Elsevier

The Lancet Oncology

Volume 17, Issue 7, July 2016, Pages 883-895
The Lancet Oncology

Articles
Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial

https://doi.org/10.1016/S1470-2045(16)30098-5Get rights and content

Summary

Background

Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens.

Methods

The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394.

Findings

Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0–464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0–470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0–288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis.

Interpretation

Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC.

Funding

Bristol-Myers Squibb.

Introduction

Small-cell lung cancer (SCLC), which accounts for roughly 14% of all lung cancers, is strongly associated with tobacco use and has high mutation rates without known oncogenic drivers.1, 2 Most patients present with extensive-stage disease characterised by widespread metastases and poor survival.2 Although 35–86% of patients respond to first-line chemotherapy, disease progresses rapidly, and outcomes with second-line treatment are poor.3, 4, 5, 6

Research in context

Evidence before this study

We searched the scientific literature for outcomes following failure of first-line treatment in patients with small-cell lung cancer (SCLC) and available subsequent treatment options. The search terms “SCLC”, “recurrent”, “relapsed”, “second-line”, “third-line”, “phase 1”, “phase 2” and/or “phase 3” were used in PubMed focusing on reports and meta-analyses during the 10-year period before the start of the trial from Jan 1, 2003, to Jan 1, 2013. To investigate the potential for immunotherapy in SCLC, the terms “SCLC” and “immune response”, “immunotherapy”, “PD-1”, “CTLA-4”, “NSCLC”, “PD-L1”, “nivolumab”, “ipilimumab”, “MK3475”, “lambrolizumab”, “MPDL3280A”, “MEDI4736”, and “tremelimumab” were used to search PubMed, congress abstracts from the annual meetings of the American Association of Cancer Research, American Society of Clinical Oncology, European Cancer Congress, and World Conference on Lung Cancer, and for ongoing trials in ClinicalTrials.gov.

The searches revealed poor survival outcomes for patients with recurrent or relapsed SCLC and no treatment options beyond second line. The following pieces of evidence underscored the rationale for investigating nivolumab and nivolumab plus ipilimumab in SCLC: SCLC is immunogenic, ipilimumab in combination with chemotherapy was active in extensive-disease SCLC, and nivolumab and nivolumab plus ipilimumab showed encouraging activity in non-small-cell lung cancer in phase 1/2 trials.

Added value of this study

Nivolumab alone and in combination with ipilimumab demonstrated durable objective responses, encouraging overall survival, and manageable safety in patients with advanced SCLC who had progressed after one or more previous regimens. To our knowledge, this is the first trial showing activity of nivolumab and nivolumab plus ipilimumab in SCLC, in a hard-to-treat population of patients with limited treatment options.

Implications of all the available evidence

Based on the notable objective responses, the duration of the responses, and the median overall survival seen with nivolumab plus ipilimumab treatment in this patient population, phase 3 studies for nivolumab and nivolumab plus ipilimumab as maintenance therapy (in non-progressing patients) after first-line chemotherapy (CheckMate 451, NCT02538666), and for nivolumab versus chemotherapy as second-line therapy (CheckMate 331, NCT02481830) in SCLC are ongoing.

Standard first-line chemotherapy for SCLC is a platinum–etoposide doublet, with topotecan as second-line therapy in the USA and European Union1 and amrubicin as second-line therapy in Japan.7 Although response with topotecan is achieved in 23% of platinum-sensitive patients and 9% of platinum-resistant or refractory patients, these responses are not durable.8

Nivolumab, a fully human IgG4 PD-1 immune-checkpoint inhibitor antibody, significantly improved overall survival and had a favourable safety profile compared with docetaxel in two phase 3 studies of patients with non-small-cell lung cancer (NSCLC) who progressed after first-line platinum-based doublet chemotherapy,9, 10 leading to its approval in the USA and the European Union for treatment of patients with locally advanced or metastatic NSCLC.11 Ipilimumab, a fully human IgG1 CTLA-4 immune-checkpoint inhibitor antibody, significantly improved overall survival compared with glycoprotein peptide 100 vaccine in patients with metastatic melanoma,12 and ipilimumab plus dacarbazine improved survival over dacarbazine alone in patients with metastatic melanoma.13 Ipilimumab is approved in the USA and the European Union for this indication.

Preclinical data suggest that the combination of PD-1 and CTLA-4 receptor blockade might improve antitumour activity,14 and the combination of nivolumab plus ipilimumab has demonstrated deep and durable responses in several tumour types.15, 16, 17 The combination of nivolumab plus ipilimumab is approved in the USA and the European Union for treatment of advanced melanoma. On the basis of efficacy of combination treatment in melanoma, CheckMate 032 was designed as a phase 1/2 trial to investigate the activity and safety of nivolumab as monotherapy or in combination with ipilimumab in several advanced or metastatic solid tumour types. The evaluation of nivolumab monotherapy and the combination of nivolumab and ipilimumab in patients with advanced or metastatic tumours for which no standard of care in advanced lines of treatment exists will potentially generate evidence of antitumour activity as a basis for further clinical development in these tumour types. Here, we report activity, safety, and biomarker analyses for the SCLC cohort.

Section snippets

Study design and participants

This was a multicentre, open-label, two-stage, multi-arm phase 1/2 trial. Patients with SCLC were enrolled at 23 sites (academic centres and hospitals) in six countries (Finland, Germany, Italy, Spain, UK, and USA; appendix p 19). Eligible patients had histologically or cytologically confirmed, limited-stage or extensive-stage SCLC, with progressive disease after at least one platinum-based chemotherapy regimen. Patients with platinum-sensitive (relapse ≥90 days after chemotherapy) or

Results

We enrolled and treated 216 patients with SCLC between Nov 18, 2013, and July 28, 2015: 98 patients in the nivolumab 3 mg/kg cohort, three patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort, 61 patients in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and 54 in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort (figure 1). Three patients in the nivolumab 3 mg/kg group, two patients in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four patients in the nivolumab

Discussion

Our findings show that nivolumab monotherapy and nivolumab plus ipilimumab provide clinically meaningful activity and an acceptable safety profile for patients with limited-stage or extensive-stage SCLC and disease progression after at least one previous platinum-containing regimen. The prognosis for patients with progression after previous treatment with platinum-based chemotherapy is poor. Patients with advanced SCLC frequently respond to first-line therapy; however, recurrence is inevitable,

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