck, and Roche. Dr. Hui reported relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, and Seagen.

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

In the first ever placebo-controlled phase 3 trial in patients with relapsed mesothelioma, immunotherapy with nivolumab significantly improved both overall survival (OS) and progression-free survival (PFS).

The CONFIRM trial involved 330 previously treated patients with mesothelioma who were randomly assigned to nivolumab or placebo for 1 year or until progression or unacceptable toxicity.

Although recruitment to the study was stopped early because of the COVID-19 pandemic, enough data accrued to show that nivolumab improved overall survival by 28% over placebo, and increased PFS by 39%.

“Nivolumab was deemed a safe and effective treatment and should be considered a new treatment option for patients with relapsed mesothelioma,” said principal investigator Dean A. Fennell, MD, PhD, professor and consultant in thoracic medical oncology, University of Leicester (England).

He presented the results at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021.

Rina Hui, MD, PhD, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, who was not involved in the study, said that these results had been a “long time coming.”

CONFIRM has added “important, encouraging data on immunotherapy in the salvage setting,” Dr. Hui said, noting that two-thirds of patients had received two or more prior lines of therapy.

Dr. Fennel noted that “a significant clinical benefit was observed in the epithelioid subtype” of the disease but not in patients with nonepithelioid disease.

However, there was “no evidence” to support programmed death–ligand 1 (PD-L1) expression as predictive of outcomes, he added, which does appear to be the case in some trials on lung cancer and other tumors.

Commenting on these observations, Dr. Hui said that PD-L1 as a predictive biomarker in mesothelioma has been “controversial,” and she emphasized that the results from CONFIRM indicate “no evidence of PD-L1 being predictive.”

However, Dr. Hui questioned the other observation that clinical benefit appeared to be seen only in the epithelioid subtype.

She emphasized that nonepithelioid disease is known to be a “more aggressive, chemoresistant subtype ... with a steep decline in the survival curves.

“Therefore, a lot of patients would not have made it to a subsequent-line clinical trial, explaining why there were only 12% in the CONFIRM study,” and so the sample size may be “too small to detect a difference in outcome,” Dr. Hui said.

Consequently, Dr. Hui said she “would not deny patients with nonepithelioid histology from considering nivolumab in the salvage setting.”

She argued that there was “no clear predictive biomarker for patient selection” emerging from the CONFIRM data.

She agreed that, in patients with mesothelioma who have progressed following platinum/pemetrexed-based chemotherapy as in the first line, “monotherapy nivolumab now can be considered as a treatment option in the second- ... or third-line setting, after second-line chemotherapy”.

However, outstanding questions remain, including whether nivolumab “provides better outcomes than second-line single agent chemotherapy or second-line gemcitabine with the [vascular endothelial growth factor receptor] inhibitor ramucirumab.”

It may also be that nivolumab plus ipilimumab might be superior to nivolumab alone in the salvage setting.

But a more fundamental question is what should be considered for salvage therapy if nivolumab and ipilimumab have already been used in the first-line setting, Dr. Hui said.

Results of first-line immunotherapy combination trials are “eagerly awaited ... to determine and develop other salvage treatments,” she commented.

Responding on Twitter, Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust in Royal Tunbridge Wells, England, echoed these comments, saying that the results were “very exciting,” but he also “can’t wait to see the first-line chemo–immunotherapy data.”

Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, commented on Twitter that there was “not a lot of safety data” in the presentation and awaits their eventual publication.

He added that it is “good to have a positive trial” in relapsed mesothelioma, “though the first-line studies will decrease the eventual impact as immunotherapy becomes involved earlier in treatment.”

 

Details of the CONFIRM results 

Relapsed mesothelioma is an “unmet need,” and, until now, “there have been no phase 3 trials which have demonstrated improved overall survival,” Dr. Fennell said in his presentation.

However, three phase 2 trials have shown that immune checkpoint targeting via PD-1 has shown useful clinical activity as a monotherapy in the relapsed setting, and one of these trials has led to approval of nivolumab in Japan for this indication.

CONFIRM was an investigator-initiated phase 3 trial in patients with relapsed mesothelioma who had received more than one prior line of therapy and had a good performance status.

Recruitment began in April 2017, and the “target sample size was 336 patients,” Dr. Fennell said, but the trial was “halted at 332 patients (in March 2020) due to the peaking of the COVID-19 pandemic in the U.K.”

“However, at the time, it was felt there were sufficient events” to justify the current analysis of the coprimary endpoints of PFS and OS, despite the latter being 59 events short of the target of 291.

Dr. Fennell said that baseline characteristics were “generally well balanced” between the nivolumab (n = 221) and placebo (n = 111) arms.

However, there were more patients with a PD-L1 tumor proportion score (TPS) of at least 1% among the patients given nivolumab, at 37% versus 29% in the placebo arm.

After a median follow-up of 17.1 months in the nivolumab arm and 14.2 months in the placebo group, overall survival was significantly longer with the active treatment, at 9.2 months versus 6.6 months with placebo (hazard ratio, 0.72; P = .018).

The proportion of patients alive at 12 months was 39.5% in the nivolumab group and 26.9% in patients given placebo. Investigator-assessed PFS was also significantly longer with nivolumab, at 3.0 months versus 1.8 months with placebo (HR, 0.61; P < .001).

The proportion of patients disease free at 12 months was 14.5% with active treatment versus 4.9% months with the placebo.

“The role for PD-L1 as a potential biomarker was assessed,” Dr. Fennell said, using the Dako 22C3 antibody, with 150 nivolumab and 84 placebo patients divided into those with a TPS <1% or ≥1%.

He noted that PD-L1 expression in the tumor “did not predict survival for patients in the CONFIRM trial,” with neither PD-L1 positive nor PD-L1 negative patients demonstrating a significant improvement in overall survival with nivolumab vs placebo.

“For histology, epithelioid mesothelioma patients benefited from nivolumab,” Dr. Fennell continued, with a hazard ratio for death of 0.71 versus placebo (P = .021). “However, for the nonepithelioid subgroup, in this immature survival analysis ... the P value was not significant,” but this was a small subgroup of patients (12% in both nivolumab and placebo groups).

The safety analysis revealed that the proportion of patients with any serious adverse events, of any grade or grade 3 or higher, was almost identical between the active and placebo arms, Dr. Fennel reported. There were five deaths (3.6%) related to a serious adverse event in the nivolumab arm and four (5.3%) in the placebo group.

This research was funded by the Stand Up to Cancer campaign for Cancer Research UK, supported by Cancer Research UK core funding at the Southampton Clinical Trials Unit, and investigator-initiated support from Bristol-Myers Squibb for free drug labeling and distribution and funding for RECIST reporting. Dr. Fennell reported relationships with Astex Therapeutics, AstraZeneca, Atara Biotherapeutics, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Inventiva, Lab 21, Merck, and Roche. Dr. Hui reported relationships with AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, and Seagen.

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

Screening for lung cancer with low-dose computed tomography (LDCT) has thus far been targeted at individuals who smoke or have smoked, but the incidence of lung cancer has been found to be increasing among people who have never smoked, and they too should undergo screening, suggest researchers from Taiwan.

“Lung cancer in never-smokers is a global rising threat,” said lead researcher Pan-Chyr Yang, MD, PhD, chair professor at the National Taiwan University Hospital and academician of Academia Sinica, Taiwan.

In Taiwan, more than half of the cases of lung cancer occur in never-smokers; among female lung cancer patients, 93% are never-smokers.

The incidence of lung cancer – in particular, adenocarcinoma – is increasing in Taiwan, even though the prevalence of smoking has fallen dramatically in men in recent years and has remained low in women.

At the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, Dr. Yang presented new results that suggest “LDCT screening for never-smokers with high risk may be feasible.”

The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) recruited over 12,000 individuals aged 55-70 years who had never smoked or had done so more than 15 years previously and had risk factors such as a family history of the disease or passive smoke exposure, or who had regularly been exposed to frying food.

Participants underwent LDCT after chest x-ray, followed by biopsy if necessary.

These procedures detected largely invasive lung cancer in 2.6% of participants. Tumors were of stage 0-I in 95% of cases.

The lung cancer detection rate of 2.6% in TALENT in never-smokers is higher than has been found in large studies of smokers, including the 1.1% rate recorded in the NLST study and the 0.9% seen in the NELSON study.

The key factor associated with increased prevalence of lung cancer was a first-degree family history of the disease, Dr. Yang reported.

Notably, having a sister with lung cancer increased the risk for the disease by 78%. Having an affected brother doubled the risk. An increase in the number of first-degree relatives with lung cancer also significantly increased the risk.
 

More research needed

The TALENT study “provides new, very original evidence on lung cancer risks, and therefore lung cancer screening eligibility could be redefined in Asia, or at least in East Asia,” said the discussant for the paper, Ugo Pastorino, MD, director of thoracic surgery at IRCCS Istituto Nazionale dei Tumori Foundation, Milan.

However, he said that “more research is needed on lung cancer biology in nonsmokers.”

There is currently no follow-up or mortality data, and given the proportion of patients who underwent invasive procedures, it could be that more than 40% of those procedures were carried out in individuals with benign disease, he cautioned.

On Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said that although family history “emerges” from the study as a potential risk factor for lung cancer, “this analysis would be much more insightful with genomic analyses of these cancers.”

Devika Das, MD, clinical assistant professor of hematology and oncology, University of Alabama at Birmingham, said that the study is “interesting,” given the rise of adenocarcinoma among never-smokers.

She agreed that further details and long-term outcomes are needed and said the key learning point was the need for a “robust” study of the biology of lung cancer in this population.

Lillian Leigh, an Australian lawyer and a lung cancer patient advocate, said the study “provides new evidence” on lung cancer risks.

“As an Asian never-smoker living with lung cancer, the TALENT trial results give me hope,” she said.
 

Details of TALENT findings

The TALENT study recruited individuals aged 55-70 years at 17 medical centers between February 2015 and July 2019.

Participants were required to be never-smokers or to have a smoking history of less than 10 pack-years and to have quit the habit more than 15 years previously.

They also had to have one of the following risk factors:

• Family history of lung cancer in up to third-degree relatives, in which case younger patients could be recruited.
• Environmental (passive) tobacco smoking history.
• Chronic lung disease, namely,  or .
• A cooking index ≥110, defined as 2/7 × the number of days of frying per week × the number of years cooking.
• Cooking without ventilation.

The participants underwent chest x-ray. If the x-ray proved negative, the team performed standard LDCT, examined blood and urine samples for lung cancer biomarkers, and administered standard questionnaires.

Participants who were found on LDCT to have solid or part-solid nodules greater than 6 mm in diameter or pure ground-glass nodules greater than 5 mm in diameter underwent biopsy or standard follow-up.

Individuals whose initial chest x-ray was positive underwent standard contrast-enhanced chest CT prior to biopsy or standard follow-up.

Of 13,207 individuals initially screened, 12,011 were enrolled. Of those, 73.8% were women. The mean age was 61.2 years, and 93.3% were never-smokers.

Among the participants, 46.4% had a first-degree family history of lung cancer; 3.0% had a second-degree family history; and 0.5% had a third-degree family history.

Environmental tobacco exposure was recorded in 83.2% of patients. Chronic lung disease was present in 9.8%; 36.7% had a cooking index ≥110; and 1.8 cooked without ventilation.

Dr. Yang said LDCT results were positive for 17.4% of patients, and 3.4% underwent invasive procedures.

Overall, lung cancer was detected in 313 participants (2.6%). Invasive lung cancer was detected in 255 (2.1%). Of those, 17.9% had multiple primary lung cancers.

Strikingly, 96.5% of the confirmed lung cancer cases were stage 0-I. The majority were stage IA, “which is higher than in other studies that have focused on heavy smokers,” Dr. Yang said. More than half of cases (58.5%) were invasive adenocarcinomas.

The prevalence of lung cancer was significantly higher among people who had a family history of the disease, at 3.2%, vs. 2.0% in those without, at a relative risk of 1.61 (P < .001).

The prevalence was higher still in individuals who had a first-degree family history of lung cancer, at 3.3%, giving a relative risk of 1.69 in comparison with those who did not have a family history (P < .001). The findings were nonsignificant for second- and third-degree relatives.

The relative risk increased even further when the first-degree relative who had a history of lung cancer was a sister, at 1.78 (P < .001), or a brother, at 2.00 (P < .001).

The relative risk was slightly lower if the patient’s relative was the mother, at 1.43 (P = .010), and was nonsignificant if the relative was the father (P = .077).

The risk for lung cancer also increased with an increase in the number of first-degree relatives with the disease, rising from 3.1% with one relative to 4.0% with two relatives, 6.7% with three relatives, and 9.1% with at least four relatives (P < .001). A similar pattern was seen for invasive lung cancer.

The other risk factors included in the study, such as environmental tobacco exposure, chronic lung disease, and cooking index, were not significantly associated with the prevalence of lung cancer.

No funding for the study has been disclosed. Dr. Yang has received honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, Merck, Eli Lilly, Roche, GlaxoSmithKline, and ONO Pharma and has served on the advisory board of OBI Pharma, CHO Pharma, and Lin BioScience. Dr. Pastorino has disclosed no relevant financial relationships.

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

Screening for lung cancer with low-dose computed tomography (LDCT) has thus far been targeted at individuals who smoke or have smoked, but the incidence of lung cancer has been found to be increasing among people who have never smoked, and they too should undergo screening, suggest researchers from Taiwan.

“Lung cancer in never-smokers is a global rising threat,” said lead researcher Pan-Chyr Yang, MD, PhD, chair professor at the National Taiwan University Hospital and academician of Academia Sinica, Taiwan.

In Taiwan, more than half of the cases of lung cancer occur in never-smokers; among female lung cancer patients, 93% are never-smokers.

The incidence of lung cancer – in particular, adenocarcinoma – is increasing in Taiwan, even though the prevalence of smoking has fallen dramatically in men in recent years and has remained low in women.

At the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, Dr. Yang presented new results that suggest “LDCT screening for never-smokers with high risk may be feasible.”

The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) recruited over 12,000 individuals aged 55-70 years who had never smoked or had done so more than 15 years previously and had risk factors such as a family history of the disease or passive smoke exposure, or who had regularly been exposed to frying food.

Participants underwent LDCT after chest x-ray, followed by biopsy if necessary.

These procedures detected largely invasive lung cancer in 2.6% of participants. Tumors were of stage 0-I in 95% of cases.

The lung cancer detection rate of 2.6% in TALENT in never-smokers is higher than has been found in large studies of smokers, including the 1.1% rate recorded in the NLST study and the 0.9% seen in the NELSON study.

The key factor associated with increased prevalence of lung cancer was a first-degree family history of the disease, Dr. Yang reported.

Notably, having a sister with lung cancer increased the risk for the disease by 78%. Having an affected brother doubled the risk. An increase in the number of first-degree relatives with lung cancer also significantly increased the risk.
 

More research needed

The TALENT study “provides new, very original evidence on lung cancer risks, and therefore lung cancer screening eligibility could be redefined in Asia, or at least in East Asia,” said the discussant for the paper, Ugo Pastorino, MD, director of thoracic surgery at IRCCS Istituto Nazionale dei Tumori Foundation, Milan.

However, he said that “more research is needed on lung cancer biology in nonsmokers.”

There is currently no follow-up or mortality data, and given the proportion of patients who underwent invasive procedures, it could be that more than 40% of those procedures were carried out in individuals with benign disease, he cautioned.

On Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said that although family history “emerges” from the study as a potential risk factor for lung cancer, “this analysis would be much more insightful with genomic analyses of these cancers.”

Devika Das, MD, clinical assistant professor of hematology and oncology, University of Alabama at Birmingham, said that the study is “interesting,” given the rise of adenocarcinoma among never-smokers.

She agreed that further details and long-term outcomes are needed and said the key learning point was the need for a “robust” study of the biology of lung cancer in this population.

Lillian Leigh, an Australian lawyer and a lung cancer patient advocate, said the study “provides new evidence” on lung cancer risks.

“As an Asian never-smoker living with lung cancer, the TALENT trial results give me hope,” she said.
 

Details of TALENT findings

The TALENT study recruited individuals aged 55-70 years at 17 medical centers between February 2015 and July 2019.

Participants were required to be never-smokers or to have a smoking history of less than 10 pack-years and to have quit the habit more than 15 years previously.

They also had to have one of the following risk factors:

• Family history of lung cancer in up to third-degree relatives, in which case younger patients could be recruited.
• Environmental (passive) tobacco smoking history.
• Chronic lung disease, namely,  or .
• A cooking index ≥110, defined as 2/7 × the number of days of frying per week × the number of years cooking.
• Cooking without ventilation.

The participants underwent chest x-ray. If the x-ray proved negative, the team performed standard LDCT, examined blood and urine samples for lung cancer biomarkers, and administered standard questionnaires.

Participants who were found on LDCT to have solid or part-solid nodules greater than 6 mm in diameter or pure ground-glass nodules greater than 5 mm in diameter underwent biopsy or standard follow-up.

Individuals whose initial chest x-ray was positive underwent standard contrast-enhanced chest CT prior to biopsy or standard follow-up.

Of 13,207 individuals initially screened, 12,011 were enrolled. Of those, 73.8% were women. The mean age was 61.2 years, and 93.3% were never-smokers.

Among the participants, 46.4% had a first-degree family history of lung cancer; 3.0% had a second-degree family history; and 0.5% had a third-degree family history.

Environmental tobacco exposure was recorded in 83.2% of patients. Chronic lung disease was present in 9.8%; 36.7% had a cooking index ≥110; and 1.8 cooked without ventilation.

Dr. Yang said LDCT results were positive for 17.4% of patients, and 3.4% underwent invasive procedures.

Overall, lung cancer was detected in 313 participants (2.6%). Invasive lung cancer was detected in 255 (2.1%). Of those, 17.9% had multiple primary lung cancers.

Strikingly, 96.5% of the confirmed lung cancer cases were stage 0-I. The majority were stage IA, “which is higher than in other studies that have focused on heavy smokers,” Dr. Yang said. More than half of cases (58.5%) were invasive adenocarcinomas.

The prevalence of lung cancer was significantly higher among people who had a family history of the disease, at 3.2%, vs. 2.0% in those without, at a relative risk of 1.61 (P < .001).

The prevalence was higher still in individuals who had a first-degree family history of lung cancer, at 3.3%, giving a relative risk of 1.69 in comparison with those who did not have a family history (P < .001). The findings were nonsignificant for second- and third-degree relatives.

The relative risk increased even further when the first-degree relative who had a history of lung cancer was a sister, at 1.78 (P < .001), or a brother, at 2.00 (P < .001).

The relative risk was slightly lower if the patient’s relative was the mother, at 1.43 (P = .010), and was nonsignificant if the relative was the father (P = .077).

The risk for lung cancer also increased with an increase in the number of first-degree relatives with the disease, rising from 3.1% with one relative to 4.0% with two relatives, 6.7% with three relatives, and 9.1% with at least four relatives (P < .001). A similar pattern was seen for invasive lung cancer.

The other risk factors included in the study, such as environmental tobacco exposure, chronic lung disease, and cooking index, were not significantly associated with the prevalence of lung cancer.

No funding for the study has been disclosed. Dr. Yang has received honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, Merck, Eli Lilly, Roche, GlaxoSmithKline, and ONO Pharma and has served on the advisory board of OBI Pharma, CHO Pharma, and Lin BioScience. Dr. Pastorino has disclosed no relevant financial relationships.

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

Screening for lung cancer with low-dose computed tomography (LDCT) has thus far been targeted at individuals who smoke or have smoked, but the incidence of lung cancer has been found to be increasing among people who have never smoked, and they too should undergo screening, suggest researchers from Taiwan.

“Lung cancer in never-smokers is a global rising threat,” said lead researcher Pan-Chyr Yang, MD, PhD, chair professor at the National Taiwan University Hospital and academician of Academia Sinica, Taiwan.

In Taiwan, more than half of the cases of lung cancer occur in never-smokers; among female lung cancer patients, 93% are never-smokers.

The incidence of lung cancer – in particular, adenocarcinoma – is increasing in Taiwan, even though the prevalence of smoking has fallen dramatically in men in recent years and has remained low in women.

At the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, Dr. Yang presented new results that suggest “LDCT screening for never-smokers with high risk may be feasible.”

The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) recruited over 12,000 individuals aged 55-70 years who had never smoked or had done so more than 15 years previously and had risk factors such as a family history of the disease or passive smoke exposure, or who had regularly been exposed to frying food.

Participants underwent LDCT after chest x-ray, followed by biopsy if necessary.

These procedures detected largely invasive lung cancer in 2.6% of participants. Tumors were of stage 0-I in 95% of cases.

The lung cancer detection rate of 2.6% in TALENT in never-smokers is higher than has been found in large studies of smokers, including the 1.1% rate recorded in the NLST study and the 0.9% seen in the NELSON study.

The key factor associated with increased prevalence of lung cancer was a first-degree family history of the disease, Dr. Yang reported.

Notably, having a sister with lung cancer increased the risk for the disease by 78%. Having an affected brother doubled the risk. An increase in the number of first-degree relatives with lung cancer also significantly increased the risk.
 

More research needed

The TALENT study “provides new, very original evidence on lung cancer risks, and therefore lung cancer screening eligibility could be redefined in Asia, or at least in East Asia,” said the discussant for the paper, Ugo Pastorino, MD, director of thoracic surgery at IRCCS Istituto Nazionale dei Tumori Foundation, Milan.

However, he said that “more research is needed on lung cancer biology in nonsmokers.”

There is currently no follow-up or mortality data, and given the proportion of patients who underwent invasive procedures, it could be that more than 40% of those procedures were carried out in individuals with benign disease, he cautioned.

On Twitter, Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, said that although family history “emerges” from the study as a potential risk factor for lung cancer, “this analysis would be much more insightful with genomic analyses of these cancers.”

Devika Das, MD, clinical assistant professor of hematology and oncology, University of Alabama at Birmingham, said that the study is “interesting,” given the rise of adenocarcinoma among never-smokers.

She agreed that further details and long-term outcomes are needed and said the key learning point was the need for a “robust” study of the biology of lung cancer in this population.

Lillian Leigh, an Australian lawyer and a lung cancer patient advocate, said the study “provides new evidence” on lung cancer risks.

“As an Asian never-smoker living with lung cancer, the TALENT trial results give me hope,” she said.
 

Details of TALENT findings

The TALENT study recruited individuals aged 55-70 years at 17 medical centers between February 2015 and July 2019.

Participants were required to be never-smokers or to have a smoking history of less than 10 pack-years and to have quit the habit more than 15 years previously.

They also had to have one of the following risk factors:

• Family history of lung cancer in up to third-degree relatives, in which case younger patients could be recruited.
• Environmental (passive) tobacco smoking history.
• Chronic lung disease, namely,  or .
• A cooking index ≥110, defined as 2/7 × the number of days of frying per week × the number of years cooking.
• Cooking without ventilation.

The participants underwent chest x-ray. If the x-ray proved negative, the team performed standard LDCT, examined blood and urine samples for lung cancer biomarkers, and administered standard questionnaires.

Participants who were found on LDCT to have solid or part-solid nodules greater than 6 mm in diameter or pure ground-glass nodules greater than 5 mm in diameter underwent biopsy or standard follow-up.

Individuals whose initial chest x-ray was positive underwent standard contrast-enhanced chest CT prior to biopsy or standard follow-up.

Of 13,207 individuals initially screened, 12,011 were enrolled. Of those, 73.8% were women. The mean age was 61.2 years, and 93.3% were never-smokers.

Among the participants, 46.4% had a first-degree family history of lung cancer; 3.0% had a second-degree family history; and 0.5% had a third-degree family history.

Environmental tobacco exposure was recorded in 83.2% of patients. Chronic lung disease was present in 9.8%; 36.7% had a cooking index ≥110; and 1.8 cooked without ventilation.

Dr. Yang said LDCT results were positive for 17.4% of patients, and 3.4% underwent invasive procedures.

Overall, lung cancer was detected in 313 participants (2.6%). Invasive lung cancer was detected in 255 (2.1%). Of those, 17.9% had multiple primary lung cancers.

Strikingly, 96.5% of the confirmed lung cancer cases were stage 0-I. The majority were stage IA, “which is higher than in other studies that have focused on heavy smokers,” Dr. Yang said. More than half of cases (58.5%) were invasive adenocarcinomas.

The prevalence of lung cancer was significantly higher among people who had a family history of the disease, at 3.2%, vs. 2.0% in those without, at a relative risk of 1.61 (P < .001).

The prevalence was higher still in individuals who had a first-degree family history of lung cancer, at 3.3%, giving a relative risk of 1.69 in comparison with those who did not have a family history (P < .001). The findings were nonsignificant for second- and third-degree relatives.

The relative risk increased even further when the first-degree relative who had a history of lung cancer was a sister, at 1.78 (P < .001), or a brother, at 2.00 (P < .001).

The relative risk was slightly lower if the patient’s relative was the mother, at 1.43 (P = .010), and was nonsignificant if the relative was the father (P = .077).

The risk for lung cancer also increased with an increase in the number of first-degree relatives with the disease, rising from 3.1% with one relative to 4.0% with two relatives, 6.7% with three relatives, and 9.1% with at least four relatives (P < .001). A similar pattern was seen for invasive lung cancer.

The other risk factors included in the study, such as environmental tobacco exposure, chronic lung disease, and cooking index, were not significantly associated with the prevalence of lung cancer.

No funding for the study has been disclosed. Dr. Yang has received honoraria from AstraZeneca, Boehringer Ingelheim, Pfizer, Merck, Eli Lilly, Roche, GlaxoSmithKline, and ONO Pharma and has served on the advisory board of OBI Pharma, CHO Pharma, and Lin BioScience. Dr. Pastorino has disclosed no relevant financial relationships.

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

Lung cancer experts have been rejoicing over new longer-term results that continue to show the combination of immunotherapy and chemotherapy doubles survival, compared with chemotherapy alone.

The results are from a 4-year follow-up of 160 patients with previously untreated stage IV non–small cell lung cancer (NSCLC) taking part in the KEYNOTE-189 trial of immunotherapy with pembrolizumab plus pemetrexed–platinum chemotherapy versus chemotherapy plus placebo.

After a median follow-up of 46.3 months, the median overall survival (OS) in the intention-to-treat population was 22.0 months with the combination versus 10.6 months with chemotherapy alone (hazard ratio, 0.60).

A similar pattern was seen for progression-free survival (PFS), with patients receiving the combination having a longer median PFS, at 9.0 months versus 4.9 months with chemotherapy alone (HR, 0.50).

“Stellar data,” Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust, Royal Tunbridge Wells, England, exclaimed on Twitter.

He described the results for the programmed death-ligand 1 (PD-L1) expression subgroups as “astonishing” and singled out the performance of the combination therapy in patients with very low (<1%) tumor PD-L1 expression, showing more than 23% of patients were alive at 3 years versus just over 5% in the group given chemotherapy alone.

Charu Aggarwal, MD, MPH, Leslye M. Heisler associate professor for lung cancer excellence, Penn Medicine, Philadelphia, said the outcomes with the combination of chemotherapy and immunotherapy were “terrific.”

Sandip P. Patel, MD, medical oncologist, associate professor of medicine, University of California, San Diego, agreed that these long-term results were “very impressive.” However, he noted the “full effect” of chemotherapy plus immunotherapy has not “fully been captured in our overall cancer mortality statistics in the U.S. yet.”

The new results were presented at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021.

Previous results from KEYNOTE-189 had already demonstrated that, after a median follow-up of 10.5 months, adding pembrolizumab to chemotherapy significantly improves both OS and PFS, compared with chemotherapy alone.

The latest results show that the combination “continued to provide overall survival and progression-free survival benefit” in extended follow-up, said study presenter Jhanelle Elaine Gray, MD, chair, department of thoracic oncology, Moffitt Cancer Center, Tampa.

The 3-year OS rate with pembrolizumab plus chemotherapy, compared with chemotherapy alone was 31.3% versus 17.4%, and the estimated 3-year PFS was 11.8% versus 1.3%.

Substantial improvements were even seen in patients with tumors that had a low level of PD-L1 expression (measured as the PD-L1 tumor proportion score [TPS]).

Dr. Gray highlighted the finding that the survival benefit with pembrolizumab plus chemotherapy was seen regardless of PD-L1 expression in the tumor, with a hazard ratio versus chemotherapy alone of 0.71 in patients with a TPS ≥ 50%, 0.66 in those with a TPS of 1%-49%, and 0.52 in patients with a TPS less than 1%. A similar pattern was seen with PFS, with a hazard ratio of 0.36 in patients with a TPS of at least 50%, 0.54 in those with a TPS of 1%-49%, and 0.68 in patients with a TPS less than 1%.

In addition, overall response rate and duration of response were also improved with combination therapy, regardless of tumor PD-L1 expression.

Among 56 patients who completed 35 cycles of pembrolizumab, the objective response rate was 87.5% (with 10.7% having a complete response and 76.8% a partial response).

At the data cutoff, 45 patients were alive, 28 did not have progressive disease, and seven had started a second course of pembrolizumab.

The side effect profile of the combination was “manageable,” Dr. Gray reported.

The combination arm was associated with more grade 3-5 treatment-related adverse events than the chemotherapy alone arm, at 52.1% versus 42.1%, and more grade 3-5 immune-related adverse events and infusion reactions, at 27.7% versus 13.4%.

Events leading to treatment discontinuation were also more common with pembrolizumab plus chemotherapy than chemotherapy, at 27.4% versus 9.9%.

The combination of pembrolizumab plus pemetrexed-platinum has already become “a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous NSCLC,” Dr. Gray commented.

The study was funded by Merck. Dr. Gray disclosed relationships with Array, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, and Merck.

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

Lung cancer experts have been rejoicing over new longer-term results that continue to show the combination of immunotherapy and chemotherapy doubles survival, compared with chemotherapy alone.

The results are from a 4-year follow-up of 160 patients with previously untreated stage IV non–small cell lung cancer (NSCLC) taking part in the KEYNOTE-189 trial of immunotherapy with pembrolizumab plus pemetrexed–platinum chemotherapy versus chemotherapy plus placebo.

After a median follow-up of 46.3 months, the median overall survival (OS) in the intention-to-treat population was 22.0 months with the combination versus 10.6 months with chemotherapy alone (hazard ratio, 0.60).

A similar pattern was seen for progression-free survival (PFS), with patients receiving the combination having a longer median PFS, at 9.0 months versus 4.9 months with chemotherapy alone (HR, 0.50).

“Stellar data,” Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust, Royal Tunbridge Wells, England, exclaimed on Twitter.

He described the results for the programmed death-ligand 1 (PD-L1) expression subgroups as “astonishing” and singled out the performance of the combination therapy in patients with very low (<1%) tumor PD-L1 expression, showing more than 23% of patients were alive at 3 years versus just over 5% in the group given chemotherapy alone.

Charu Aggarwal, MD, MPH, Leslye M. Heisler associate professor for lung cancer excellence, Penn Medicine, Philadelphia, said the outcomes with the combination of chemotherapy and immunotherapy were “terrific.”

Sandip P. Patel, MD, medical oncologist, associate professor of medicine, University of California, San Diego, agreed that these long-term results were “very impressive.” However, he noted the “full effect” of chemotherapy plus immunotherapy has not “fully been captured in our overall cancer mortality statistics in the U.S. yet.”

The new results were presented at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021.

Previous results from KEYNOTE-189 had already demonstrated that, after a median follow-up of 10.5 months, adding pembrolizumab to chemotherapy significantly improves both OS and PFS, compared with chemotherapy alone.

The latest results show that the combination “continued to provide overall survival and progression-free survival benefit” in extended follow-up, said study presenter Jhanelle Elaine Gray, MD, chair, department of thoracic oncology, Moffitt Cancer Center, Tampa.

The 3-year OS rate with pembrolizumab plus chemotherapy, compared with chemotherapy alone was 31.3% versus 17.4%, and the estimated 3-year PFS was 11.8% versus 1.3%.

Substantial improvements were even seen in patients with tumors that had a low level of PD-L1 expression (measured as the PD-L1 tumor proportion score [TPS]).

Dr. Gray highlighted the finding that the survival benefit with pembrolizumab plus chemotherapy was seen regardless of PD-L1 expression in the tumor, with a hazard ratio versus chemotherapy alone of 0.71 in patients with a TPS ≥ 50%, 0.66 in those with a TPS of 1%-49%, and 0.52 in patients with a TPS less than 1%. A similar pattern was seen with PFS, with a hazard ratio of 0.36 in patients with a TPS of at least 50%, 0.54 in those with a TPS of 1%-49%, and 0.68 in patients with a TPS less than 1%.

In addition, overall response rate and duration of response were also improved with combination therapy, regardless of tumor PD-L1 expression.

Among 56 patients who completed 35 cycles of pembrolizumab, the objective response rate was 87.5% (with 10.7% having a complete response and 76.8% a partial response).

At the data cutoff, 45 patients were alive, 28 did not have progressive disease, and seven had started a second course of pembrolizumab.

The side effect profile of the combination was “manageable,” Dr. Gray reported.

The combination arm was associated with more grade 3-5 treatment-related adverse events than the chemotherapy alone arm, at 52.1% versus 42.1%, and more grade 3-5 immune-related adverse events and infusion reactions, at 27.7% versus 13.4%.

Events leading to treatment discontinuation were also more common with pembrolizumab plus chemotherapy than chemotherapy, at 27.4% versus 9.9%.

The combination of pembrolizumab plus pemetrexed-platinum has already become “a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous NSCLC,” Dr. Gray commented.

The study was funded by Merck. Dr. Gray disclosed relationships with Array, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, and Merck.

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

Lung cancer experts have been rejoicing over new longer-term results that continue to show the combination of immunotherapy and chemotherapy doubles survival, compared with chemotherapy alone.

The results are from a 4-year follow-up of 160 patients with previously untreated stage IV non–small cell lung cancer (NSCLC) taking part in the KEYNOTE-189 trial of immunotherapy with pembrolizumab plus pemetrexed–platinum chemotherapy versus chemotherapy plus placebo.

After a median follow-up of 46.3 months, the median overall survival (OS) in the intention-to-treat population was 22.0 months with the combination versus 10.6 months with chemotherapy alone (hazard ratio, 0.60).

A similar pattern was seen for progression-free survival (PFS), with patients receiving the combination having a longer median PFS, at 9.0 months versus 4.9 months with chemotherapy alone (HR, 0.50).

“Stellar data,” Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust, Royal Tunbridge Wells, England, exclaimed on Twitter.

He described the results for the programmed death-ligand 1 (PD-L1) expression subgroups as “astonishing” and singled out the performance of the combination therapy in patients with very low (<1%) tumor PD-L1 expression, showing more than 23% of patients were alive at 3 years versus just over 5% in the group given chemotherapy alone.

Charu Aggarwal, MD, MPH, Leslye M. Heisler associate professor for lung cancer excellence, Penn Medicine, Philadelphia, said the outcomes with the combination of chemotherapy and immunotherapy were “terrific.”

Sandip P. Patel, MD, medical oncologist, associate professor of medicine, University of California, San Diego, agreed that these long-term results were “very impressive.” However, he noted the “full effect” of chemotherapy plus immunotherapy has not “fully been captured in our overall cancer mortality statistics in the U.S. yet.”

The new results were presented at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021.

Previous results from KEYNOTE-189 had already demonstrated that, after a median follow-up of 10.5 months, adding pembrolizumab to chemotherapy significantly improves both OS and PFS, compared with chemotherapy alone.

The latest results show that the combination “continued to provide overall survival and progression-free survival benefit” in extended follow-up, said study presenter Jhanelle Elaine Gray, MD, chair, department of thoracic oncology, Moffitt Cancer Center, Tampa.

The 3-year OS rate with pembrolizumab plus chemotherapy, compared with chemotherapy alone was 31.3% versus 17.4%, and the estimated 3-year PFS was 11.8% versus 1.3%.

Substantial improvements were even seen in patients with tumors that had a low level of PD-L1 expression (measured as the PD-L1 tumor proportion score [TPS]).

Dr. Gray highlighted the finding that the survival benefit with pembrolizumab plus chemotherapy was seen regardless of PD-L1 expression in the tumor, with a hazard ratio versus chemotherapy alone of 0.71 in patients with a TPS ≥ 50%, 0.66 in those with a TPS of 1%-49%, and 0.52 in patients with a TPS less than 1%. A similar pattern was seen with PFS, with a hazard ratio of 0.36 in patients with a TPS of at least 50%, 0.54 in those with a TPS of 1%-49%, and 0.68 in patients with a TPS less than 1%.

In addition, overall response rate and duration of response were also improved with combination therapy, regardless of tumor PD-L1 expression.

Among 56 patients who completed 35 cycles of pembrolizumab, the objective response rate was 87.5% (with 10.7% having a complete response and 76.8% a partial response).

At the data cutoff, 45 patients were alive, 28 did not have progressive disease, and seven had started a second course of pembrolizumab.

The side effect profile of the combination was “manageable,” Dr. Gray reported.

The combination arm was associated with more grade 3-5 treatment-related adverse events than the chemotherapy alone arm, at 52.1% versus 42.1%, and more grade 3-5 immune-related adverse events and infusion reactions, at 27.7% versus 13.4%.

Events leading to treatment discontinuation were also more common with pembrolizumab plus chemotherapy than chemotherapy, at 27.4% versus 9.9%.

The combination of pembrolizumab plus pemetrexed-platinum has already become “a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous NSCLC,” Dr. Gray commented.

The study was funded by Merck. Dr. Gray disclosed relationships with Array, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, and Merck.

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