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Combined immune checkpoint blockade shows promise for small cell lung cancer
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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
Reference:
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.
Perspective
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Jorge Nieva, MD
The treatment for second-line small cell lung cancer is suboptimal. The standard treatment has been topotecan — we have not had any FDA approved drugs beyond that in many years, though there may be new treatments approved soon. Topotecan provides median survival of 5.8 months. The abstract presented by Hellman showing 25% long-term responders for the combination arm is really exciting.
It is not entirely surprising that PD-L1 did not predict outcomes in this study, because it has not been perfectly predictive in any other disease. Clearly, we do not completely understand who is and is not going to respond to these therapies. A number of different biomarkers have been proposed across diseases, including PD-L1 expression, total tumor mutational burden and tumor-infiltrating lymphocytes. Other data presented in this session suggested the expression checkpoint related proteins on immune cells at the tumor edge also may be important.
There is certainly a lot more toxicity when you add a CTLA-4 antagonist to nivolumab (Opdivo, Bristol-Myers Squibb). Thirty-three percent of patients experienced grade 3 or grade 4 toxicity with the combination, which is fairly high considering that most of the toxicity is nonhematologic. Nonhematologic toxicities are a little more concerning because they can be harder to manage than hematologic toxicities. Still, there was not a high rate of treatment discontinuation, and most patients improved from their toxicities after discontinuation and in many cases application of corticosteroids. When dealing with a disease like small cell lung cancer that affects primarily elderly and frail individuals, we need to recognize the increased toxicity associated with combination treatments as a real concern.
Cost is another concern as we combine immunotherapy agents. As we find that patients often do better with the combinations from a standpoint of control of their cancer, we are going to have to begin to have some serious discussions about the total cost of care. However, in this case, patients only received four doses of ipilimumab (Yervoy, Bristol-Myers Squibb), so it does not need to be administered on an ongoing basis like some other cancer treatments.
It is very pleasing to see studies conducted in this space with over 400 patients enrolled, as well as to see this much investment being made in small cell lung cancer, a disease that has been largely ignored as its incidence has been declining. If you look at the landscape of previous trials in second-line therapy for this disease, although our current standard of topotecan is relatively modest in terms of its achievements, it is a standard that has been very difficult to beat for many years. It is great to see drugs succeeded in space where so many drugs have tried to improve on topotecan and failed.
It will be good to see more randomized data of this treatment, but this experience gives us data on over 400 patients, and the combination is listed in the National Comprehensive Center Network guidelines. Given that, we likely will see a lot of oncologists using this combination because the alternatives that are currently FDA approved are unsatisfactory.
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