Lung Cancer

Checkpoint inhibition for consolidation after chemoradiotherapy (CRT) showed promising survival benefit in patients with unresectable stage III non–small cell lung cancer (NSCLC) in two recent studies, including one looking at the investigational agent sugemalimab and one assessing durvalumab in a real-world setting.

Statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with sugemalimab versus placebo in the randomized, phase 3 GEMSTONE-301 study, and consolidation durvalumab showed effectiveness in a real-world cohort in the PACIFIC-R study.

Findings from both studies were presented at the 2021 European Society for Medical Oncology Congress.
 

GEMSTONE-301

Median progression-free survival among 381 patients randomized 2:1 to receive 1,200 mg of sugemalimab or placebo every 3 weeks after either concurrent or sequential chemoradiotherapy was 9.0 versus 5.8 months, in the treatment arms, respectively (hazard ratio, 0.64) (Abstract LBA43), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.

Patients were recruited from 50 sites, and one-third had received sequential CRT. Progression-free survival was assessed at median follow up of 14 months.

“The 12- and 18-month PFS rates were 45% vs. 26% and 39% vs. 23%, respectively,” Dr. Wu said.

Of note, the PFS benefit was observed both for patients who underwent sequential CRT (median PFS, 8.1 vs. 4.1 months with sugemalimab vs. placebo; hazard ratio, 0.59) and for those who received concurrent CRT (median PFS, 10.5 vs. 6.4 months; HR, 0.66).

Overall survival (OS) data were not mature at the time of the presentation, but a trend favoring sugemalimab was observed (HR, 0.44) he noted.

Sugemalimab, an investigational anti–programmed death-ligand 1 (PD-L1 )monoclonal antibody, was well tolerated; grade 3 or higher treatment-emergent adverse events (AEs) occurred in 24.3% of patients in the sugemalimab group and in 23.8% in the placebo group.

Concurrent chemoradiotherapy followed by immunotherapy is the standard of care for patients with unresectable stage III NSCLC, but nearly half undergo sequential CRT because they can’t tolerate concurrent treatment, Dr. Wu explained, describing the rationale for the study – the first phase 3 trial looking at both concurrent and sequential CRT in this patient population.

The results provide evidence for sugemalimab as a consolidation treatment for those who did not progress following either approach to CRT, he concluded.
 

PACIFIC-R study

The large, international, observational PACIFIC-R study also looked at consolidation in a real-world setting, and confirmed a PFS benefit with durvalumab in stage III NSCLC patients who had completed concurrent or sequential platinum-based CRT within the previous 12 weeks without evidence of disease progression (Abstract 1171MO).

“The median real-world PFS in this cohort was 21.7 months, which is higher than that in the durvalumab arm in the PACIFIC trial, which was 16.9 months,” reported Nicolas Girard, MD, a professor at Institut Curie, Paris.

The PACIFIC trial set the standard for durvalumab-based consolidation after CRT, and ongoing survival benefit was confirmed by 5-year follow-up data, he noted.

The PACIFIC-R trial included 1,399 patients from 11 countries who were treated as part of an expanded-access program following the PACIFIC trial.

Median time to durvalumab initiation after the end of radiotherapy in the cohort was 56 days. Overall median durvalumab treatment duration was 11 months, and the median number of infusions was 22, Dr. Girard said.

Pneumonitis was the most common adverse event leading to discontinuation: 214 (18.5%) patients experienced any-grade pneumonitis and/or interstitial lung disease, and 9.5 discontinued the study as a result. Most cases were mild or moderate, he said.

Subgroup analyses showed that real-world PFS was higher among patients with stage IIIa disease and those with PD-L1–positive tumors, those with nonsquamous disease histology, and those who received concurrent CRT.

“For example, in those with stage IIIa disease, the median real-world PFS was 23.7 months versus 19.2 months in patients with stage IIIb and c disease,” he said.

“PACIFIC-R demonstrated the efficacy of durvalumab consolidation in patients with unresectable stage III non–small cell lung cancer after completion of chemoradiotherapy,” said Dr. Girard. “The effectiveness of durvalumab was consistent among key subgroups, as was safety, when comparing the data with that of PACIFIC.

“The future read-outs of OS will further provide insight into the effectiveness of this regimen.”

Session chair Lizza E. Hendriks, MD, PhD, of Maastricht (the Netherlands) University, applauded the inclusion of patients undergoing sequential CRT in the GEMSTONE-301 and PACIFIC-R studies, noting that it is “very important to have data in sequential radiochemotherapy populations” given the substantial number of patients who require a sequential approach because of poor performance status, difficulty tolerating concurrent CRT, or logistical reasons, such as an inability to travel to receive concurrent CRT.

The GEMSTONE-301 study was funded by CStone Pharmaceuticals. Dr. Wu reported having no disclosures. The PACIFIC-R study was funded by AstraZeneca. Dr. Girard reported financial relationships with AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Hendriks reported financial relationships with numerous companies.

[email protected]

Checkpoint inhibition for consolidation after chemoradiotherapy (CRT) showed promising survival benefit in patients with unresectable stage III non–small cell lung cancer (NSCLC) in two recent studies, including one looking at the investigational agent sugemalimab and one assessing durvalumab in a real-world setting.

Statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with sugemalimab versus placebo in the randomized, phase 3 GEMSTONE-301 study, and consolidation durvalumab showed effectiveness in a real-world cohort in the PACIFIC-R study.

Findings from both studies were presented at the 2021 European Society for Medical Oncology Congress.
 

GEMSTONE-301

Median progression-free survival among 381 patients randomized 2:1 to receive 1,200 mg of sugemalimab or placebo every 3 weeks after either concurrent or sequential chemoradiotherapy was 9.0 versus 5.8 months, in the treatment arms, respectively (hazard ratio, 0.64) (Abstract LBA43), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.

Patients were recruited from 50 sites, and one-third had received sequential CRT. Progression-free survival was assessed at median follow up of 14 months.

“The 12- and 18-month PFS rates were 45% vs. 26% and 39% vs. 23%, respectively,” Dr. Wu said.

Of note, the PFS benefit was observed both for patients who underwent sequential CRT (median PFS, 8.1 vs. 4.1 months with sugemalimab vs. placebo; hazard ratio, 0.59) and for those who received concurrent CRT (median PFS, 10.5 vs. 6.4 months; HR, 0.66).

Overall survival (OS) data were not mature at the time of the presentation, but a trend favoring sugemalimab was observed (HR, 0.44) he noted.

Sugemalimab, an investigational anti–programmed death-ligand 1 (PD-L1 )monoclonal antibody, was well tolerated; grade 3 or higher treatment-emergent adverse events (AEs) occurred in 24.3% of patients in the sugemalimab group and in 23.8% in the placebo group.

Concurrent chemoradiotherapy followed by immunotherapy is the standard of care for patients with unresectable stage III NSCLC, but nearly half undergo sequential CRT because they can’t tolerate concurrent treatment, Dr. Wu explained, describing the rationale for the study – the first phase 3 trial looking at both concurrent and sequential CRT in this patient population.

The results provide evidence for sugemalimab as a consolidation treatment for those who did not progress following either approach to CRT, he concluded.
 

PACIFIC-R study

The large, international, observational PACIFIC-R study also looked at consolidation in a real-world setting, and confirmed a PFS benefit with durvalumab in stage III NSCLC patients who had completed concurrent or sequential platinum-based CRT within the previous 12 weeks without evidence of disease progression (Abstract 1171MO).

“The median real-world PFS in this cohort was 21.7 months, which is higher than that in the durvalumab arm in the PACIFIC trial, which was 16.9 months,” reported Nicolas Girard, MD, a professor at Institut Curie, Paris.

The PACIFIC trial set the standard for durvalumab-based consolidation after CRT, and ongoing survival benefit was confirmed by 5-year follow-up data, he noted.

The PACIFIC-R trial included 1,399 patients from 11 countries who were treated as part of an expanded-access program following the PACIFIC trial.

Median time to durvalumab initiation after the end of radiotherapy in the cohort was 56 days. Overall median durvalumab treatment duration was 11 months, and the median number of infusions was 22, Dr. Girard said.

Pneumonitis was the most common adverse event leading to discontinuation: 214 (18.5%) patients experienced any-grade pneumonitis and/or interstitial lung disease, and 9.5 discontinued the study as a result. Most cases were mild or moderate, he said.

Subgroup analyses showed that real-world PFS was higher among patients with stage IIIa disease and those with PD-L1–positive tumors, those with nonsquamous disease histology, and those who received concurrent CRT.

“For example, in those with stage IIIa disease, the median real-world PFS was 23.7 months versus 19.2 months in patients with stage IIIb and c disease,” he said.

“PACIFIC-R demonstrated the efficacy of durvalumab consolidation in patients with unresectable stage III non–small cell lung cancer after completion of chemoradiotherapy,” said Dr. Girard. “The effectiveness of durvalumab was consistent among key subgroups, as was safety, when comparing the data with that of PACIFIC.

“The future read-outs of OS will further provide insight into the effectiveness of this regimen.”

Session chair Lizza E. Hendriks, MD, PhD, of Maastricht (the Netherlands) University, applauded the inclusion of patients undergoing sequential CRT in the GEMSTONE-301 and PACIFIC-R studies, noting that it is “very important to have data in sequential radiochemotherapy populations” given the substantial number of patients who require a sequential approach because of poor performance status, difficulty tolerating concurrent CRT, or logistical reasons, such as an inability to travel to receive concurrent CRT.

The GEMSTONE-301 study was funded by CStone Pharmaceuticals. Dr. Wu reported having no disclosures. The PACIFIC-R study was funded by AstraZeneca. Dr. Girard reported financial relationships with AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Hendriks reported financial relationships with numerous companies.

[email protected]

Checkpoint inhibition for consolidation after chemoradiotherapy (CRT) showed promising survival benefit in patients with unresectable stage III non–small cell lung cancer (NSCLC) in two recent studies, including one looking at the investigational agent sugemalimab and one assessing durvalumab in a real-world setting.

Statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with sugemalimab versus placebo in the randomized, phase 3 GEMSTONE-301 study, and consolidation durvalumab showed effectiveness in a real-world cohort in the PACIFIC-R study.

Findings from both studies were presented at the 2021 European Society for Medical Oncology Congress.
 

GEMSTONE-301

Median progression-free survival among 381 patients randomized 2:1 to receive 1,200 mg of sugemalimab or placebo every 3 weeks after either concurrent or sequential chemoradiotherapy was 9.0 versus 5.8 months, in the treatment arms, respectively (hazard ratio, 0.64) (Abstract LBA43), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.

Patients were recruited from 50 sites, and one-third had received sequential CRT. Progression-free survival was assessed at median follow up of 14 months.

“The 12- and 18-month PFS rates were 45% vs. 26% and 39% vs. 23%, respectively,” Dr. Wu said.

Of note, the PFS benefit was observed both for patients who underwent sequential CRT (median PFS, 8.1 vs. 4.1 months with sugemalimab vs. placebo; hazard ratio, 0.59) and for those who received concurrent CRT (median PFS, 10.5 vs. 6.4 months; HR, 0.66).

Overall survival (OS) data were not mature at the time of the presentation, but a trend favoring sugemalimab was observed (HR, 0.44) he noted.

Sugemalimab, an investigational anti–programmed death-ligand 1 (PD-L1 )monoclonal antibody, was well tolerated; grade 3 or higher treatment-emergent adverse events (AEs) occurred in 24.3% of patients in the sugemalimab group and in 23.8% in the placebo group.

Concurrent chemoradiotherapy followed by immunotherapy is the standard of care for patients with unresectable stage III NSCLC, but nearly half undergo sequential CRT because they can’t tolerate concurrent treatment, Dr. Wu explained, describing the rationale for the study – the first phase 3 trial looking at both concurrent and sequential CRT in this patient population.

The results provide evidence for sugemalimab as a consolidation treatment for those who did not progress following either approach to CRT, he concluded.
 

PACIFIC-R study

The large, international, observational PACIFIC-R study also looked at consolidation in a real-world setting, and confirmed a PFS benefit with durvalumab in stage III NSCLC patients who had completed concurrent or sequential platinum-based CRT within the previous 12 weeks without evidence of disease progression (Abstract 1171MO).

“The median real-world PFS in this cohort was 21.7 months, which is higher than that in the durvalumab arm in the PACIFIC trial, which was 16.9 months,” reported Nicolas Girard, MD, a professor at Institut Curie, Paris.

The PACIFIC trial set the standard for durvalumab-based consolidation after CRT, and ongoing survival benefit was confirmed by 5-year follow-up data, he noted.

The PACIFIC-R trial included 1,399 patients from 11 countries who were treated as part of an expanded-access program following the PACIFIC trial.

Median time to durvalumab initiation after the end of radiotherapy in the cohort was 56 days. Overall median durvalumab treatment duration was 11 months, and the median number of infusions was 22, Dr. Girard said.

Pneumonitis was the most common adverse event leading to discontinuation: 214 (18.5%) patients experienced any-grade pneumonitis and/or interstitial lung disease, and 9.5 discontinued the study as a result. Most cases were mild or moderate, he said.

Subgroup analyses showed that real-world PFS was higher among patients with stage IIIa disease and those with PD-L1–positive tumors, those with nonsquamous disease histology, and those who received concurrent CRT.

“For example, in those with stage IIIa disease, the median real-world PFS was 23.7 months versus 19.2 months in patients with stage IIIb and c disease,” he said.

“PACIFIC-R demonstrated the efficacy of durvalumab consolidation in patients with unresectable stage III non–small cell lung cancer after completion of chemoradiotherapy,” said Dr. Girard. “The effectiveness of durvalumab was consistent among key subgroups, as was safety, when comparing the data with that of PACIFIC.

“The future read-outs of OS will further provide insight into the effectiveness of this regimen.”

Session chair Lizza E. Hendriks, MD, PhD, of Maastricht (the Netherlands) University, applauded the inclusion of patients undergoing sequential CRT in the GEMSTONE-301 and PACIFIC-R studies, noting that it is “very important to have data in sequential radiochemotherapy populations” given the substantial number of patients who require a sequential approach because of poor performance status, difficulty tolerating concurrent CRT, or logistical reasons, such as an inability to travel to receive concurrent CRT.

The GEMSTONE-301 study was funded by CStone Pharmaceuticals. Dr. Wu reported having no disclosures. The PACIFIC-R study was funded by AstraZeneca. Dr. Girard reported financial relationships with AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Hendriks reported financial relationships with numerous companies.

[email protected]

Once-daily dosing of poziotinib shows clinically meaningful efficacy for patients with treatment-naive non–small cell lung cancer (NSCLC) HER2 exon 20 mutations, according to results of the ZENITH20 trial presented at the 2021 European Society for Medical Oncology Congress. Tumor reductions, stated lead author Robin Cornelissen, PhD, MD, Erasmus University, Rotterdam, the Netherlands, were seen in 88% of patients.

EGFR and HER2 exon 20 insertion mutations are rare subsets accounting for about 10% each of all mutations and 2%-4% each in NSCLC. “There is no approved therapy for either treatment-naive or previously treated NSCLC with HER2 exon 20 mutations,” Dr. Cornelissen said in a virtual oral presentation (abstract LBA46) on Sept. 18. While chemotherapy agents with or without checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) are currently utilized, none are specific to exon 20 mutations, and historical response rates from mostly small uncontrolled studies vary widely from about 6.9%-35%, with median progression-free survival (PFS) ranging from 3 to 7 months. Poziotinib is a potent oral pan-HER TKI with activity in patients with EGFR or HER2 exon 20–mutated NSCLC.

Dr. Cornelissen presented preliminary safety and efficacy data from the phase 2 ZENITH20, a seven-cohort global clinical trial, specifically from cohort 4 (daily dosing) which included 48 HER2 exon 20 insertion NSCLC patients (median age, 60.5 years; female/male, 26/22) treated first-line with oral daily poziotinib (16 mg). The majority were White (75%), female (54%), and nonsmokers (69%) with an Eastern Cooperative Oncology Group performance status of 1 (65%).The primary endpoint was objective response rate evaluated centrally by an independent image review committee using RECIST 1.1 criteria.

All patients have experienced treatment-related adverse events (TRAEs) with 10% considered serious, and permanent discontinuation in 13%. About 83% of patients had dose interruptions and 76% had dose reductions. The most common adverse events were diarrhea (any grade, 83%; grade 3, 15%), rash (any grade, 69%; grade 3, 35%), stomatitis/mucosal inflammation (any grade, 81%; grade 3, 21%), and paronychia (any grade, 46%; grade 3 8%). Pneumonitis occurred in two patients (4%), with one grade 3 (2%). No grade 4/5 TRAEs were reported.

Discontinuations in 44 patients (92%), Dr. Cornelissen said, are attributed to death (5/10%), disease progression (30/63%), adverse events (1/2%), and other (8/17%), with treatment ongoing in 4 patients (8%).

The rate for the primary endpoint of ORR was 43.8% (n = 21) (95% confidence interval, 29.5%-58.8%).Tumor reductions have been observed in 42/48 patients (88%) with a median reduction of 35%. One complete response was reported (2.1%), with partial responses in 20 (41.7%), stable disease in 15 (31.3%), progressive disease in 7 (14.6%), and 5 (10.4%) not evaluable. The disease control rate was 75.0%.

Among secondary endpoints, median duration of response (DoR) was 5.4 months (range, 2.8 to >19.1), with 42% of patients having response duration greater than6 months and 24% greater than 12 months. Median PFS was 5.6 months (range, 0 to >20.2), with progression-free survival duration greater than6 months in 42% and duration greater than12 months in 26%.

Dr. Cornelissen concluded: “Poziotinib shows clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.” The toxicity profile, he added, is manageable and in line with previous poziotinib studies and other second-generation EGFR TKIs.

Noting that improved tolerability and antitumor activity have been observed in the cohort 5 (8 mg b.i.d.) interim analysis, Dr. Cornelissen said that cohort 4 is ongoing with patients enrolling at 8-mg b.i.d. dosing.

HER2 mutations represents 1.7%-2.2% of NSCLC, with high-sequence homology with EGFR mutation, observed ESMO-appointed discussant Daniel S.W. Tan, PhD, National Cancer Center in Singapore. He pointed out that, while HER2 antibody drug conjugates and TKIs have gained approval in other cancer types (e.g., breast, gastric), currently no HER2 therapies are approved in NSCLC. Reviewing ZENITH20 findings (risk ratio, 43.8%; DoR, 5.4 months; PFS, 5.6 months), Dr. Tan stated that poziotinib is an active agent in HER2 mutated NSCLC. “One concern that remains for me is the safety profile that will require further evaluation in order to determine optimal dosing,” he said.

Potential combinations, he added, need to be explored to improve the durability of response. “Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to a frontline setting. Also, we do need to give due consideration to strategies to improve HER2 testing rates in order to expand on clinical experience. This argues for the importance of broad upfront next generation sequencing testing in NSCLC.”

The study was funded by Spectrum Pharmaceuticals. Other authors associated with the research disclosed full or part-time employment with Spectrum.

Once-daily dosing of poziotinib shows clinically meaningful efficacy for patients with treatment-naive non–small cell lung cancer (NSCLC) HER2 exon 20 mutations, according to results of the ZENITH20 trial presented at the 2021 European Society for Medical Oncology Congress. Tumor reductions, stated lead author Robin Cornelissen, PhD, MD, Erasmus University, Rotterdam, the Netherlands, were seen in 88% of patients.

EGFR and HER2 exon 20 insertion mutations are rare subsets accounting for about 10% each of all mutations and 2%-4% each in NSCLC. “There is no approved therapy for either treatment-naive or previously treated NSCLC with HER2 exon 20 mutations,” Dr. Cornelissen said in a virtual oral presentation (abstract LBA46) on Sept. 18. While chemotherapy agents with or without checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) are currently utilized, none are specific to exon 20 mutations, and historical response rates from mostly small uncontrolled studies vary widely from about 6.9%-35%, with median progression-free survival (PFS) ranging from 3 to 7 months. Poziotinib is a potent oral pan-HER TKI with activity in patients with EGFR or HER2 exon 20–mutated NSCLC.

Dr. Cornelissen presented preliminary safety and efficacy data from the phase 2 ZENITH20, a seven-cohort global clinical trial, specifically from cohort 4 (daily dosing) which included 48 HER2 exon 20 insertion NSCLC patients (median age, 60.5 years; female/male, 26/22) treated first-line with oral daily poziotinib (16 mg). The majority were White (75%), female (54%), and nonsmokers (69%) with an Eastern Cooperative Oncology Group performance status of 1 (65%).The primary endpoint was objective response rate evaluated centrally by an independent image review committee using RECIST 1.1 criteria.

All patients have experienced treatment-related adverse events (TRAEs) with 10% considered serious, and permanent discontinuation in 13%. About 83% of patients had dose interruptions and 76% had dose reductions. The most common adverse events were diarrhea (any grade, 83%; grade 3, 15%), rash (any grade, 69%; grade 3, 35%), stomatitis/mucosal inflammation (any grade, 81%; grade 3, 21%), and paronychia (any grade, 46%; grade 3 8%). Pneumonitis occurred in two patients (4%), with one grade 3 (2%). No grade 4/5 TRAEs were reported.

Discontinuations in 44 patients (92%), Dr. Cornelissen said, are attributed to death (5/10%), disease progression (30/63%), adverse events (1/2%), and other (8/17%), with treatment ongoing in 4 patients (8%).

The rate for the primary endpoint of ORR was 43.8% (n = 21) (95% confidence interval, 29.5%-58.8%).Tumor reductions have been observed in 42/48 patients (88%) with a median reduction of 35%. One complete response was reported (2.1%), with partial responses in 20 (41.7%), stable disease in 15 (31.3%), progressive disease in 7 (14.6%), and 5 (10.4%) not evaluable. The disease control rate was 75.0%.

Among secondary endpoints, median duration of response (DoR) was 5.4 months (range, 2.8 to >19.1), with 42% of patients having response duration greater than6 months and 24% greater than 12 months. Median PFS was 5.6 months (range, 0 to >20.2), with progression-free survival duration greater than6 months in 42% and duration greater than12 months in 26%.

Dr. Cornelissen concluded: “Poziotinib shows clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.” The toxicity profile, he added, is manageable and in line with previous poziotinib studies and other second-generation EGFR TKIs.

Noting that improved tolerability and antitumor activity have been observed in the cohort 5 (8 mg b.i.d.) interim analysis, Dr. Cornelissen said that cohort 4 is ongoing with patients enrolling at 8-mg b.i.d. dosing.

HER2 mutations represents 1.7%-2.2% of NSCLC, with high-sequence homology with EGFR mutation, observed ESMO-appointed discussant Daniel S.W. Tan, PhD, National Cancer Center in Singapore. He pointed out that, while HER2 antibody drug conjugates and TKIs have gained approval in other cancer types (e.g., breast, gastric), currently no HER2 therapies are approved in NSCLC. Reviewing ZENITH20 findings (risk ratio, 43.8%; DoR, 5.4 months; PFS, 5.6 months), Dr. Tan stated that poziotinib is an active agent in HER2 mutated NSCLC. “One concern that remains for me is the safety profile that will require further evaluation in order to determine optimal dosing,” he said.

Potential combinations, he added, need to be explored to improve the durability of response. “Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to a frontline setting. Also, we do need to give due consideration to strategies to improve HER2 testing rates in order to expand on clinical experience. This argues for the importance of broad upfront next generation sequencing testing in NSCLC.”

The study was funded by Spectrum Pharmaceuticals. Other authors associated with the research disclosed full or part-time employment with Spectrum.

Once-daily dosing of poziotinib shows clinically meaningful efficacy for patients with treatment-naive non–small cell lung cancer (NSCLC) HER2 exon 20 mutations, according to results of the ZENITH20 trial presented at the 2021 European Society for Medical Oncology Congress. Tumor reductions, stated lead author Robin Cornelissen, PhD, MD, Erasmus University, Rotterdam, the Netherlands, were seen in 88% of patients.

EGFR and HER2 exon 20 insertion mutations are rare subsets accounting for about 10% each of all mutations and 2%-4% each in NSCLC. “There is no approved therapy for either treatment-naive or previously treated NSCLC with HER2 exon 20 mutations,” Dr. Cornelissen said in a virtual oral presentation (abstract LBA46) on Sept. 18. While chemotherapy agents with or without checkpoint inhibitors and tyrosine kinase inhibitors (TKIs) are currently utilized, none are specific to exon 20 mutations, and historical response rates from mostly small uncontrolled studies vary widely from about 6.9%-35%, with median progression-free survival (PFS) ranging from 3 to 7 months. Poziotinib is a potent oral pan-HER TKI with activity in patients with EGFR or HER2 exon 20–mutated NSCLC.

Dr. Cornelissen presented preliminary safety and efficacy data from the phase 2 ZENITH20, a seven-cohort global clinical trial, specifically from cohort 4 (daily dosing) which included 48 HER2 exon 20 insertion NSCLC patients (median age, 60.5 years; female/male, 26/22) treated first-line with oral daily poziotinib (16 mg). The majority were White (75%), female (54%), and nonsmokers (69%) with an Eastern Cooperative Oncology Group performance status of 1 (65%).The primary endpoint was objective response rate evaluated centrally by an independent image review committee using RECIST 1.1 criteria.

All patients have experienced treatment-related adverse events (TRAEs) with 10% considered serious, and permanent discontinuation in 13%. About 83% of patients had dose interruptions and 76% had dose reductions. The most common adverse events were diarrhea (any grade, 83%; grade 3, 15%), rash (any grade, 69%; grade 3, 35%), stomatitis/mucosal inflammation (any grade, 81%; grade 3, 21%), and paronychia (any grade, 46%; grade 3 8%). Pneumonitis occurred in two patients (4%), with one grade 3 (2%). No grade 4/5 TRAEs were reported.

Discontinuations in 44 patients (92%), Dr. Cornelissen said, are attributed to death (5/10%), disease progression (30/63%), adverse events (1/2%), and other (8/17%), with treatment ongoing in 4 patients (8%).

The rate for the primary endpoint of ORR was 43.8% (n = 21) (95% confidence interval, 29.5%-58.8%).Tumor reductions have been observed in 42/48 patients (88%) with a median reduction of 35%. One complete response was reported (2.1%), with partial responses in 20 (41.7%), stable disease in 15 (31.3%), progressive disease in 7 (14.6%), and 5 (10.4%) not evaluable. The disease control rate was 75.0%.

Among secondary endpoints, median duration of response (DoR) was 5.4 months (range, 2.8 to >19.1), with 42% of patients having response duration greater than6 months and 24% greater than 12 months. Median PFS was 5.6 months (range, 0 to >20.2), with progression-free survival duration greater than6 months in 42% and duration greater than12 months in 26%.

Dr. Cornelissen concluded: “Poziotinib shows clinically meaningful efficacy for treatment-naive NSCLC HER2 exon 20 mutations with [daily] dosing.” The toxicity profile, he added, is manageable and in line with previous poziotinib studies and other second-generation EGFR TKIs.

Noting that improved tolerability and antitumor activity have been observed in the cohort 5 (8 mg b.i.d.) interim analysis, Dr. Cornelissen said that cohort 4 is ongoing with patients enrolling at 8-mg b.i.d. dosing.

HER2 mutations represents 1.7%-2.2% of NSCLC, with high-sequence homology with EGFR mutation, observed ESMO-appointed discussant Daniel S.W. Tan, PhD, National Cancer Center in Singapore. He pointed out that, while HER2 antibody drug conjugates and TKIs have gained approval in other cancer types (e.g., breast, gastric), currently no HER2 therapies are approved in NSCLC. Reviewing ZENITH20 findings (risk ratio, 43.8%; DoR, 5.4 months; PFS, 5.6 months), Dr. Tan stated that poziotinib is an active agent in HER2 mutated NSCLC. “One concern that remains for me is the safety profile that will require further evaluation in order to determine optimal dosing,” he said.

Potential combinations, he added, need to be explored to improve the durability of response. “Until we can properly characterize this and other important aspects such as CNS activity, we need to be cautious about transitioning to a frontline setting. Also, we do need to give due consideration to strategies to improve HER2 testing rates in order to expand on clinical experience. This argues for the importance of broad upfront next generation sequencing testing in NSCLC.”

The study was funded by Spectrum Pharmaceuticals. Other authors associated with the research disclosed full or part-time employment with Spectrum.

The 34% reduction in disease recurrence for adjuvant atezolizumab in PD-L1 tumor cells of at least 50% stage II-IIIA patients in the IMpower010 clinical trial, may change the standard of care for early-stage non–small cell lung cancer (NSCLC), according to Enriqueta Felip, MD, the head of thoracic and head and neck cancer unit at Vall d’Hebron Institute of Oncology, Hospital, Barcelona.

IMpower010 is the first positive randomized phase 3 study to show significant disease-free survival (DFS) improvement with adjuvant cancer immunotherapy (atezolizumab, anti–programmed death–ligand 1, and platinum-based chemotherapy) in this population, Dr. Felip said in a presentation at the 2021 European Society for Medical Oncology Congress on Sept. 20 (abstract LBA9).

High unmet need

Up to 60% of patients with stage I-III NSCLC still experience disease relapse despite having received treatment, Dr. Felip said. IMpower010 included 1,280 patients who received up to four cycles of chemotherapy (cisplatin with pemetrexed, gemcitabine, docetaxel, or vinorelbine) after completely resected stage IB-IIIA NSCLC. Patients were randomized to open label to atezolizumab (1,200 mg every 21 days for 16 cycles or best supportive care (BSC). The primary endpoint of investigator-assessed DFS in the stage II-IIIA population (n = 1,005) was stratified according to three groups: PD-L1 tumor cells of at least 1% (stage II-IIIA), all-randomized (stage II-IIIA) and intention-to-treat (stage IB-IIIA).

Median disease-free survival in PD-L1 tumor cells of at least 1% was not estimated in the atezolizumab group and was 35.3 months in the BSC group (95% CI, 29.0 to NE). In the all-randomized group, median DFS was 42.3 months in the atezolizumab group (95% CI, 36.0 to NE) and 35.3 months in the BSC group (95% CI, 30.4-46.4) with a stratified hazard ratio of 0.79 (95% CI, 0.64-0.96; P = .02). In the intent-to-treat population, median DFS was not evaluable in the atezolizumab group and 37.2 months in the BSC group (95% CI, 31.6 to NE) with a hazard ratio of 0.81 (95% CI, 0.67-0.99; P = .04).
 

DFS hazard ratio 0.43 in TC ≥50% group

Looking at DFS by PD-L1 status in the population with and without known EGFR/ALK+ disease, Dr. Felip said that the hazard ratio for the tumor cells of at least 50% group (n = 229) was 0.43 (95% CI, 0.27-0.68), as compared with 0.87 (95% CI, 0.60-1.26) for the tumor cells 1%-49% group. With EGFR/ALK+ patients excluded, the respective HRs were similar (0.43/0.82). Considering DFS events including only disease recurrence, disease incidence was 29.4%/44.7% in the atezolizumab and BSC groups, respectively for those with PD-L1 tumor cells of at least 1%. The same pattern of atezolizumab benefit persisted in the all-randomized and intent-to-treat groups.

An assessment according to regions of relapse (locoregional only, distant only, locoregional and distant, CNS only, second primary lung) revealed no differences in the three groups. Analysis of time from randomization to relapse revealed regional differences in the PD-L1 tumor cells of at least 1% group with a median time to any relapse of 17.6 months in the atezolizumab group and 10.9 months in the BSC group. Time from randomization to relapse was generally similar for atezolizumab and best supportive care in the all randomized and intent-to-treat groups (about 11-12 months).

“The greatest magnitude of disease-free survival benefit was observed in the PD-L1 tumor cell of at least 50% population with a hazard ratio of 0.43,” Dr. Felip said. In a post hoc analysis excluding patients with known EFGR/ALK with NSCLC, she said that hazard ratios were numerically improved in most PD-L1 subgroups. Postrelapse cancer immunotherapies were used at a higher rate in the BSC arm of the trial. “Longer-term follow-up is warranted and may reveal differences in relapse patterns and treatment options.
 

Playing with the immune system

Benjamin Besse, MD, director of oncology and chair of the EORTC Lung Group at Paris-Saclay University, acknowledged the disease-free survival benefit with atezolizumab in IMpower010 and underscored that adjuvant immunotherapy has been changing treatment in resected cancers across tumor types (i.e., melanoma, renal cell carcinoma, NSCLC). He voiced some concerns, including the absence of benefit in PD-L1 less than 1%, pneumonectomy and EGFRmut/ALK+ patients, and generally the potential “when you play with the immune system for there to be a dark side too.” Dr. Besse said delayed side effects in 43.2% of patients , citing a recent report of chronic, mostly grade 1-2 immune-related adverse events following (>12 weeks after discontinuation) adjuvant anti–PD-1 therapy for high-risk resected melanoma. He mentioned, however, that the rate of second primary lung tumors in the atezolizumab group (1.4%) was lower than in the BSC group (2.6%), with generally similar rates between immuno- and nonimmunotherapies in melanoma and breast cancer trials.

“IMpower 010 is the first adjuvant study establishing immune checkpoint blockade as a new standard of care. We need to cure more, not to delay relapse,” he said. The optimal population for treatment is still yet to be defined, as is the best perioperative strategy, Dr. Besse added. “If approved I would prescribe adjuvant atezolizumab ... until I see the overall survival curves.”

IMpower010 was funded by–F. Hoffmann-La Roche. Dr. Felip disclosed numerous financial interests, including having received financial support from F. Hoffmann–La Roche, AstraZeneca, Amgen, and Merck, among other pharmaceutical companies.

The 34% reduction in disease recurrence for adjuvant atezolizumab in PD-L1 tumor cells of at least 50% stage II-IIIA patients in the IMpower010 clinical trial, may change the standard of care for early-stage non–small cell lung cancer (NSCLC), according to Enriqueta Felip, MD, the head of thoracic and head and neck cancer unit at Vall d’Hebron Institute of Oncology, Hospital, Barcelona.

IMpower010 is the first positive randomized phase 3 study to show significant disease-free survival (DFS) improvement with adjuvant cancer immunotherapy (atezolizumab, anti–programmed death–ligand 1, and platinum-based chemotherapy) in this population, Dr. Felip said in a presentation at the 2021 European Society for Medical Oncology Congress on Sept. 20 (abstract LBA9).

High unmet need

Up to 60% of patients with stage I-III NSCLC still experience disease relapse despite having received treatment, Dr. Felip said. IMpower010 included 1,280 patients who received up to four cycles of chemotherapy (cisplatin with pemetrexed, gemcitabine, docetaxel, or vinorelbine) after completely resected stage IB-IIIA NSCLC. Patients were randomized to open label to atezolizumab (1,200 mg every 21 days for 16 cycles or best supportive care (BSC). The primary endpoint of investigator-assessed DFS in the stage II-IIIA population (n = 1,005) was stratified according to three groups: PD-L1 tumor cells of at least 1% (stage II-IIIA), all-randomized (stage II-IIIA) and intention-to-treat (stage IB-IIIA).

Median disease-free survival in PD-L1 tumor cells of at least 1% was not estimated in the atezolizumab group and was 35.3 months in the BSC group (95% CI, 29.0 to NE). In the all-randomized group, median DFS was 42.3 months in the atezolizumab group (95% CI, 36.0 to NE) and 35.3 months in the BSC group (95% CI, 30.4-46.4) with a stratified hazard ratio of 0.79 (95% CI, 0.64-0.96; P = .02). In the intent-to-treat population, median DFS was not evaluable in the atezolizumab group and 37.2 months in the BSC group (95% CI, 31.6 to NE) with a hazard ratio of 0.81 (95% CI, 0.67-0.99; P = .04).
 

DFS hazard ratio 0.43 in TC ≥50% group

Looking at DFS by PD-L1 status in the population with and without known EGFR/ALK+ disease, Dr. Felip said that the hazard ratio for the tumor cells of at least 50% group (n = 229) was 0.43 (95% CI, 0.27-0.68), as compared with 0.87 (95% CI, 0.60-1.26) for the tumor cells 1%-49% group. With EGFR/ALK+ patients excluded, the respective HRs were similar (0.43/0.82). Considering DFS events including only disease recurrence, disease incidence was 29.4%/44.7% in the atezolizumab and BSC groups, respectively for those with PD-L1 tumor cells of at least 1%. The same pattern of atezolizumab benefit persisted in the all-randomized and intent-to-treat groups.

An assessment according to regions of relapse (locoregional only, distant only, locoregional and distant, CNS only, second primary lung) revealed no differences in the three groups. Analysis of time from randomization to relapse revealed regional differences in the PD-L1 tumor cells of at least 1% group with a median time to any relapse of 17.6 months in the atezolizumab group and 10.9 months in the BSC group. Time from randomization to relapse was generally similar for atezolizumab and best supportive care in the all randomized and intent-to-treat groups (about 11-12 months).

“The greatest magnitude of disease-free survival benefit was observed in the PD-L1 tumor cell of at least 50% population with a hazard ratio of 0.43,” Dr. Felip said. In a post hoc analysis excluding patients with known EFGR/ALK with NSCLC, she said that hazard ratios were numerically improved in most PD-L1 subgroups. Postrelapse cancer immunotherapies were used at a higher rate in the BSC arm of the trial. “Longer-term follow-up is warranted and may reveal differences in relapse patterns and treatment options.
 

Playing with the immune system

Benjamin Besse, MD, director of oncology and chair of the EORTC Lung Group at Paris-Saclay University, acknowledged the disease-free survival benefit with atezolizumab in IMpower010 and underscored that adjuvant immunotherapy has been changing treatment in resected cancers across tumor types (i.e., melanoma, renal cell carcinoma, NSCLC). He voiced some concerns, including the absence of benefit in PD-L1 less than 1%, pneumonectomy and EGFRmut/ALK+ patients, and generally the potential “when you play with the immune system for there to be a dark side too.” Dr. Besse said delayed side effects in 43.2% of patients , citing a recent report of chronic, mostly grade 1-2 immune-related adverse events following (>12 weeks after discontinuation) adjuvant anti–PD-1 therapy for high-risk resected melanoma. He mentioned, however, that the rate of second primary lung tumors in the atezolizumab group (1.4%) was lower than in the BSC group (2.6%), with generally similar rates between immuno- and nonimmunotherapies in melanoma and breast cancer trials.

“IMpower 010 is the first adjuvant study establishing immune checkpoint blockade as a new standard of care. We need to cure more, not to delay relapse,” he said. The optimal population for treatment is still yet to be defined, as is the best perioperative strategy, Dr. Besse added. “If approved I would prescribe adjuvant atezolizumab ... until I see the overall survival curves.”

IMpower010 was funded by–F. Hoffmann-La Roche. Dr. Felip disclosed numerous financial interests, including having received financial support from F. Hoffmann–La Roche, AstraZeneca, Amgen, and Merck, among other pharmaceutical companies.

The 34% reduction in disease recurrence for adjuvant atezolizumab in PD-L1 tumor cells of at least 50% stage II-IIIA patients in the IMpower010 clinical trial, may change the standard of care for early-stage non–small cell lung cancer (NSCLC), according to Enriqueta Felip, MD, the head of thoracic and head and neck cancer unit at Vall d’Hebron Institute of Oncology, Hospital, Barcelona.

IMpower010 is the first positive randomized phase 3 study to show significant disease-free survival (DFS) improvement with adjuvant cancer immunotherapy (atezolizumab, anti–programmed death–ligand 1, and platinum-based chemotherapy) in this population, Dr. Felip said in a presentation at the 2021 European Society for Medical Oncology Congress on Sept. 20 (abstract LBA9).

High unmet need

Up to 60% of patients with stage I-III NSCLC still experience disease relapse despite having received treatment, Dr. Felip said. IMpower010 included 1,280 patients who received up to four cycles of chemotherapy (cisplatin with pemetrexed, gemcitabine, docetaxel, or vinorelbine) after completely resected stage IB-IIIA NSCLC. Patients were randomized to open label to atezolizumab (1,200 mg every 21 days for 16 cycles or best supportive care (BSC). The primary endpoint of investigator-assessed DFS in the stage II-IIIA population (n = 1,005) was stratified according to three groups: PD-L1 tumor cells of at least 1% (stage II-IIIA), all-randomized (stage II-IIIA) and intention-to-treat (stage IB-IIIA).

Median disease-free survival in PD-L1 tumor cells of at least 1% was not estimated in the atezolizumab group and was 35.3 months in the BSC group (95% CI, 29.0 to NE). In the all-randomized group, median DFS was 42.3 months in the atezolizumab group (95% CI, 36.0 to NE) and 35.3 months in the BSC group (95% CI, 30.4-46.4) with a stratified hazard ratio of 0.79 (95% CI, 0.64-0.96; P = .02). In the intent-to-treat population, median DFS was not evaluable in the atezolizumab group and 37.2 months in the BSC group (95% CI, 31.6 to NE) with a hazard ratio of 0.81 (95% CI, 0.67-0.99; P = .04).
 

DFS hazard ratio 0.43 in TC ≥50% group

Looking at DFS by PD-L1 status in the population with and without known EGFR/ALK+ disease, Dr. Felip said that the hazard ratio for the tumor cells of at least 50% group (n = 229) was 0.43 (95% CI, 0.27-0.68), as compared with 0.87 (95% CI, 0.60-1.26) for the tumor cells 1%-49% group. With EGFR/ALK+ patients excluded, the respective HRs were similar (0.43/0.82). Considering DFS events including only disease recurrence, disease incidence was 29.4%/44.7% in the atezolizumab and BSC groups, respectively for those with PD-L1 tumor cells of at least 1%. The same pattern of atezolizumab benefit persisted in the all-randomized and intent-to-treat groups.

An assessment according to regions of relapse (locoregional only, distant only, locoregional and distant, CNS only, second primary lung) revealed no differences in the three groups. Analysis of time from randomization to relapse revealed regional differences in the PD-L1 tumor cells of at least 1% group with a median time to any relapse of 17.6 months in the atezolizumab group and 10.9 months in the BSC group. Time from randomization to relapse was generally similar for atezolizumab and best supportive care in the all randomized and intent-to-treat groups (about 11-12 months).

“The greatest magnitude of disease-free survival benefit was observed in the PD-L1 tumor cell of at least 50% population with a hazard ratio of 0.43,” Dr. Felip said. In a post hoc analysis excluding patients with known EFGR/ALK with NSCLC, she said that hazard ratios were numerically improved in most PD-L1 subgroups. Postrelapse cancer immunotherapies were used at a higher rate in the BSC arm of the trial. “Longer-term follow-up is warranted and may reveal differences in relapse patterns and treatment options.
 

Playing with the immune system

Benjamin Besse, MD, director of oncology and chair of the EORTC Lung Group at Paris-Saclay University, acknowledged the disease-free survival benefit with atezolizumab in IMpower010 and underscored that adjuvant immunotherapy has been changing treatment in resected cancers across tumor types (i.e., melanoma, renal cell carcinoma, NSCLC). He voiced some concerns, including the absence of benefit in PD-L1 less than 1%, pneumonectomy and EGFRmut/ALK+ patients, and generally the potential “when you play with the immune system for there to be a dark side too.” Dr. Besse said delayed side effects in 43.2% of patients , citing a recent report of chronic, mostly grade 1-2 immune-related adverse events following (>12 weeks after discontinuation) adjuvant anti–PD-1 therapy for high-risk resected melanoma. He mentioned, however, that the rate of second primary lung tumors in the atezolizumab group (1.4%) was lower than in the BSC group (2.6%), with generally similar rates between immuno- and nonimmunotherapies in melanoma and breast cancer trials.

“IMpower 010 is the first adjuvant study establishing immune checkpoint blockade as a new standard of care. We need to cure more, not to delay relapse,” he said. The optimal population for treatment is still yet to be defined, as is the best perioperative strategy, Dr. Besse added. “If approved I would prescribe adjuvant atezolizumab ... until I see the overall survival curves.”

IMpower010 was funded by–F. Hoffmann-La Roche. Dr. Felip disclosed numerous financial interests, including having received financial support from F. Hoffmann–La Roche, AstraZeneca, Amgen, and Merck, among other pharmaceutical companies.

Foregoing chemotherapy in favor of cancer immunotherapy (CIT) alone for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) and high programmed death–ligand 1 (PD-L1) expression did not impact survival outcomes in a retrospective cohort of U.S. patients – except in a subgroup of nonsmokers.

Median overall survival was similar at 21.0 months and 22.1 months in 169 patients who received cancer immunotherapy plus chemotherapy and 351 who received cancer immunotherapy monotherapy, respectively (adjusted hazard ratio, 1.03). Median real-world progression-free survival (PFS) was also similar in the two groups (10.8 vs. 11.5 months; aHR, 1.04), Solange Peters, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 17 (abstract VP2_2021).

However, in a small subgroup of 50 never-smokers, CIT plus chemotherapy showed significant and meaningful improvement in both overall survival and real-world progression-free survival, compared with CIT monotherapy, said Dr. Peters, ESMO president and professor and chair of medical oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The hazard ratios for overall survival and progression-free survival, after adjusting for baseline characteristics, were 0.50 and 0.40 in this subgroup, Dr. Peters said.

She and her colleagues reviewed data from the nationwide Flatiron Health Electronic Health Record–derived deidentified database for patients with metastatic nonsquamous NSCLC with a PD-L1 tumor proportion score at least 50% expression who initiated first-line CIT monotherapy or CIT plus chemotherapy between Oct. 24, 2016, and Feb. 28, 2019.

Median follow-up was 23.5 and 19.9 months in the monotherapy and combination therapy groups, respectively.

The findings are notable because “this is a very important scientific question, which by the way, is a daily question we have,” Dr. Peters said during a plenary debate session at the conference.

“One in four patients [with metastatic nonsquamous NSCLC has] this high PDL expression,” she explained, noting that both treatment approaches are commonly used in the first-line setting in this patient population.

The findings highlight the value of “well-conducted real-world evidence trials” in the absence of randomized trial results, she said.

Invited discussant Marina Chiara Garassino, MBBS, professor of medicine at the University of Chicago, also acknowledged the importance of the findings, noting the “multiple possibilities” for treatment selection in the metastatic nonsquamous NSCLC patient population.

Although patients with PD-L1 expression below 50% derive clear benefit from combination versus single-agent therapy, treatment selection for those with high PD-L1 expression is “very tricky and debatable,” she said.

For those with high PD-L1 expression, the choice is less clear and wrought with uncertainties – particularly for certain subgroups like never-smokers and those with PD-L1 expression over 90%, she said.

The findings reinforce those seen in prior meta-analyses and other clinical trials, particularly with respect to the role of smoking history when making treatment decisions.

“After these results and previous subgroup analyses, in my opinion, in [patients with] PD-L1 expression over 50%, we should consider the combination of chemotherapy and immunotherapy,” she said.

Conversely, findings from this study showing no difference in outcomes between the treatment approaches in patients with brain or liver metastases are based on small numbers and lack power for drawing any conclusions, she said. It also remains unclear whether there is a differential effect for women and those with PD-L1 expression over 90%, high tumor mutation burden, performance score greater than 2, and age over 75 years.

Both Dr. Garassino and Dr. Peters said they are looking to the INSIGNA trial, which is currently recruiting patients in the United States to evaluate the timing of pembrolizumab alone or with chemotherapy as first-line treatment and maintenance in NSCLC, to provide more clarification regarding the best treatment approaches.

This study was funded by F. Hoffmann–La Roche. Dr. Peters and Dr. Garassino each disclosed personal and/or institutional financial relationships with numerous pharmaceutical companies.

[email protected]

Foregoing chemotherapy in favor of cancer immunotherapy (CIT) alone for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) and high programmed death–ligand 1 (PD-L1) expression did not impact survival outcomes in a retrospective cohort of U.S. patients – except in a subgroup of nonsmokers.

Median overall survival was similar at 21.0 months and 22.1 months in 169 patients who received cancer immunotherapy plus chemotherapy and 351 who received cancer immunotherapy monotherapy, respectively (adjusted hazard ratio, 1.03). Median real-world progression-free survival (PFS) was also similar in the two groups (10.8 vs. 11.5 months; aHR, 1.04), Solange Peters, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 17 (abstract VP2_2021).

However, in a small subgroup of 50 never-smokers, CIT plus chemotherapy showed significant and meaningful improvement in both overall survival and real-world progression-free survival, compared with CIT monotherapy, said Dr. Peters, ESMO president and professor and chair of medical oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The hazard ratios for overall survival and progression-free survival, after adjusting for baseline characteristics, were 0.50 and 0.40 in this subgroup, Dr. Peters said.

She and her colleagues reviewed data from the nationwide Flatiron Health Electronic Health Record–derived deidentified database for patients with metastatic nonsquamous NSCLC with a PD-L1 tumor proportion score at least 50% expression who initiated first-line CIT monotherapy or CIT plus chemotherapy between Oct. 24, 2016, and Feb. 28, 2019.

Median follow-up was 23.5 and 19.9 months in the monotherapy and combination therapy groups, respectively.

The findings are notable because “this is a very important scientific question, which by the way, is a daily question we have,” Dr. Peters said during a plenary debate session at the conference.

“One in four patients [with metastatic nonsquamous NSCLC has] this high PDL expression,” she explained, noting that both treatment approaches are commonly used in the first-line setting in this patient population.

The findings highlight the value of “well-conducted real-world evidence trials” in the absence of randomized trial results, she said.

Invited discussant Marina Chiara Garassino, MBBS, professor of medicine at the University of Chicago, also acknowledged the importance of the findings, noting the “multiple possibilities” for treatment selection in the metastatic nonsquamous NSCLC patient population.

Although patients with PD-L1 expression below 50% derive clear benefit from combination versus single-agent therapy, treatment selection for those with high PD-L1 expression is “very tricky and debatable,” she said.

For those with high PD-L1 expression, the choice is less clear and wrought with uncertainties – particularly for certain subgroups like never-smokers and those with PD-L1 expression over 90%, she said.

The findings reinforce those seen in prior meta-analyses and other clinical trials, particularly with respect to the role of smoking history when making treatment decisions.

“After these results and previous subgroup analyses, in my opinion, in [patients with] PD-L1 expression over 50%, we should consider the combination of chemotherapy and immunotherapy,” she said.

Conversely, findings from this study showing no difference in outcomes between the treatment approaches in patients with brain or liver metastases are based on small numbers and lack power for drawing any conclusions, she said. It also remains unclear whether there is a differential effect for women and those with PD-L1 expression over 90%, high tumor mutation burden, performance score greater than 2, and age over 75 years.

Both Dr. Garassino and Dr. Peters said they are looking to the INSIGNA trial, which is currently recruiting patients in the United States to evaluate the timing of pembrolizumab alone or with chemotherapy as first-line treatment and maintenance in NSCLC, to provide more clarification regarding the best treatment approaches.

This study was funded by F. Hoffmann–La Roche. Dr. Peters and Dr. Garassino each disclosed personal and/or institutional financial relationships with numerous pharmaceutical companies.

[email protected]

Foregoing chemotherapy in favor of cancer immunotherapy (CIT) alone for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) and high programmed death–ligand 1 (PD-L1) expression did not impact survival outcomes in a retrospective cohort of U.S. patients – except in a subgroup of nonsmokers.

Median overall survival was similar at 21.0 months and 22.1 months in 169 patients who received cancer immunotherapy plus chemotherapy and 351 who received cancer immunotherapy monotherapy, respectively (adjusted hazard ratio, 1.03). Median real-world progression-free survival (PFS) was also similar in the two groups (10.8 vs. 11.5 months; aHR, 1.04), Solange Peters, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 17 (abstract VP2_2021).

However, in a small subgroup of 50 never-smokers, CIT plus chemotherapy showed significant and meaningful improvement in both overall survival and real-world progression-free survival, compared with CIT monotherapy, said Dr. Peters, ESMO president and professor and chair of medical oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The hazard ratios for overall survival and progression-free survival, after adjusting for baseline characteristics, were 0.50 and 0.40 in this subgroup, Dr. Peters said.

She and her colleagues reviewed data from the nationwide Flatiron Health Electronic Health Record–derived deidentified database for patients with metastatic nonsquamous NSCLC with a PD-L1 tumor proportion score at least 50% expression who initiated first-line CIT monotherapy or CIT plus chemotherapy between Oct. 24, 2016, and Feb. 28, 2019.

Median follow-up was 23.5 and 19.9 months in the monotherapy and combination therapy groups, respectively.

The findings are notable because “this is a very important scientific question, which by the way, is a daily question we have,” Dr. Peters said during a plenary debate session at the conference.

“One in four patients [with metastatic nonsquamous NSCLC has] this high PDL expression,” she explained, noting that both treatment approaches are commonly used in the first-line setting in this patient population.

The findings highlight the value of “well-conducted real-world evidence trials” in the absence of randomized trial results, she said.

Invited discussant Marina Chiara Garassino, MBBS, professor of medicine at the University of Chicago, also acknowledged the importance of the findings, noting the “multiple possibilities” for treatment selection in the metastatic nonsquamous NSCLC patient population.

Although patients with PD-L1 expression below 50% derive clear benefit from combination versus single-agent therapy, treatment selection for those with high PD-L1 expression is “very tricky and debatable,” she said.

For those with high PD-L1 expression, the choice is less clear and wrought with uncertainties – particularly for certain subgroups like never-smokers and those with PD-L1 expression over 90%, she said.

The findings reinforce those seen in prior meta-analyses and other clinical trials, particularly with respect to the role of smoking history when making treatment decisions.

“After these results and previous subgroup analyses, in my opinion, in [patients with] PD-L1 expression over 50%, we should consider the combination of chemotherapy and immunotherapy,” she said.

Conversely, findings from this study showing no difference in outcomes between the treatment approaches in patients with brain or liver metastases are based on small numbers and lack power for drawing any conclusions, she said. It also remains unclear whether there is a differential effect for women and those with PD-L1 expression over 90%, high tumor mutation burden, performance score greater than 2, and age over 75 years.

Both Dr. Garassino and Dr. Peters said they are looking to the INSIGNA trial, which is currently recruiting patients in the United States to evaluate the timing of pembrolizumab alone or with chemotherapy as first-line treatment and maintenance in NSCLC, to provide more clarification regarding the best treatment approaches.

This study was funded by F. Hoffmann–La Roche. Dr. Peters and Dr. Garassino each disclosed personal and/or institutional financial relationships with numerous pharmaceutical companies.

[email protected]

Patients in their 90s with cancer tolerated immunotherapy well with few serious adverse effects, and they lived for an average of 1.6 years after treatment, a small new study within the US Department of Veterans Affairs (VA) health system reports.

Only 6.3% of 48 patients who were treated with immune checkpoint inhibitors experienced the most severe types of side effects – grade III/IV events – and a total of 27% had any adverse effects, according to the report, which was presented at the 2021 annual meeting of the Association of VA Hematology/Oncology (AVAHO) being held virtually and inperson in Denver Colorado, September 24 to September 26, 2021.

“Our project should help give confidence to oncologists treating the elderly,” said Andrew Joseph Benefield, MD, a hematology/oncology fellow at Wake Forest Baptist Medical Center, in an interview. “Immunotherapy can be given safely and likely effectively in select individuals over the age of 90 with good performance status.”

Benefield and colleagues launched their study to gain insight into a little-studied area: How does cancer treatment affects nonagenarians? “I think many oncologists have been in a situation where they encounter an individual over the age of 90 years who has a good performance status, and they've wondered if immunotherapy would be helpful and safe, particularly given our knowledge of waning immune strength as people age,” he said.

The researchers retrospectively tracked patients with cancer who were at least 90 years old from 2016 to 2017 and were treated with immune checkpoint inhibitors. Most were fit or fairly fit with Eastern Cooperative Oncology Group (ECOG) physical performance scales of 0 or 1 (n = 26), and nearly all had cancer in stage IV (n = 42). Melanoma was the most common type of cancer (n = 19), followed by non-small-cell lung cancer (n = 15). Patients were treated with an average of 12.2 cycles.

“In general, we saw that treatment was well-tolerated,” Dr. Benefield said. “We also noted that a trend toward better long-term survival outcomes in individuals with very good performance status at the start of treatment. We hope to parse this out more as we add more data to our data-set, as the numbers are still too small for confident direct comparison.”

Dr. Benefield said he has treated a limited number of patients in their 90s who were highly physical fit for their age and “very eager” to be treated. “They wanted to do anything they could to maintain their lifestyle,” he said. “In my experience, aggressive supportive care and close monitoring for developing toxicities has been most helpful.”

The researchers don’t know the causes of death of many of the patients, and it’s not clear how they fared in their final days. Still, Dr. Benefield said, “extending someone's life by more than 1 year with relatively low risk of adverse effects is reasonable.”

Oncologist Melisa Wong, MD, MAS, of the University of California, San Francisco, reviewed the study and said in an interview that it “a valuable description of outcomes for nonagenarians receiving immunotherapy in the VA healthcare system.” As she noted, “many other studies of immunotherapy among older adults focus on patients aged 65 or 70 and older while very few focus on octogenarians or nonagenarians.”

The findings suggest that “it is important to move beyond chronological age and assess patients’ physiologic age through a geriatric assessment,” she said. “Geriatric assessment-derived risk scores have been shown to predict chemotherapy toxicity for older adults and research to develop similar tools for immunotherapy are ongoing.”

However, she cautioned that older patients may become suffer so much from the most common side effect of immunotherapy -- fatigue – that “their independence is at stake.”

“Some of these patient choose to stop immunotherapy because the side effects aren’t worth it anymore,” she said. “The challenge for oncologists is not knowing in advance which patients will fall into each of these categories.”

She added that her geriatric oncology research focuses on improving risk stratification for older adults, such as those who are at least 70 with lung adenocarcinoma.

Oncologist Grant R. Williams, MD, MSPH, director of the Cancer & Aging Program at the University of Alabama at Birmingham, agreed in an interview that comprehensive geriatric assessments are important to guide treatment in the oldest adults. “In addition, it is important to elicit the goals of treatment as well,” he said. “For older adults that are fit or at least pre-frail and desire aggressive treatment, immunotherapy is a very reasonable approach, particularly when patients are closely monitored for side effects.”

No study funding is reported. The authors report no disclosures. Dr. Wong discloses an immediate family member is an employee and stock holder of Genentech. Dr. Williams has no disclosures.

Patients in their 90s with cancer tolerated immunotherapy well with few serious adverse effects, and they lived for an average of 1.6 years after treatment, a small new study within the US Department of Veterans Affairs (VA) health system reports.

Only 6.3% of 48 patients who were treated with immune checkpoint inhibitors experienced the most severe types of side effects – grade III/IV events – and a total of 27% had any adverse effects, according to the report, which was presented at the 2021 annual meeting of the Association of VA Hematology/Oncology (AVAHO) being held virtually and inperson in Denver Colorado, September 24 to September 26, 2021.

“Our project should help give confidence to oncologists treating the elderly,” said Andrew Joseph Benefield, MD, a hematology/oncology fellow at Wake Forest Baptist Medical Center, in an interview. “Immunotherapy can be given safely and likely effectively in select individuals over the age of 90 with good performance status.”

Benefield and colleagues launched their study to gain insight into a little-studied area: How does cancer treatment affects nonagenarians? “I think many oncologists have been in a situation where they encounter an individual over the age of 90 years who has a good performance status, and they've wondered if immunotherapy would be helpful and safe, particularly given our knowledge of waning immune strength as people age,” he said.

The researchers retrospectively tracked patients with cancer who were at least 90 years old from 2016 to 2017 and were treated with immune checkpoint inhibitors. Most were fit or fairly fit with Eastern Cooperative Oncology Group (ECOG) physical performance scales of 0 or 1 (n = 26), and nearly all had cancer in stage IV (n = 42). Melanoma was the most common type of cancer (n = 19), followed by non-small-cell lung cancer (n = 15). Patients were treated with an average of 12.2 cycles.

“In general, we saw that treatment was well-tolerated,” Dr. Benefield said. “We also noted that a trend toward better long-term survival outcomes in individuals with very good performance status at the start of treatment. We hope to parse this out more as we add more data to our data-set, as the numbers are still too small for confident direct comparison.”

Dr. Benefield said he has treated a limited number of patients in their 90s who were highly physical fit for their age and “very eager” to be treated. “They wanted to do anything they could to maintain their lifestyle,” he said. “In my experience, aggressive supportive care and close monitoring for developing toxicities has been most helpful.”

The researchers don’t know the causes of death of many of the patients, and it’s not clear how they fared in their final days. Still, Dr. Benefield said, “extending someone's life by more than 1 year with relatively low risk of adverse effects is reasonable.”

Oncologist Melisa Wong, MD, MAS, of the University of California, San Francisco, reviewed the study and said in an interview that it “a valuable description of outcomes for nonagenarians receiving immunotherapy in the VA healthcare system.” As she noted, “many other studies of immunotherapy among older adults focus on patients aged 65 or 70 and older while very few focus on octogenarians or nonagenarians.”

The findings suggest that “it is important to move beyond chronological age and assess patients’ physiologic age through a geriatric assessment,” she said. “Geriatric assessment-derived risk scores have been shown to predict chemotherapy toxicity for older adults and research to develop similar tools for immunotherapy are ongoing.”

However, she cautioned that older patients may become suffer so much from the most common side effect of immunotherapy -- fatigue – that “their independence is at stake.”

“Some of these patient choose to stop immunotherapy because the side effects aren’t worth it anymore,” she said. “The challenge for oncologists is not knowing in advance which patients will fall into each of these categories.”

She added that her geriatric oncology research focuses on improving risk stratification for older adults, such as those who are at least 70 with lung adenocarcinoma.

Oncologist Grant R. Williams, MD, MSPH, director of the Cancer & Aging Program at the University of Alabama at Birmingham, agreed in an interview that comprehensive geriatric assessments are important to guide treatment in the oldest adults. “In addition, it is important to elicit the goals of treatment as well,” he said. “For older adults that are fit or at least pre-frail and desire aggressive treatment, immunotherapy is a very reasonable approach, particularly when patients are closely monitored for side effects.”

No study funding is reported. The authors report no disclosures. Dr. Wong discloses an immediate family member is an employee and stock holder of Genentech. Dr. Williams has no disclosures.

Patients in their 90s with cancer tolerated immunotherapy well with few serious adverse effects, and they lived for an average of 1.6 years after treatment, a small new study within the US Department of Veterans Affairs (VA) health system reports.

Only 6.3% of 48 patients who were treated with immune checkpoint inhibitors experienced the most severe types of side effects – grade III/IV events – and a total of 27% had any adverse effects, according to the report, which was presented at the 2021 annual meeting of the Association of VA Hematology/Oncology (AVAHO) being held virtually and inperson in Denver Colorado, September 24 to September 26, 2021.

“Our project should help give confidence to oncologists treating the elderly,” said Andrew Joseph Benefield, MD, a hematology/oncology fellow at Wake Forest Baptist Medical Center, in an interview. “Immunotherapy can be given safely and likely effectively in select individuals over the age of 90 with good performance status.”

Benefield and colleagues launched their study to gain insight into a little-studied area: How does cancer treatment affects nonagenarians? “I think many oncologists have been in a situation where they encounter an individual over the age of 90 years who has a good performance status, and they've wondered if immunotherapy would be helpful and safe, particularly given our knowledge of waning immune strength as people age,” he said.

The researchers retrospectively tracked patients with cancer who were at least 90 years old from 2016 to 2017 and were treated with immune checkpoint inhibitors. Most were fit or fairly fit with Eastern Cooperative Oncology Group (ECOG) physical performance scales of 0 or 1 (n = 26), and nearly all had cancer in stage IV (n = 42). Melanoma was the most common type of cancer (n = 19), followed by non-small-cell lung cancer (n = 15). Patients were treated with an average of 12.2 cycles.

“In general, we saw that treatment was well-tolerated,” Dr. Benefield said. “We also noted that a trend toward better long-term survival outcomes in individuals with very good performance status at the start of treatment. We hope to parse this out more as we add more data to our data-set, as the numbers are still too small for confident direct comparison.”

Dr. Benefield said he has treated a limited number of patients in their 90s who were highly physical fit for their age and “very eager” to be treated. “They wanted to do anything they could to maintain their lifestyle,” he said. “In my experience, aggressive supportive care and close monitoring for developing toxicities has been most helpful.”

The researchers don’t know the causes of death of many of the patients, and it’s not clear how they fared in their final days. Still, Dr. Benefield said, “extending someone's life by more than 1 year with relatively low risk of adverse effects is reasonable.”

Oncologist Melisa Wong, MD, MAS, of the University of California, San Francisco, reviewed the study and said in an interview that it “a valuable description of outcomes for nonagenarians receiving immunotherapy in the VA healthcare system.” As she noted, “many other studies of immunotherapy among older adults focus on patients aged 65 or 70 and older while very few focus on octogenarians or nonagenarians.”

The findings suggest that “it is important to move beyond chronological age and assess patients’ physiologic age through a geriatric assessment,” she said. “Geriatric assessment-derived risk scores have been shown to predict chemotherapy toxicity for older adults and research to develop similar tools for immunotherapy are ongoing.”

However, she cautioned that older patients may become suffer so much from the most common side effect of immunotherapy -- fatigue – that “their independence is at stake.”

“Some of these patient choose to stop immunotherapy because the side effects aren’t worth it anymore,” she said. “The challenge for oncologists is not knowing in advance which patients will fall into each of these categories.”

She added that her geriatric oncology research focuses on improving risk stratification for older adults, such as those who are at least 70 with lung adenocarcinoma.

Oncologist Grant R. Williams, MD, MSPH, director of the Cancer & Aging Program at the University of Alabama at Birmingham, agreed in an interview that comprehensive geriatric assessments are important to guide treatment in the oldest adults. “In addition, it is important to elicit the goals of treatment as well,” he said. “For older adults that are fit or at least pre-frail and desire aggressive treatment, immunotherapy is a very reasonable approach, particularly when patients are closely monitored for side effects.”

No study funding is reported. The authors report no disclosures. Dr. Wong discloses an immediate family member is an employee and stock holder of Genentech. Dr. Williams has no disclosures.

Combination bevacizumab and osimertinib provided no progression-free survival benefit over osimertinib alone for the first-line treatment of advanced epidermal growth factor receptor (EGFR)–mutated nonsquamous non–small cell lung cancer (NSCLC) in patients in an open-label, phase 2 study.

Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).

“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.

However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.

Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.

Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.

The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.

Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.

Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.

The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.

“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.

“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”

The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”

This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.

This article was updated Sept. 24, 2021.

[email protected]

Combination bevacizumab and osimertinib provided no progression-free survival benefit over osimertinib alone for the first-line treatment of advanced epidermal growth factor receptor (EGFR)–mutated nonsquamous non–small cell lung cancer (NSCLC) in patients in an open-label, phase 2 study.

Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).

“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.

However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.

Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.

Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.

The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.

Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.

Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.

The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.

“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.

“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”

The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”

This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.

This article was updated Sept. 24, 2021.

[email protected]

Combination bevacizumab and osimertinib provided no progression-free survival benefit over osimertinib alone for the first-line treatment of advanced epidermal growth factor receptor (EGFR)–mutated nonsquamous non–small cell lung cancer (NSCLC) in patients in an open-label, phase 2 study.

Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).

“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.

However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.

Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.

Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.

The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.

Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.

Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.

The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.

“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.

“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”

The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”

This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.

This article was updated Sept. 24, 2021.

[email protected]

In heavily pretreated patients with advanced non–small cell lung cancer (NSCLC) and actionable genomic alterations (AGAs), the antitumor activity of datopotamab deruxtecan in the phase 1 TROPION-PanTumor01 study is encouraging, according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).

Limited benefit from existing treatments

Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.

TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
 

Subgroup with AGAs

The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.

Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”

The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
 

Further evaluation ongoing

Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.

Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”

Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”

The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.

This article was updated Sept. 24, 2021.

In heavily pretreated patients with advanced non–small cell lung cancer (NSCLC) and actionable genomic alterations (AGAs), the antitumor activity of datopotamab deruxtecan in the phase 1 TROPION-PanTumor01 study is encouraging, according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).

Limited benefit from existing treatments

Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.

TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
 

Subgroup with AGAs

The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.

Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”

The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
 

Further evaluation ongoing

Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.

Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”

Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”

The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.

This article was updated Sept. 24, 2021.

In heavily pretreated patients with advanced non–small cell lung cancer (NSCLC) and actionable genomic alterations (AGAs), the antitumor activity of datopotamab deruxtecan in the phase 1 TROPION-PanTumor01 study is encouraging, according to Edward B. Garon, MD, of the University of California, Los Angeles. Prior results from TROPION-PanTumor01, have demonstrated similarly encouraging activity and a manageable safety profile for Dato-DXd, Dr. Garon said in a 2021 European Society for Medical Oncology Congress virtual oral presentation on Sept. 19 (abstract LBA49).

Limited benefit from existing treatments

Once tyrosine kinase inhibitors and platinum chemotherapy have failed, patients with advanced/metastatic NSCLC with AGAs (e.g., EGFR or ALK mutations) derive limited benefit from existing treatments, Dr. Garon observed. Datopotamab deruxtecan is an antibody-drug conjugate composed of a humanized anti-TROP2 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. TROP2 is highly expressed in NSCLC, regardless of genomic mutation status and has been associated with poor prognosis. Patients in TROPION-PanTumor01 were not selected based on TROP2 expression or AGA status, Dr. Garon noted.

TROPION-PanTumor01 (NCT03401385), an ongoing multicenter, open-label, dose-expansion study evaluating datopotamab deruxtecan in solid tumors, including NSCLC in 210 patients, is assessing safety, pharmacokinetics, antitumor activity, and biomarkers. All included patients (n = 180; median age, 62 years; 56% female) had progressed after standard treatment or had measurable disease and had no standard treatment available. Stable/treated brain metastases were permitted.
 

Subgroup with AGAs

The current report includes outcomes from the subgroup of 34 patients with AGAs, who were treated with 4 (n = 8), 6 (n = 10), and 8 mg/kg (n = 16) of datopotamab deruxtecan. AGAs were EGFR in 29 patients, ALK in 3, and ROS1 and RET in 1 each. Most patients (82%) had received three or more prior regimens; 85% had prior TKI, and among EGFR mutation patients, 69% had received osimertinib. Prior systemic treatment consisted of immunotherapy in 41%, platinum-based chemotherapy in 91%, and tyrosine kinase inhibitor in 85%. The primary objectives were to establish the maximum tolerated dose, safety, and tolerability. Efficacy was a secondary outcome.

Treatment-emergent adverse events were reported in all patients, with grade 3 or higher events in 53%. Most common were grade 1-2 nausea, stomatitis, fatigue, and alopecia. Drug-attributed events in 88% were grade 3 or higher in 38%. Treatment-emergent adverse events led to discontinuation in 15%, dose interruption in 27% and dose reductions in 15%. One case of grade 5 interstitial lung disease, in the 8-mg group, was adjudicated as drug related. “The safety profile of Dato-DXd was manageable and consistent with that observed in the overall NSCLC population in TROPION-PanTumor01,” Dr. Garon said, “and were primarily nonhematologic.”

The objective response rate was 35%, all partial responses. The stable disease rate was 41%; the progressive disease rate was 6%. Median duration of response was 9.5 months (95% confidence interval, 3.3-NE). Dr. Garon noted that clinical activity was observed in EGFR (Ex 19del, L858R) including after osimertinib and across other AGAs.
 

Further evaluation ongoing

Further evaluation of datopotamab deruxtecan is ongoing in the TROPION-Lung05 study among NSCLC patients with AGAs after targeted therapy and platinum-based chemotherapy options have been exhausted. Eligible AGAs include EGFR (including exon 20 insertions), ALK, ROS1, RET, BRAF, NTRK and MET exon 14 skipping.

Session moderator David Gandara, MD, University of California Davis Health, questioned the rationale for targeting oncogene driven cancers with this particular drug: “Is this just because this is felt to be an unmet need, or is there higher expression or some other biologic rationale?”

Dr. Garon responded, “Why are we looking at these driver mutation–positive patients? I think it has less to do with mechanism and more to do with the differences in treatment between these driver mutation positive patients and the rest of the population. This is a group of patients which has TROP2, but TROP2 expression is seen really across non–small cell lung cancer. But, in fact, one of the reasons it has been postulated that TROP2 is not a good biomarker for this class of drugs to date, is that its expression is so ubiquitous in the disease.”

The study was funded by Daiichi Sankyo. Dr. Garon disclosed numerous pharmaceutical-related financial interests.

This article was updated Sept. 24, 2021.

The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) offers a durable, long-term survival benefit over chemotherapy for patients with unresectable malignant pleural mesothelioma (MPM), confirms a 3-year updated analysis of the CheckMate 743 trial.

After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.

Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.

She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.

Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.

As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.

On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.

The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.

Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.

In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.

The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.

This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.

There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.

Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.

Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
 

Study details

Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.

A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.

The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.

Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.

However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.

Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.

An inverse finding was observed when patients were stratified by tumor histology.

In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.

At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.

Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.

Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.

Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.

This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.

This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.

The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.

However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.

Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.

Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.

Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.

The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.

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

The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) offers a durable, long-term survival benefit over chemotherapy for patients with unresectable malignant pleural mesothelioma (MPM), confirms a 3-year updated analysis of the CheckMate 743 trial.

After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.

Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.

She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.

Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.

As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.

On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.

The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.

Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.

In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.

The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.

This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.

There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.

Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.

Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
 

Study details

Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.

A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.

The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.

Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.

However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.

Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.

An inverse finding was observed when patients were stratified by tumor histology.

In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.

At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.

Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.

Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.

Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.

This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.

This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.

The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.

However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.

Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.

Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.

Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.

The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.

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

The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) offers a durable, long-term survival benefit over chemotherapy for patients with unresectable malignant pleural mesothelioma (MPM), confirms a 3-year updated analysis of the CheckMate 743 trial.

After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.

Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.

She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.

Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.

As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.

On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.

The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.

Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.

In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.

The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.

This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.

There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.

Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.

Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
 

Study details

Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.

A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.

The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.

Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.

However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.

Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.

An inverse finding was observed when patients were stratified by tumor histology.

In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.

At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.

Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.

Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.

Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.

This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.

This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.

The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.

However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.

Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.

Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.

Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.

The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[email protected]

Three new cancer drugs have been recommended for approval in Europe, as well as new indications for two already marketed immunotherapies. The positive opinions were issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) at its September meeting.

The CHMP recommended the granting of a conditional marketing authorization for pralsetinib (Gavreto) for the treatment of non–small cell lung cancer (NSCLC).

Specifically, pralsetinib is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced NSCLC not previously treated with a RET inhibitor.

Available as 100 mg capsules, pralsetinib is a RET-receptor tyrosine kinase inhibitor, targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET).

Pralsetinib’s benefits are its objective response rate and response duration in patients with RET-fusion positive NSCLC, as observed in a pivotal phase 1/2, open-label, multi-cohort, single-arm study.

The most common side effects are anemia, increased aspartate aminotransferase, neutropenia, constipation, musculoskeletal pain, fatigue, leukopenia, increased alanine aminotransferase, and hypertension.

CHMP also recommended ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib (Gleevec).

Available as 50 mg tablets, ripretinib is a protein kinase inhibitor designed to selectively block the oncogenic KIT and PDGFRA kinases by inhibiting their active conformation.

Ripretinib improved progression-free survival in patients with GIST.

The most common side effects are fatigue, alopecia, nausea, myalgia, constipation, diarrhea, palmar-plantar erythrodysesthesia syndrome, weight loss, and vomiting.

The third drug recommended for approval was zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström’s macroglobulinemia who have received at least one prior therapy or who are to receive the drug as first-line treatment (and are unsuitable for chemo-immunotherapy).

Available as 80 mg capsules, zanubrutinib is a Bruton’s tyrosine kinase inhibitor that blocks the activity of BTK, inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Zanubrutinib has demonstrated a clinically meaningful rate of very good partial response and/or complete response.

The most common side effects are neutropenia, thrombocytopenia, upper respiratory tract infection, hemorrhage/hematoma, rash, bruising, anemia, musculoskeletal pain, diarrhea, pneumonia, and cough.
 

Two new indications for already marketed drugs

CHMP also recommended an extension of the indications for two immunotherapies.

Pembrolizumab (Keytruda) will now also have an indication for use in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS greater than or equal to 10 and who have not received prior chemotherapy for metastatic disease

Nivolumab (Opdivo) received an extension of indication to include use, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in the firstline treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) greater than or equal to 5.

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

Three new cancer drugs have been recommended for approval in Europe, as well as new indications for two already marketed immunotherapies. The positive opinions were issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) at its September meeting.

The CHMP recommended the granting of a conditional marketing authorization for pralsetinib (Gavreto) for the treatment of non–small cell lung cancer (NSCLC).

Specifically, pralsetinib is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced NSCLC not previously treated with a RET inhibitor.

Available as 100 mg capsules, pralsetinib is a RET-receptor tyrosine kinase inhibitor, targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET).

Pralsetinib’s benefits are its objective response rate and response duration in patients with RET-fusion positive NSCLC, as observed in a pivotal phase 1/2, open-label, multi-cohort, single-arm study.

The most common side effects are anemia, increased aspartate aminotransferase, neutropenia, constipation, musculoskeletal pain, fatigue, leukopenia, increased alanine aminotransferase, and hypertension.

CHMP also recommended ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib (Gleevec).

Available as 50 mg tablets, ripretinib is a protein kinase inhibitor designed to selectively block the oncogenic KIT and PDGFRA kinases by inhibiting their active conformation.

Ripretinib improved progression-free survival in patients with GIST.

The most common side effects are fatigue, alopecia, nausea, myalgia, constipation, diarrhea, palmar-plantar erythrodysesthesia syndrome, weight loss, and vomiting.

The third drug recommended for approval was zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström’s macroglobulinemia who have received at least one prior therapy or who are to receive the drug as first-line treatment (and are unsuitable for chemo-immunotherapy).

Available as 80 mg capsules, zanubrutinib is a Bruton’s tyrosine kinase inhibitor that blocks the activity of BTK, inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Zanubrutinib has demonstrated a clinically meaningful rate of very good partial response and/or complete response.

The most common side effects are neutropenia, thrombocytopenia, upper respiratory tract infection, hemorrhage/hematoma, rash, bruising, anemia, musculoskeletal pain, diarrhea, pneumonia, and cough.
 

Two new indications for already marketed drugs

CHMP also recommended an extension of the indications for two immunotherapies.

Pembrolizumab (Keytruda) will now also have an indication for use in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS greater than or equal to 10 and who have not received prior chemotherapy for metastatic disease

Nivolumab (Opdivo) received an extension of indication to include use, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in the firstline treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) greater than or equal to 5.

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

Three new cancer drugs have been recommended for approval in Europe, as well as new indications for two already marketed immunotherapies. The positive opinions were issued by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) at its September meeting.

The CHMP recommended the granting of a conditional marketing authorization for pralsetinib (Gavreto) for the treatment of non–small cell lung cancer (NSCLC).

Specifically, pralsetinib is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced NSCLC not previously treated with a RET inhibitor.

Available as 100 mg capsules, pralsetinib is a RET-receptor tyrosine kinase inhibitor, targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET).

Pralsetinib’s benefits are its objective response rate and response duration in patients with RET-fusion positive NSCLC, as observed in a pivotal phase 1/2, open-label, multi-cohort, single-arm study.

The most common side effects are anemia, increased aspartate aminotransferase, neutropenia, constipation, musculoskeletal pain, fatigue, leukopenia, increased alanine aminotransferase, and hypertension.

CHMP also recommended ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib (Gleevec).

Available as 50 mg tablets, ripretinib is a protein kinase inhibitor designed to selectively block the oncogenic KIT and PDGFRA kinases by inhibiting their active conformation.

Ripretinib improved progression-free survival in patients with GIST.

The most common side effects are fatigue, alopecia, nausea, myalgia, constipation, diarrhea, palmar-plantar erythrodysesthesia syndrome, weight loss, and vomiting.

The third drug recommended for approval was zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström’s macroglobulinemia who have received at least one prior therapy or who are to receive the drug as first-line treatment (and are unsuitable for chemo-immunotherapy).

Available as 80 mg capsules, zanubrutinib is a Bruton’s tyrosine kinase inhibitor that blocks the activity of BTK, inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Zanubrutinib has demonstrated a clinically meaningful rate of very good partial response and/or complete response.

The most common side effects are neutropenia, thrombocytopenia, upper respiratory tract infection, hemorrhage/hematoma, rash, bruising, anemia, musculoskeletal pain, diarrhea, pneumonia, and cough.
 

Two new indications for already marketed drugs

CHMP also recommended an extension of the indications for two immunotherapies.

Pembrolizumab (Keytruda) will now also have an indication for use in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS greater than or equal to 10 and who have not received prior chemotherapy for metastatic disease

Nivolumab (Opdivo) received an extension of indication to include use, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in the firstline treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) greater than or equal to 5.

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