Lung Cancer

The Food and Drug Administration has granted accelerated approval to selpercatinib (Retevmo) in 40-mg and 80-mg capsules for adults with locally advanced or metastatic RET fusion–positive solid tumors that have progressed during or following systemic treatment, or for patients for whom there are no good alternative treatments.

In 2020, selpercatinib received accelerated approval for lung and thyroid RET-positive tumors; that approval transitioned to a regular approval for non–small cell lung cancer on Sept. 21. The latest approval expands the drug label to include an array of RET-positive tumor types, including pancreatic and colorectal cancers.

The approval was based on data from the phase 1/2 LIBRETTO-001 trial, which evaluated 41 patients with RET fusion–positive tumors. Thirty-seven patients (90%) had received prior systemic therapy, with almost one-third receiving three or more. Primary efficacy measures were overall response rate and duration of response.

Among the 41 patients, the overall response rate was 44%, with a duration of response of 24.5 months. Additionally, for 67% of patients, results lasted at least 6 months.

“In the LIBRETTO-001 trial, selpercatinib demonstrated clinically meaningful and durable responses across a variety of tumor types in patients with RET-driven cancers,” Vivek Subbiah, MD, coinvestigator for the trial, said in a press release. “These data and FDA approval of the tumor-agnostic indication underscore the importance of routine, comprehensive genomic testing for patients across a wide variety of tumor types.”

The most common cancers in the study were pancreatic adenocarcinoma (27%), colorectal cancer (24%), and salivary cancer (10%).

The recommended selpercatinib dose, based on body weight, is 120 mg orally twice daily for people who weigh less than 110 pounds or 160 mg orally twice daily for who weigh 110 pounds or more.

The most common adverse reactions were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

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

The Food and Drug Administration has granted accelerated approval to selpercatinib (Retevmo) in 40-mg and 80-mg capsules for adults with locally advanced or metastatic RET fusion–positive solid tumors that have progressed during or following systemic treatment, or for patients for whom there are no good alternative treatments.

In 2020, selpercatinib received accelerated approval for lung and thyroid RET-positive tumors; that approval transitioned to a regular approval for non–small cell lung cancer on Sept. 21. The latest approval expands the drug label to include an array of RET-positive tumor types, including pancreatic and colorectal cancers.

The approval was based on data from the phase 1/2 LIBRETTO-001 trial, which evaluated 41 patients with RET fusion–positive tumors. Thirty-seven patients (90%) had received prior systemic therapy, with almost one-third receiving three or more. Primary efficacy measures were overall response rate and duration of response.

Among the 41 patients, the overall response rate was 44%, with a duration of response of 24.5 months. Additionally, for 67% of patients, results lasted at least 6 months.

“In the LIBRETTO-001 trial, selpercatinib demonstrated clinically meaningful and durable responses across a variety of tumor types in patients with RET-driven cancers,” Vivek Subbiah, MD, coinvestigator for the trial, said in a press release. “These data and FDA approval of the tumor-agnostic indication underscore the importance of routine, comprehensive genomic testing for patients across a wide variety of tumor types.”

The most common cancers in the study were pancreatic adenocarcinoma (27%), colorectal cancer (24%), and salivary cancer (10%).

The recommended selpercatinib dose, based on body weight, is 120 mg orally twice daily for people who weigh less than 110 pounds or 160 mg orally twice daily for who weigh 110 pounds or more.

The most common adverse reactions were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

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

The Food and Drug Administration has granted accelerated approval to selpercatinib (Retevmo) in 40-mg and 80-mg capsules for adults with locally advanced or metastatic RET fusion–positive solid tumors that have progressed during or following systemic treatment, or for patients for whom there are no good alternative treatments.

In 2020, selpercatinib received accelerated approval for lung and thyroid RET-positive tumors; that approval transitioned to a regular approval for non–small cell lung cancer on Sept. 21. The latest approval expands the drug label to include an array of RET-positive tumor types, including pancreatic and colorectal cancers.

The approval was based on data from the phase 1/2 LIBRETTO-001 trial, which evaluated 41 patients with RET fusion–positive tumors. Thirty-seven patients (90%) had received prior systemic therapy, with almost one-third receiving three or more. Primary efficacy measures were overall response rate and duration of response.

Among the 41 patients, the overall response rate was 44%, with a duration of response of 24.5 months. Additionally, for 67% of patients, results lasted at least 6 months.

“In the LIBRETTO-001 trial, selpercatinib demonstrated clinically meaningful and durable responses across a variety of tumor types in patients with RET-driven cancers,” Vivek Subbiah, MD, coinvestigator for the trial, said in a press release. “These data and FDA approval of the tumor-agnostic indication underscore the importance of routine, comprehensive genomic testing for patients across a wide variety of tumor types.”

The most common cancers in the study were pancreatic adenocarcinoma (27%), colorectal cancer (24%), and salivary cancer (10%).

The recommended selpercatinib dose, based on body weight, is 120 mg orally twice daily for people who weigh less than 110 pounds or 160 mg orally twice daily for who weigh 110 pounds or more.

The most common adverse reactions were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache.

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

High body mass index (BMI) values are associated with higher survival among metastatic cancer patients treated with first- and second-line immune checkpoint inhibitors (ICIs), but the relationship was only present in males.

That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.

He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.

Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.

On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.

Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
 

The study data

The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m²; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.

For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).

Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.

High body mass index (BMI) values are associated with higher survival among metastatic cancer patients treated with first- and second-line immune checkpoint inhibitors (ICIs), but the relationship was only present in males.

That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.

He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.

Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.

On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.

Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
 

The study data

The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m²; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.

For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).

Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.

High body mass index (BMI) values are associated with higher survival among metastatic cancer patients treated with first- and second-line immune checkpoint inhibitors (ICIs), but the relationship was only present in males.

That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.

He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.

Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.

On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.

Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
 

The study data

The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m²; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.

For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).

Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.

PARIS – For patients with non–small cell lung cancers (NSCLC) bearing the KRAS G12C mutation that have progressed on prior therapies, the first-in-class KRAS G12C inhibitor sotorasib (Lumykras) was associated with better progression-free survival (PFS) and objective response rates than docetaxel in the randomized, phase 3 CodeBreaK 200 trial.

­Among 345 patients who had experienced disease progression after prior platinum-based chemotherapy and an immune checkpoint inhibitor, 1-year PFS rates at a median follow-up of 17.7 months were 24.8% for patients randomized to receive sotorasib versus 10.1% for patients assigned to docetaxel, reported Melissa L, Johnson, MD, from the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.

“In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C non–small cell lung cancer,” she said in a media briefing prior to her presentation of the data in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
 

First phase 3, randomized, controlled trial

The trial is the first head-to-head, randomized comparison pitting a KRAS G12C inhibitor against the standard of care in patients with NSCLC.

Approximately 30% of patients with NSCLC have KRAS driver mutations, and KRAS G12C–mutant NSCLC comprises an estimated 13% of all NSCLC cases, Dr. Johnson said.

Sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the 2020 ESMO annual meeting. It is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
 

CodeBreaK 200 details

A total of 345 patients from sites in the United States, Europe, Asia and Australia were enrolled and randomly assigned to receive either oral sotorasib 960 mg daily, or intravenous docetaxel 75 mg/m² every 3 weeks.

As noted before, the trial met its primary endpoint of a statistically significant improvement in PFS with sotorasib as measured by independent central reviewers blinded to study assignment, with a hazard ratio of 0.66 (P = .002). Median PFS with sotorasib was 5.6 months, compared with 4.5 months for docetaxel.

The objective response rate was significantly improved for sotorasib versus docetaxel (28.1% vs. 13.2%, P < .001), as was the disease control rate at 82.5% for sotorasib versus 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for this endpoint.

Sotorasib was also superior to docetaxel at forestalling deterioration of patients’ global health status, physical functioning, and cancer-related symptoms such as dyspnea and cough. There was no significant difference between the study arms in reported chest pain, however.

Grade 3 or greater treatment-related adverse events occurred in 33.1% of patients with sotorasib, compared with 40.4% of patients on docetaxel.
 

‘Tremendous advance’

“I think the conduct of this study is impressive, it’s well designed, it was well run, any imbalances really favored the control arm, and I think that this advance is relevant not just for performance status 0 and 1 KRAS G12C–mutant patients, but even beyond, to performance status 2 and perhaps even performance status 3,” commented Natasha Leighl, MD, MMSc, from the Princess Margaret Cancer Center, Toronto, the invited discussant.

Comparing the drug performance of the respective arms, Dr. Leighl said that “I don’t think I’ve ever seen such good outcomes in a randomized trial with the chemotherapy, but unfortunately sotorasib performed a little bit less well than we had hoped.”

Nonetheless, “I think CodeBreaK 200 is a tremendous advance for patients. It is a confirmatory positive trial, and I think sotorasib is the new standard of care in patients who have received chemo and immunotherapy for KRAS G12C–mutant lung cancer,” she said.

CodeBreaK 200 was supported by Amgen. Dr. Johnson disclosed a consulting and advisory role with payments to her institution from Amgen and others. Dr. Leighl disclosed institutional grant funding and personal honoraria from Amgen and others.

PARIS – For patients with non–small cell lung cancers (NSCLC) bearing the KRAS G12C mutation that have progressed on prior therapies, the first-in-class KRAS G12C inhibitor sotorasib (Lumykras) was associated with better progression-free survival (PFS) and objective response rates than docetaxel in the randomized, phase 3 CodeBreaK 200 trial.

­Among 345 patients who had experienced disease progression after prior platinum-based chemotherapy and an immune checkpoint inhibitor, 1-year PFS rates at a median follow-up of 17.7 months were 24.8% for patients randomized to receive sotorasib versus 10.1% for patients assigned to docetaxel, reported Melissa L, Johnson, MD, from the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.

“In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C non–small cell lung cancer,” she said in a media briefing prior to her presentation of the data in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
 

First phase 3, randomized, controlled trial

The trial is the first head-to-head, randomized comparison pitting a KRAS G12C inhibitor against the standard of care in patients with NSCLC.

Approximately 30% of patients with NSCLC have KRAS driver mutations, and KRAS G12C–mutant NSCLC comprises an estimated 13% of all NSCLC cases, Dr. Johnson said.

Sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the 2020 ESMO annual meeting. It is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
 

CodeBreaK 200 details

A total of 345 patients from sites in the United States, Europe, Asia and Australia were enrolled and randomly assigned to receive either oral sotorasib 960 mg daily, or intravenous docetaxel 75 mg/m² every 3 weeks.

As noted before, the trial met its primary endpoint of a statistically significant improvement in PFS with sotorasib as measured by independent central reviewers blinded to study assignment, with a hazard ratio of 0.66 (P = .002). Median PFS with sotorasib was 5.6 months, compared with 4.5 months for docetaxel.

The objective response rate was significantly improved for sotorasib versus docetaxel (28.1% vs. 13.2%, P < .001), as was the disease control rate at 82.5% for sotorasib versus 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for this endpoint.

Sotorasib was also superior to docetaxel at forestalling deterioration of patients’ global health status, physical functioning, and cancer-related symptoms such as dyspnea and cough. There was no significant difference between the study arms in reported chest pain, however.

Grade 3 or greater treatment-related adverse events occurred in 33.1% of patients with sotorasib, compared with 40.4% of patients on docetaxel.
 

‘Tremendous advance’

“I think the conduct of this study is impressive, it’s well designed, it was well run, any imbalances really favored the control arm, and I think that this advance is relevant not just for performance status 0 and 1 KRAS G12C–mutant patients, but even beyond, to performance status 2 and perhaps even performance status 3,” commented Natasha Leighl, MD, MMSc, from the Princess Margaret Cancer Center, Toronto, the invited discussant.

Comparing the drug performance of the respective arms, Dr. Leighl said that “I don’t think I’ve ever seen such good outcomes in a randomized trial with the chemotherapy, but unfortunately sotorasib performed a little bit less well than we had hoped.”

Nonetheless, “I think CodeBreaK 200 is a tremendous advance for patients. It is a confirmatory positive trial, and I think sotorasib is the new standard of care in patients who have received chemo and immunotherapy for KRAS G12C–mutant lung cancer,” she said.

CodeBreaK 200 was supported by Amgen. Dr. Johnson disclosed a consulting and advisory role with payments to her institution from Amgen and others. Dr. Leighl disclosed institutional grant funding and personal honoraria from Amgen and others.

PARIS – For patients with non–small cell lung cancers (NSCLC) bearing the KRAS G12C mutation that have progressed on prior therapies, the first-in-class KRAS G12C inhibitor sotorasib (Lumykras) was associated with better progression-free survival (PFS) and objective response rates than docetaxel in the randomized, phase 3 CodeBreaK 200 trial.

­Among 345 patients who had experienced disease progression after prior platinum-based chemotherapy and an immune checkpoint inhibitor, 1-year PFS rates at a median follow-up of 17.7 months were 24.8% for patients randomized to receive sotorasib versus 10.1% for patients assigned to docetaxel, reported Melissa L, Johnson, MD, from the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.

“In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C non–small cell lung cancer,” she said in a media briefing prior to her presentation of the data in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
 

First phase 3, randomized, controlled trial

The trial is the first head-to-head, randomized comparison pitting a KRAS G12C inhibitor against the standard of care in patients with NSCLC.

Approximately 30% of patients with NSCLC have KRAS driver mutations, and KRAS G12C–mutant NSCLC comprises an estimated 13% of all NSCLC cases, Dr. Johnson said.

Sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the 2020 ESMO annual meeting. It is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
 

CodeBreaK 200 details

A total of 345 patients from sites in the United States, Europe, Asia and Australia were enrolled and randomly assigned to receive either oral sotorasib 960 mg daily, or intravenous docetaxel 75 mg/m² every 3 weeks.

As noted before, the trial met its primary endpoint of a statistically significant improvement in PFS with sotorasib as measured by independent central reviewers blinded to study assignment, with a hazard ratio of 0.66 (P = .002). Median PFS with sotorasib was 5.6 months, compared with 4.5 months for docetaxel.

The objective response rate was significantly improved for sotorasib versus docetaxel (28.1% vs. 13.2%, P < .001), as was the disease control rate at 82.5% for sotorasib versus 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for this endpoint.

Sotorasib was also superior to docetaxel at forestalling deterioration of patients’ global health status, physical functioning, and cancer-related symptoms such as dyspnea and cough. There was no significant difference between the study arms in reported chest pain, however.

Grade 3 or greater treatment-related adverse events occurred in 33.1% of patients with sotorasib, compared with 40.4% of patients on docetaxel.
 

‘Tremendous advance’

“I think the conduct of this study is impressive, it’s well designed, it was well run, any imbalances really favored the control arm, and I think that this advance is relevant not just for performance status 0 and 1 KRAS G12C–mutant patients, but even beyond, to performance status 2 and perhaps even performance status 3,” commented Natasha Leighl, MD, MMSc, from the Princess Margaret Cancer Center, Toronto, the invited discussant.

Comparing the drug performance of the respective arms, Dr. Leighl said that “I don’t think I’ve ever seen such good outcomes in a randomized trial with the chemotherapy, but unfortunately sotorasib performed a little bit less well than we had hoped.”

Nonetheless, “I think CodeBreaK 200 is a tremendous advance for patients. It is a confirmatory positive trial, and I think sotorasib is the new standard of care in patients who have received chemo and immunotherapy for KRAS G12C–mutant lung cancer,” she said.

CodeBreaK 200 was supported by Amgen. Dr. Johnson disclosed a consulting and advisory role with payments to her institution from Amgen and others. Dr. Leighl disclosed institutional grant funding and personal honoraria from Amgen and others.

PARIS – Patients with untreated non–small cell lung cancer (NSCLC) who could not withstand the rigors of platinum-based chemotherapy regimens had significantly better overall survival when treated with the immune checkpoint inhibitor atezolizumab (Tecentriq), compared with their counterparts treated with either vinorelbine or gemcitabine in a phase 3 randomized trial.

Among 353 patients with treatment-naive stage 3B to 4 NSCLC who were not candidates for platinum-based chemotherapy because of poor performance status (PS), advanced age, or significant comorbidities, the median overall survival (OS) was 10.3 months for patients treated with atezolizumab vs. 9.2 months for patients assigned to receive the investigator’s choice of single-agent chemotherapy.

This difference translated into a hazard ratio for death with atezolizumab of 0.78 (P = .028), Siow Ming Lee, MD, PhD, of University College London, reported at the ESMO Congress.

The 2-year OS rate with atezolizumab was 24.3%, compared with 12.4% for single-agent chemotherapy.

“When I saw the data, I was amazed. One of four patients survived for 2 years!” he said in an interview.

Neil Osterweil/MDedge News

Excluded from clinical trials

“Cancer chemotherapy has changed the treatment landscape for the metastatic NSCLC population, but these treatments are mainly recommended for fit patients,” Dr. Lee said during his presentation of the data in a presidential symposium.

First-line pivotal trials for lung cancer patients comparing either single-agent immunotherapy or an immunotherapy/chemotherapy combination have all been conducted in fit patients, with ECOG PS of 0 or 1, he noted.

“In reality, we still have a large population of unfit NSCLC patients, of at least 40%, many of which we cannot treat with standard platinum chemotherapy. There are many elderly patients with poor performance status, and the elderly with many comorbidities, and they are frequently on many drug medications, which we see frequently in our clinic,” he said.
 

Study details

To see whether immunotherapy could improve outcomes for unfit patients, investigators designed the IPSOS trial, a phase 3 multicenter open-label study of efficacy, safety, and patient-reported outcomes with atezolizumab compared with single-agent chemotherapy.

Patients from 23 centers in North America, South America, Europe, and Asia who were ineligible for platinum-based chemotherapy because of ECOG performance status of 2 or 3, or who were aged 70 or older with performance status 0 or 1 but with multiple comorbidities or other contraindications to platinum were stratified by histology, programmed death-ligand-1 (PD-L1) expression, and brain metastases, and were then randomly assigned to receive either atezolizumab 1,200 mg intravenously every 3 weeks (302 patients), or to investigator’s choice of either vinorelbine delivered orally or intravenously, according to local practice, or intravenous gemcitabine given intravenously per local practice (151 patients).

As noted before, overall survival, the primary endpoint, was significantly better with atezolizumab, translating into a 22% reduction in risk of death compared with chemotherapy.

The 1-year OS rates were 43.7% with atezolizumab vs. 36.6% with chemotherapy, and the 2-year rates were 24.3% vs. 12.4%, respectively.

­­A subgroup analysis showed trends toward better benefit for immunotherapy regardless of age, sex, race, performance status, history of tobacco use, tumor histology, stage, presence of liver metastases, number of metastatic sites, or PD-L1 expression levels. The benefit of atezolizumab was also significantly better among patients without brain metastases.

The median duration of response was 14 months with ateziluzmab vs. 7.8 months with chemotherapy. Respective objective response rates were 16.9% vs. 15.5%. Median progression-free survival, a secondary endpoint, was 4.2 months with atezolizumab and 4 months with chemotherapy, a difference that was not statistically significant. Median treatment duration was 3.5 months with atezolizumab, 2.3 months with gemcitabine, and 1.8 months with vinorelbine. Treatment-related adverse events of any grade occurred in 57% of patients on immunotherapy vs. 80.3% of those on chemotherapy. Grade 3 or 4 adverse events related to therapy occurred in 16.3% vs. 33.3%, respectively. About 13% of patients in each arm had an adverse event leading to drug discontinuation. There were three treatment-related deaths among patients on atezolizumab, and four among patients on chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilizing of health-related quality-of-life domains of functioning, and significant improvement in delaying the time to deterioration of chest pain.
 

Age is not prognostic

“I think it’s important though to remember that in this study there are very distinct populations of patients. Poor performance status and comorbidities are prognostic, but age is not,” Dr. Leighl said in her discussion.

“In terms of current standards, performance status 3 patients are currently recommended to have best supportive care unless a targeted therapy is available for them, and while PS 2 patients have been excluded from checkpoint inhibitor trials, we treat most of these patients the same way. In this study in particular, patients had to be ineligible for platinum doublet therapy, but of course this definition was subjective,” she said.

She also commented that “if we’re now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge.”

It will be important to identify more clearly those patients aged 80 and older who might benefit from atezolizumab in this setting by better incorporating biomarkers such as PD-L1 levels to determine who can benefit from therapy and who might be spared the necessity of coming into the hospital or clinic for regular intravenous infusions, she added.

The study was supported by F. Hoffman-La Roche. Dr. Lee disclosed research funding from the company to his institution. Dr. Leighl disclosed institutional grant funding and personal fees from Roche and others.

PARIS – Patients with untreated non–small cell lung cancer (NSCLC) who could not withstand the rigors of platinum-based chemotherapy regimens had significantly better overall survival when treated with the immune checkpoint inhibitor atezolizumab (Tecentriq), compared with their counterparts treated with either vinorelbine or gemcitabine in a phase 3 randomized trial.

Among 353 patients with treatment-naive stage 3B to 4 NSCLC who were not candidates for platinum-based chemotherapy because of poor performance status (PS), advanced age, or significant comorbidities, the median overall survival (OS) was 10.3 months for patients treated with atezolizumab vs. 9.2 months for patients assigned to receive the investigator’s choice of single-agent chemotherapy.

This difference translated into a hazard ratio for death with atezolizumab of 0.78 (P = .028), Siow Ming Lee, MD, PhD, of University College London, reported at the ESMO Congress.

The 2-year OS rate with atezolizumab was 24.3%, compared with 12.4% for single-agent chemotherapy.

“When I saw the data, I was amazed. One of four patients survived for 2 years!” he said in an interview.

Neil Osterweil/MDedge News

Excluded from clinical trials

“Cancer chemotherapy has changed the treatment landscape for the metastatic NSCLC population, but these treatments are mainly recommended for fit patients,” Dr. Lee said during his presentation of the data in a presidential symposium.

First-line pivotal trials for lung cancer patients comparing either single-agent immunotherapy or an immunotherapy/chemotherapy combination have all been conducted in fit patients, with ECOG PS of 0 or 1, he noted.

“In reality, we still have a large population of unfit NSCLC patients, of at least 40%, many of which we cannot treat with standard platinum chemotherapy. There are many elderly patients with poor performance status, and the elderly with many comorbidities, and they are frequently on many drug medications, which we see frequently in our clinic,” he said.
 

Study details

To see whether immunotherapy could improve outcomes for unfit patients, investigators designed the IPSOS trial, a phase 3 multicenter open-label study of efficacy, safety, and patient-reported outcomes with atezolizumab compared with single-agent chemotherapy.

Patients from 23 centers in North America, South America, Europe, and Asia who were ineligible for platinum-based chemotherapy because of ECOG performance status of 2 or 3, or who were aged 70 or older with performance status 0 or 1 but with multiple comorbidities or other contraindications to platinum were stratified by histology, programmed death-ligand-1 (PD-L1) expression, and brain metastases, and were then randomly assigned to receive either atezolizumab 1,200 mg intravenously every 3 weeks (302 patients), or to investigator’s choice of either vinorelbine delivered orally or intravenously, according to local practice, or intravenous gemcitabine given intravenously per local practice (151 patients).

As noted before, overall survival, the primary endpoint, was significantly better with atezolizumab, translating into a 22% reduction in risk of death compared with chemotherapy.

The 1-year OS rates were 43.7% with atezolizumab vs. 36.6% with chemotherapy, and the 2-year rates were 24.3% vs. 12.4%, respectively.

­­A subgroup analysis showed trends toward better benefit for immunotherapy regardless of age, sex, race, performance status, history of tobacco use, tumor histology, stage, presence of liver metastases, number of metastatic sites, or PD-L1 expression levels. The benefit of atezolizumab was also significantly better among patients without brain metastases.

The median duration of response was 14 months with ateziluzmab vs. 7.8 months with chemotherapy. Respective objective response rates were 16.9% vs. 15.5%. Median progression-free survival, a secondary endpoint, was 4.2 months with atezolizumab and 4 months with chemotherapy, a difference that was not statistically significant. Median treatment duration was 3.5 months with atezolizumab, 2.3 months with gemcitabine, and 1.8 months with vinorelbine. Treatment-related adverse events of any grade occurred in 57% of patients on immunotherapy vs. 80.3% of those on chemotherapy. Grade 3 or 4 adverse events related to therapy occurred in 16.3% vs. 33.3%, respectively. About 13% of patients in each arm had an adverse event leading to drug discontinuation. There were three treatment-related deaths among patients on atezolizumab, and four among patients on chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilizing of health-related quality-of-life domains of functioning, and significant improvement in delaying the time to deterioration of chest pain.
 

Age is not prognostic

“I think it’s important though to remember that in this study there are very distinct populations of patients. Poor performance status and comorbidities are prognostic, but age is not,” Dr. Leighl said in her discussion.

“In terms of current standards, performance status 3 patients are currently recommended to have best supportive care unless a targeted therapy is available for them, and while PS 2 patients have been excluded from checkpoint inhibitor trials, we treat most of these patients the same way. In this study in particular, patients had to be ineligible for platinum doublet therapy, but of course this definition was subjective,” she said.

She also commented that “if we’re now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge.”

It will be important to identify more clearly those patients aged 80 and older who might benefit from atezolizumab in this setting by better incorporating biomarkers such as PD-L1 levels to determine who can benefit from therapy and who might be spared the necessity of coming into the hospital or clinic for regular intravenous infusions, she added.

The study was supported by F. Hoffman-La Roche. Dr. Lee disclosed research funding from the company to his institution. Dr. Leighl disclosed institutional grant funding and personal fees from Roche and others.

PARIS – Patients with untreated non–small cell lung cancer (NSCLC) who could not withstand the rigors of platinum-based chemotherapy regimens had significantly better overall survival when treated with the immune checkpoint inhibitor atezolizumab (Tecentriq), compared with their counterparts treated with either vinorelbine or gemcitabine in a phase 3 randomized trial.

Among 353 patients with treatment-naive stage 3B to 4 NSCLC who were not candidates for platinum-based chemotherapy because of poor performance status (PS), advanced age, or significant comorbidities, the median overall survival (OS) was 10.3 months for patients treated with atezolizumab vs. 9.2 months for patients assigned to receive the investigator’s choice of single-agent chemotherapy.

This difference translated into a hazard ratio for death with atezolizumab of 0.78 (P = .028), Siow Ming Lee, MD, PhD, of University College London, reported at the ESMO Congress.

The 2-year OS rate with atezolizumab was 24.3%, compared with 12.4% for single-agent chemotherapy.

“When I saw the data, I was amazed. One of four patients survived for 2 years!” he said in an interview.

Neil Osterweil/MDedge News

Excluded from clinical trials

“Cancer chemotherapy has changed the treatment landscape for the metastatic NSCLC population, but these treatments are mainly recommended for fit patients,” Dr. Lee said during his presentation of the data in a presidential symposium.

First-line pivotal trials for lung cancer patients comparing either single-agent immunotherapy or an immunotherapy/chemotherapy combination have all been conducted in fit patients, with ECOG PS of 0 or 1, he noted.

“In reality, we still have a large population of unfit NSCLC patients, of at least 40%, many of which we cannot treat with standard platinum chemotherapy. There are many elderly patients with poor performance status, and the elderly with many comorbidities, and they are frequently on many drug medications, which we see frequently in our clinic,” he said.
 

Study details

To see whether immunotherapy could improve outcomes for unfit patients, investigators designed the IPSOS trial, a phase 3 multicenter open-label study of efficacy, safety, and patient-reported outcomes with atezolizumab compared with single-agent chemotherapy.

Patients from 23 centers in North America, South America, Europe, and Asia who were ineligible for platinum-based chemotherapy because of ECOG performance status of 2 or 3, or who were aged 70 or older with performance status 0 or 1 but with multiple comorbidities or other contraindications to platinum were stratified by histology, programmed death-ligand-1 (PD-L1) expression, and brain metastases, and were then randomly assigned to receive either atezolizumab 1,200 mg intravenously every 3 weeks (302 patients), or to investigator’s choice of either vinorelbine delivered orally or intravenously, according to local practice, or intravenous gemcitabine given intravenously per local practice (151 patients).

As noted before, overall survival, the primary endpoint, was significantly better with atezolizumab, translating into a 22% reduction in risk of death compared with chemotherapy.

The 1-year OS rates were 43.7% with atezolizumab vs. 36.6% with chemotherapy, and the 2-year rates were 24.3% vs. 12.4%, respectively.

­­A subgroup analysis showed trends toward better benefit for immunotherapy regardless of age, sex, race, performance status, history of tobacco use, tumor histology, stage, presence of liver metastases, number of metastatic sites, or PD-L1 expression levels. The benefit of atezolizumab was also significantly better among patients without brain metastases.

The median duration of response was 14 months with ateziluzmab vs. 7.8 months with chemotherapy. Respective objective response rates were 16.9% vs. 15.5%. Median progression-free survival, a secondary endpoint, was 4.2 months with atezolizumab and 4 months with chemotherapy, a difference that was not statistically significant. Median treatment duration was 3.5 months with atezolizumab, 2.3 months with gemcitabine, and 1.8 months with vinorelbine. Treatment-related adverse events of any grade occurred in 57% of patients on immunotherapy vs. 80.3% of those on chemotherapy. Grade 3 or 4 adverse events related to therapy occurred in 16.3% vs. 33.3%, respectively. About 13% of patients in each arm had an adverse event leading to drug discontinuation. There were three treatment-related deaths among patients on atezolizumab, and four among patients on chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilizing of health-related quality-of-life domains of functioning, and significant improvement in delaying the time to deterioration of chest pain.
 

Age is not prognostic

“I think it’s important though to remember that in this study there are very distinct populations of patients. Poor performance status and comorbidities are prognostic, but age is not,” Dr. Leighl said in her discussion.

“In terms of current standards, performance status 3 patients are currently recommended to have best supportive care unless a targeted therapy is available for them, and while PS 2 patients have been excluded from checkpoint inhibitor trials, we treat most of these patients the same way. In this study in particular, patients had to be ineligible for platinum doublet therapy, but of course this definition was subjective,” she said.

She also commented that “if we’re now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge.”

It will be important to identify more clearly those patients aged 80 and older who might benefit from atezolizumab in this setting by better incorporating biomarkers such as PD-L1 levels to determine who can benefit from therapy and who might be spared the necessity of coming into the hospital or clinic for regular intravenous infusions, she added.

The study was supported by F. Hoffman-La Roche. Dr. Lee disclosed research funding from the company to his institution. Dr. Leighl disclosed institutional grant funding and personal fees from Roche and others.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

On the basis of this presentation, and the findings from the chest x-ray (as shown), the likely diagnosis is non–small cell lung cancer (NSCLC), Pancoast tumor, also known as superior sulcus tumor. Pancoast tumors are rare, representing about 3%-5% of all lung cancers, and invade the structures in the apex of the chest, including the first thoracic ribs or periosteum, the lower nerve roots of the bronchial plexus, the sympathetic chain and stellate ganglion, or the subclavian vessels. The majority of Pancoast tumors are non–small cell carcinomas.

Because of their pulmonary location, Pancoast tumors are characterized by several distinct symptoms. As seen in this case, patients often present with shoulder pain that worsens over time, especially with invasion of the chest wall and brachial plexus. The pain may radiate to the neck; axilla; anterior chest wall; and medial aspect of the arm, forearm, and wrist. If Pancoast tumors infiltrate the ulnar nerve, patients may present with weakness and muscle atrophy of the intrinsic muscles of the hand. In addition, invasion of the sympathetic chain and of the inferior cervical ganglion can cause Horner syndrome (ptosis, miosis, enophthalmos, and anhidrosis). Lastly, upper-arm edema may develop, signaling invasion and potentially occlusion of the subclavian vein.

During workup, CT-guided core biopsy is the first-line diagnostic test for Pancoast tumors. CT of the chest can confirm the presence of an apical mass and its position in relation to other structures of the thoracic inlet. MRI can further assess suspected brachial plexus, subclavian vessels, spine, and neural foramina invasion, specifying the extent of the disease and of the amount of nerve-root involvement.

For resectable Pancoast tumors, the National Comprehensive Cancer Network recommends chemoradiation, followed by surgical resection and chemotherapy. Preoperative chemoradiation together with surgical resection has shown a 2-year survival between 50% and 70%. Depending on biomarker status (certain EGFR mutations or programmed death ligand 1 levels ≥ 1%), the addition of either atezolizumab or osimertinib is advised. However, the positioning of Pancoast tumors can pose a surgical challenge, and if the lesion remains unresectable after preoperative concurrent chemoradiation, then consolidation immunotherapy with durvalumab is recommended.

Karl J. D'Silva, MD, Clinical Assistant Professor, Department of Medicine, Tufts University School of Medicine, Boston; Medical Director, Department of Oncology and Hematology, Lahey Hospital and Medical Center, Peabody, Massachusetts.

Karl J. D'Silva, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

On the basis of this presentation, and the findings from the chest x-ray (as shown), the likely diagnosis is non–small cell lung cancer (NSCLC), Pancoast tumor, also known as superior sulcus tumor. Pancoast tumors are rare, representing about 3%-5% of all lung cancers, and invade the structures in the apex of the chest, including the first thoracic ribs or periosteum, the lower nerve roots of the bronchial plexus, the sympathetic chain and stellate ganglion, or the subclavian vessels. The majority of Pancoast tumors are non–small cell carcinomas.

Because of their pulmonary location, Pancoast tumors are characterized by several distinct symptoms. As seen in this case, patients often present with shoulder pain that worsens over time, especially with invasion of the chest wall and brachial plexus. The pain may radiate to the neck; axilla; anterior chest wall; and medial aspect of the arm, forearm, and wrist. If Pancoast tumors infiltrate the ulnar nerve, patients may present with weakness and muscle atrophy of the intrinsic muscles of the hand. In addition, invasion of the sympathetic chain and of the inferior cervical ganglion can cause Horner syndrome (ptosis, miosis, enophthalmos, and anhidrosis). Lastly, upper-arm edema may develop, signaling invasion and potentially occlusion of the subclavian vein.

During workup, CT-guided core biopsy is the first-line diagnostic test for Pancoast tumors. CT of the chest can confirm the presence of an apical mass and its position in relation to other structures of the thoracic inlet. MRI can further assess suspected brachial plexus, subclavian vessels, spine, and neural foramina invasion, specifying the extent of the disease and of the amount of nerve-root involvement.

For resectable Pancoast tumors, the National Comprehensive Cancer Network recommends chemoradiation, followed by surgical resection and chemotherapy. Preoperative chemoradiation together with surgical resection has shown a 2-year survival between 50% and 70%. Depending on biomarker status (certain EGFR mutations or programmed death ligand 1 levels ≥ 1%), the addition of either atezolizumab or osimertinib is advised. However, the positioning of Pancoast tumors can pose a surgical challenge, and if the lesion remains unresectable after preoperative concurrent chemoradiation, then consolidation immunotherapy with durvalumab is recommended.

Karl J. D'Silva, MD, Clinical Assistant Professor, Department of Medicine, Tufts University School of Medicine, Boston; Medical Director, Department of Oncology and Hematology, Lahey Hospital and Medical Center, Peabody, Massachusetts.

Karl J. D'Silva, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

On the basis of this presentation, and the findings from the chest x-ray (as shown), the likely diagnosis is non–small cell lung cancer (NSCLC), Pancoast tumor, also known as superior sulcus tumor. Pancoast tumors are rare, representing about 3%-5% of all lung cancers, and invade the structures in the apex of the chest, including the first thoracic ribs or periosteum, the lower nerve roots of the bronchial plexus, the sympathetic chain and stellate ganglion, or the subclavian vessels. The majority of Pancoast tumors are non–small cell carcinomas.

Because of their pulmonary location, Pancoast tumors are characterized by several distinct symptoms. As seen in this case, patients often present with shoulder pain that worsens over time, especially with invasion of the chest wall and brachial plexus. The pain may radiate to the neck; axilla; anterior chest wall; and medial aspect of the arm, forearm, and wrist. If Pancoast tumors infiltrate the ulnar nerve, patients may present with weakness and muscle atrophy of the intrinsic muscles of the hand. In addition, invasion of the sympathetic chain and of the inferior cervical ganglion can cause Horner syndrome (ptosis, miosis, enophthalmos, and anhidrosis). Lastly, upper-arm edema may develop, signaling invasion and potentially occlusion of the subclavian vein.

During workup, CT-guided core biopsy is the first-line diagnostic test for Pancoast tumors. CT of the chest can confirm the presence of an apical mass and its position in relation to other structures of the thoracic inlet. MRI can further assess suspected brachial plexus, subclavian vessels, spine, and neural foramina invasion, specifying the extent of the disease and of the amount of nerve-root involvement.

For resectable Pancoast tumors, the National Comprehensive Cancer Network recommends chemoradiation, followed by surgical resection and chemotherapy. Preoperative chemoradiation together with surgical resection has shown a 2-year survival between 50% and 70%. Depending on biomarker status (certain EGFR mutations or programmed death ligand 1 levels ≥ 1%), the addition of either atezolizumab or osimertinib is advised. However, the positioning of Pancoast tumors can pose a surgical challenge, and if the lesion remains unresectable after preoperative concurrent chemoradiation, then consolidation immunotherapy with durvalumab is recommended.

Karl J. D'Silva, MD, Clinical Assistant Professor, Department of Medicine, Tufts University School of Medicine, Boston; Medical Director, Department of Oncology and Hematology, Lahey Hospital and Medical Center, Peabody, Massachusetts.

Karl J. D'Silva, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients who undergo lung cancer surgery and who receive long-term opioids for pain relief have an elevated risk of all-cause mortality at 2 years, a new study suggests. That risk was 40% higher than among patients who did not receive opioids.

“This is the first study to identify the association of new long-term opioid use with poorer long-term survival outcomes after lung cancer surgery using real-world data based on a national registration database,” said the authors, led by In-Ae Song, MD, Seoul National University Bundang Hospital, Seongnam, South Korea.

“New long-term opioid use may be associated with poor long-term survival outcomes, especially in potent opioid users,” they concluded.

Long-term opioid use might promote protumor activity secondary to immunosuppression along with migration of tumor cells and angiogenesis, the authors suggested.

The study was published online in Regional Anesthesia and Pain.

The finding comes from a study that used the South Korean National Health Insurance database as a nationwide registration data source. “All patients undergoing lung cancer surgery between 2011 and 2018 were included,” the authors noted.

In total, 54,509 patients were included in the final analysis. Six months after undergoing the procedure, 3,325 patients (6.1%) had been prescribed opioids continuously and regularly. These patients constituted the new long-term opioid user group.

This finding fits in with those from past studies that have suggested that new long-term postoperative pain is reported in 4%-12% of patients who undergo lung cancer surgeries, the authors commented.

The new study found that all-cause mortality at 2 years was significantly higher in the new long-term opioid user group than it was in the non–opioid user group (17.3% vs. 9.3%; P < .001).

Moreover, the new long-term opioid user group were at 43% higher risk of 2-year lung cancer mortality and 29% higher risk of 2-year non–lung cancer mortality.

The investigators divided the patients who had received long-term opioids into two subgroups – those who received more potent opioids (1.6%), and those who received less potent opioids (4.5%).

There was a big difference in the results for all-cause mortality.

Compared with nonopioid users, long-term use of less potent opioids was associated with a 2-year mortality risk of only 22% (P < .001), whereas the patients who used potent opioids were at a 92% increased risk of all-cause mortality.

A number of risk factors were associated with an increased rate of new long-term opioid use. These included older age, being male, length of stay in hospital, and comorbidities.

In addition, patients who were more likely to receive long-term opioids included those who had received neoadjuvant and adjuvant chemotherapy and those who had experienced preoperative anxiety disorder or insomnia disorder.

In contrast, patients who underwent video-assisted thoracoscopic surgery were less likely to receive long-term opioids, the authors noted.

The authors disclosed no relevant financial relationships.

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

Patients who undergo lung cancer surgery and who receive long-term opioids for pain relief have an elevated risk of all-cause mortality at 2 years, a new study suggests. That risk was 40% higher than among patients who did not receive opioids.

“This is the first study to identify the association of new long-term opioid use with poorer long-term survival outcomes after lung cancer surgery using real-world data based on a national registration database,” said the authors, led by In-Ae Song, MD, Seoul National University Bundang Hospital, Seongnam, South Korea.

“New long-term opioid use may be associated with poor long-term survival outcomes, especially in potent opioid users,” they concluded.

Long-term opioid use might promote protumor activity secondary to immunosuppression along with migration of tumor cells and angiogenesis, the authors suggested.

The study was published online in Regional Anesthesia and Pain.

The finding comes from a study that used the South Korean National Health Insurance database as a nationwide registration data source. “All patients undergoing lung cancer surgery between 2011 and 2018 were included,” the authors noted.

In total, 54,509 patients were included in the final analysis. Six months after undergoing the procedure, 3,325 patients (6.1%) had been prescribed opioids continuously and regularly. These patients constituted the new long-term opioid user group.

This finding fits in with those from past studies that have suggested that new long-term postoperative pain is reported in 4%-12% of patients who undergo lung cancer surgeries, the authors commented.

The new study found that all-cause mortality at 2 years was significantly higher in the new long-term opioid user group than it was in the non–opioid user group (17.3% vs. 9.3%; P < .001).

Moreover, the new long-term opioid user group were at 43% higher risk of 2-year lung cancer mortality and 29% higher risk of 2-year non–lung cancer mortality.

The investigators divided the patients who had received long-term opioids into two subgroups – those who received more potent opioids (1.6%), and those who received less potent opioids (4.5%).

There was a big difference in the results for all-cause mortality.

Compared with nonopioid users, long-term use of less potent opioids was associated with a 2-year mortality risk of only 22% (P < .001), whereas the patients who used potent opioids were at a 92% increased risk of all-cause mortality.

A number of risk factors were associated with an increased rate of new long-term opioid use. These included older age, being male, length of stay in hospital, and comorbidities.

In addition, patients who were more likely to receive long-term opioids included those who had received neoadjuvant and adjuvant chemotherapy and those who had experienced preoperative anxiety disorder or insomnia disorder.

In contrast, patients who underwent video-assisted thoracoscopic surgery were less likely to receive long-term opioids, the authors noted.

The authors disclosed no relevant financial relationships.

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

Patients who undergo lung cancer surgery and who receive long-term opioids for pain relief have an elevated risk of all-cause mortality at 2 years, a new study suggests. That risk was 40% higher than among patients who did not receive opioids.

“This is the first study to identify the association of new long-term opioid use with poorer long-term survival outcomes after lung cancer surgery using real-world data based on a national registration database,” said the authors, led by In-Ae Song, MD, Seoul National University Bundang Hospital, Seongnam, South Korea.

“New long-term opioid use may be associated with poor long-term survival outcomes, especially in potent opioid users,” they concluded.

Long-term opioid use might promote protumor activity secondary to immunosuppression along with migration of tumor cells and angiogenesis, the authors suggested.

The study was published online in Regional Anesthesia and Pain.

The finding comes from a study that used the South Korean National Health Insurance database as a nationwide registration data source. “All patients undergoing lung cancer surgery between 2011 and 2018 were included,” the authors noted.

In total, 54,509 patients were included in the final analysis. Six months after undergoing the procedure, 3,325 patients (6.1%) had been prescribed opioids continuously and regularly. These patients constituted the new long-term opioid user group.

This finding fits in with those from past studies that have suggested that new long-term postoperative pain is reported in 4%-12% of patients who undergo lung cancer surgeries, the authors commented.

The new study found that all-cause mortality at 2 years was significantly higher in the new long-term opioid user group than it was in the non–opioid user group (17.3% vs. 9.3%; P < .001).

Moreover, the new long-term opioid user group were at 43% higher risk of 2-year lung cancer mortality and 29% higher risk of 2-year non–lung cancer mortality.

The investigators divided the patients who had received long-term opioids into two subgroups – those who received more potent opioids (1.6%), and those who received less potent opioids (4.5%).

There was a big difference in the results for all-cause mortality.

Compared with nonopioid users, long-term use of less potent opioids was associated with a 2-year mortality risk of only 22% (P < .001), whereas the patients who used potent opioids were at a 92% increased risk of all-cause mortality.

A number of risk factors were associated with an increased rate of new long-term opioid use. These included older age, being male, length of stay in hospital, and comorbidities.

In addition, patients who were more likely to receive long-term opioids included those who had received neoadjuvant and adjuvant chemotherapy and those who had experienced preoperative anxiety disorder or insomnia disorder.

In contrast, patients who underwent video-assisted thoracoscopic surgery were less likely to receive long-term opioids, the authors noted.

The authors disclosed no relevant financial relationships.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The study was funded by Bristol Myers Squibb.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The study was funded by Bristol Myers Squibb.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The study was funded by Bristol Myers Squibb.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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