Elsevier

The Lancet Oncology

Volume 16, Issue 4, April 2015, Pages 375-384
The Lancet Oncology

Articles
Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial

https://doi.org/10.1016/S1470-2045(15)70076-8Get rights and content

Summary

Background

Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma.

Methods

In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAFV 600 mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m2 every 3 weeks or paclitaxel 175 mg/m2 combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746.

Findings

Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5–40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5–23·1) of 47 patients in the ICC group. Grade 3–4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3–4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred.

Interpretation

Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need.

Funding

Bristol-Myers Squibb.

Introduction

The checkpoint inhibitor protein PD-1 is located on T cells and pro-B cells, and interacts with its ligands PD-L1 and PD-L2 to inhibit T cell activation and proliferation, thereby promoting immunological self-tolerance.1, 2, 3, 4, 5 PD-1 is highly expressed on T cells from patients with tumours, and causes tumour-related immune suppression.6 Checkpoint protein inhibition directed against the interaction of PD-1 with PD-L1 on tumour cells has emerged as an effective therapeutic option for various cancers, including melanoma, renal cell cancer, and non-small-cell lung cancer.7 High proportions of patients achieving a response with excellent duration have occurred in patients with metastatic melanoma given antibodies that block PD-1.7, 8, 9, 10, 11, 12, 13, 14 Patients with head and neck squamous cancer, ovarian cancer, bladder cancer, and Hodgkin's lymphoma are also responsive to antibody treatment directed against PD-1 and PD-L1.15, 16, 17, 18

Research in context

Evidence before this study

To identify other studies of inhibitors of PD-1 or PD-L1 in advanced cancers, including melanoma, we did a detailed search of PubMed and congress abstracts from the annual meetings of the American Society of Clinical Oncology, European Society of Medical Oncology/European Cancer Congress, and Society for Melanoma Research, between Jan 1, 2010 and Jan 13, 2015. We used the search terms “PD-1”, “PD-L1”, “nivolumab”, “MK-3475”, “pembrolizumab”, “lambrolizumab”, “MPDL3280A”, and “MEDI4736”. Our search identified several non-randomised, non-controlled phase 1/2 studies with promising levels of antitumour response for PD-1 and PD-L1 inhibitors in patients with advanced solid tumours, including melanoma. Although these data suggest activity for PD-1 inhibition in patients with melanoma that have progressed after ipilimumab and BRAF inhibitors, the sample sizes were too small to allow firm conclusions to be drawn on the efficacy and safety of PD-1 inhibition. Our review identified only one randomised, controlled, phase 3 study comparing an anti-PD-1 drug (nivolumab) with dacarbazine, but this study was done in treatment-naive patients who had BRAF wild-type tumours.

Added value of this study

For the patient population investigated in this study, treatment options are very restricted, and no prospective, randomised, controlled trial comparing an anti-PD-1 drug with any approved treatment has been done. Our data show that nivolumab led to clinically meaningful improvements in the proportion of patients achieving an objective response and provided a manageable safety profile when compared with chemotherapy.

Implications of all the available evidence

Nivolumab can now be deemed a new treatment option for patients that have progressed after ipilimumab, or a BRAF inhibitor and ipilimumab if their melanoma is BRAFV600-mutated. These data resulted in the accelerated approval of nivolumab by the US Food and Drug Administration for this indication in December, 2014.

Nivolumab is a fully human IgG4 PD-1 immune checkpoint inhibitor with broad anticancer activity in early studies.7, 8 In a phase 1 study,8 nivolumab given at doses of 0·1–10 mg/kg produced a response in 31% of 107 previously treated, ipilimumab-naive patients with metastatic melanoma. The median duration of response at all doses was 22 months, with a median overall survival of 17·3 months.8 In another phase 1/2 trial,11 nivolumab given alone or with a peptide vaccine produced a response in 26% of patients and a median survival of 18 months in 90 patients with metastatic melanoma with disease progression after receiving ipilimumab. In a phase 3 study of treatment-naive patients with metastatic melanoma,14 nivolumab resulted in 40% of patients achieving an objective response compared with 14% of those treated with dacarbazine. We did a randomised phase 3 trial to compare nivolumab with investigator's choice of chemotherapy (ICC) in patients whose disease had progressed after previous ipilimumab treatment, or both ipilimumab and a BRAF inhibitor if tumours harboured a BRAFV600 mutation. Here we present the results of the initial planned analysis of objective responses.

Section snippets

Study design and patients

In this randomised, controlled, open-label, phase 3 study, we recruited patients at 90 sites in 14 countries. Eligible patients were aged 18 years or older and had histologically confirmed, unresectable stage IIIC or IV metastatic melanoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients with BRAF wild-type tumours must have had progression after anti-CTLA-4 treatment, such as ipilimumab, and patients with a BRAFV600 mutation-positive tumour mutation must have

Results

From Dec 21, 2012, to Jan 10, 2014, we screened 631 patients at 90 sites in 14 countries, randomly allocating 272 patients nivolumab and 133 ICC (appendix, figure 1). The most common reasons for screening failure were because patients no longer met study criteria (198 [31%] patients) or withdrew consent (17 [3%]). In the nivolumab group, four (1%) patients did not receive study treatment compared with 31 (23%) patients in the ICC arm; the most common reason for not being treated was no longer

Discussion

Anti-PD-1 and anti-PD-L1 antibodies have shown broad-ranging antitumour activity in early-phase trials.24, 25, 26, 27 In this study, the proportion of patients with an objective response was higher for nivolumab than for ICC; there was no clinically or statistically significant difference in progression-free survival in the intention-to-treat objective response population. We noted complete responses more frequently in the nivolumab group than the ICC group. The absence of significant

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