Combined immune checkpoint blockade shows promise for small cell lung cancer
CHICAGO — Nivolumab plus ipilimumab led to durable responses in previously treated patients with small cell lung cancer, according to results from the CheckMate 032 trial presented at the ASCO Annual Meeting.
“Unfortunately, outcomes and treatment options for patients with recurrent small cell lung cancer are poor,” Matthew David Hellmann, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, said during his presentation. “New breakthroughs in the space are critically needed.”
The CheckMate 032 trial aims to evaluate multiple regimens of nivolumab (Opdivo, Bristol-Myers Squibb) with or without ipilimumab (Yervoy, Bristol-Myers Squibb) in various tumor types.
Based on early data demonstrating tolerability and efficacy in a nonrandomized cohort of patients with recurrent small cell lung cancer, researchers conducted longer-term follow-up and added a randomized expansion cohort of these patients.
In the original, nonrandomized treatment arms, 98 patients received 3 mg/kg nivolumab, and 61 patients received 1 mg/kg nivolumab plus 3 mg/kg ipilimumab every 3 weeks for four cycles followed by 3 mg/kg nivolumab every 2 weeks. In the randomized expansion cohort, researchers stratified 250 patients by number of prior therapies and assigned them 3:2 to arms with those same dosing schedules.
Objective response rate served as the primary endpoint for both cohorts.
Median follow-up of the nonrandomized cohort was approximately 18 months.
In the nonrandomized arms, ORR was 23% (95% CI, 13-36) with combination treatment and 11% (95% CI, 6-19) with nivolumab alone. Responses occurred early, after a median 1 to 2 months, and appeared durable, lasting 14 to 18 months, Hellmann said.
ORR appeared higher in patients with PD-L1 expression less than 1% in both the nivolumab monotherapy (14% vs. 9%) and combination (32% vs. 10%) cohorts.
“Unlike non–small cell lung cancer and other diseases, in small cell lung cancer, PD-L1 expression appears to be both uncommon and unhelpful for enriching for response,” Hellmann said. “Moreover, response rates to both nivolumab and nivolumab plus ipilimumab were actually numerically higher in those who had no PD-L1 expression, compared with those who had any PD-L1 expression.”
A greater proportion of patients treated with the combination achieved 1-year OS (40% vs. 27%) and 2-year OS (26% vs. 14%).
“OS in this cohort was particularly promising and distinctive of the durable benefit that is possible with immunotherapy,” Hellmann said. “The numerical difference between these two arms may highlight the potential value of combination therapy for appropriate patients. But, more importantly, the 1- and 2-year survival in both treatment arms is fairly remarkable given that, in this setting in even highly selective phase 1 trials, 2-year survival rarely, if ever, exceeds 10%.”
These promising data prompted the initiation of the randomized expansion cohort. Preliminary interim analysis data from this cohort occurred after a minimum follow-up of 3 months.
Median age was 63 years in the nivolumab arm (n = 145; 59% men) and 65 years in the combination arm (n = 95; 51% men).
Results showed ORR was 12% with nivolumab alone and 21% with the combination, which closely mirrored the nonrandomized data, Hellmann said.
At 3 months, a greater proportion of patients in the combination arm also achieved PFS (30% vs. 18%), but rates of OS were similar (64% vs. 65%). Researchers will continue to follow these patients, Hellmann said.
Researchers conducted pooled subgroup and safety analyses using the randomized and nonrandomized cohorts.
ORR for the combination remained higher in patients treated in the second-line (19% vs. 12%) and third-line and beyond (26% vs. 11%) settings. This finding persisted in platinum-sensitive (26% vs. 13) and -resistant (15% vs. 10%) patients.
More patients treated with the combination experienced any-grade (73% vs. 55%) and grade 3 to grade 4 (37% vs. 12%) adverse events. Seventy-eight percent of immune-related toxicity in the combination arm and 45% in the nivolumab arm resolved.
Five treatment-related deaths occurred, four of which occurred with combination treatment due to myasthenia gravis, pneumonitis, seizures/encephalitis and autoimmune hepatitis.
“As expected, the response rates [in the nonrandomized cohort] have been durable and translated to promising survival advantages, with a quarter of patients treated with nivolumab plus ipilimumab estimated to be alive at 2 years,” Hellmann said. “This results is simply not possible with other types of anticancer therapy in this disease.”
Following the efficacy observed in this study, phase 3 CheckMate 451 and CheckMate 331 trials are ongoing to assess the role of nivolumab in small cell lung cancer. – by Alexandra Todak
Hellmann MD, et al. Abstract 8503. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosure: Hellmann reports consultant/advisory roles with AstraZeneca/MedImmune, Bristol-Myers Squibb, Genentech, Janssen, Merck and Novartis, and research funding from Bristol-Myers Squibb and Genentech/Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.