In patients who have advanced non-small-cell lung cancer (NSCLC) without targetable mutations, first-line treatment is platinum-based combination chemotherapy. This approach has been the standard of care for the past three decades with few improvements in outcomes,1, 2 and is characterised by moderate-to-severe toxicities, including haematological adverse events and non-haematological toxicities, such as fatigue, nausea, vomiting, and alopecia. The proportion of patients who achieved a response to chemotherapy remains in the 30% range;1, 3, 4 responses are rarely durable, and nearly half of patients die within 1 year.3, 4, 5 A profound need exists for treatment strategies to improve long-term survival in patients with newly diagnosed advanced NSCLC.
Research in context
Evidence before this study
We searched PubMed for reports published between Jan 1, 2010, and Aug 24, 2016, without language restrictions, using the search terms “immunotherapy”, “nivolumab”, “pembrolizumab”, “durvalumab”, “atezolizumab”, “ipilimumab”, “tremelimumab”, “anti-PD-1”, “anti-PD-L1”, or “anti-CTLA-4” with “combination” and “lung”. Anti-PD-1 monotherapies have shown improved survival compared with docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. Recently, a response rate of 23% was reported with the combination of durvalumab plus tremelimumab in patients with advanced NSCLC, most of whom had been previously treated with chemotherapy. In patients with melanoma, the combination of nivolumab plus ipilimumab showed improved response and survival compared with either agent alone. The present study was designed to examine the safety and efficacy of nivolumab plus ipilimumab in patients with chemotherapy-naive, advanced NSCLC.
Added value of this study
The results of this trial show that the combination of nivolumab and ipilimumab is well tolerated and is associated with promising, durable, clinical activity. Response rates were at least comparable with those achieved with first-line platinum-based chemotherapy and seemed to exceed the activity expected with nivolumab monotherapy based on previously reported phase 1 data, especially in patients with PD-L1-positive NSCLC.
Implications of all the available evidence
To our knowledge, the results of this study represent the first suggestion of improved benefit relative to anti-PD-1 monotherapy in patients with NSCLC and highlight the potential role for immunotherapy combinations as first-line treatment for NSCLC. Based on these findings, first-line combination treatment with nivolumab and ipilimumab is being prospectively assessed in patients with advanced NSCLC in an ongoing phase 3 study.
Antibodies that inhibit immune checkpoints such as CTLA-4 and PD-1 have improved outcomes for patients with several different types of cancers.6, 7, 8, 9, 10, 11, 12 In NSCLC, nivolumab (a fully human IgG4 antibody against PD-1) improves overall survival compared with docetaxel in patients with previously treated advanced NSCLC.10, 11 The proportion of patients responding to nivolumab ranges from 15% to 20% in unselected patients,10, 11, 13 and responses have tended to be durable, persisting for months or years even after discontinuation of therapy.13
Since PD-1 and CTLA-4 modulate effector T-cell activation, proliferation, and function through distinct, complementary mechanisms,14 the combination of nivolumab plus ipilimumab (a fully human IgG1 antibody against CTLA-4) represents a rational approach to improve antitumour immunity. In patients with metastatic melanoma, the combination of nivolumab and ipilimumab has enhanced activity relative to either monotherapy,15, 16 and median overall survival was not reached after a minimum of 2 years follow-up.17 The combination is approved in the USA and Europe for patients with melanoma.
Given the established safety and activity of nivolumab monotherapy in previously treated advanced NSCLC and the long-term survival reported with combination immunotherapy in melanoma, this portion of the phase 1 multicohort CheckMate 012 study was designed to assess nivolumab plus ipilimumab as first-line therapy for patients with advanced NSCLC. Separate cohorts of this study in which nivolumab was given as monotherapy or in combination with other therapies have been reported previously.18, 19