Elsevier

The Lancet Oncology

Volume 16, Issue 8, August 2015, Pages 908-918
The Lancet Oncology

Articles
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial

https://doi.org/10.1016/S1470-2045(15)00083-2Get rights and content

Summary

Background

Patients with melanoma that progresses on ipilimumab and, if BRAFV600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma.

Methods

We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAFV600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0–1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAFV600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients.

Findings

Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45–0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39–0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27–41) in the pembrolizumab 2 mg/kg group, 38% (31–45) in the 10 mg/kg group, and 16% (10–22) in the chemotherapy group. Treatment-related grade 3–4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3–4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3–4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy.

Interpretation

These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma.

Funding

Merck Sharp & Dohme.

Introduction

In the past 4 years, melanoma treatment has remarkably improved because of the successful clinical development of therapies targeting the MAPK pathway and the development of immune checkpoint inhibitors that reactivate the anticancer immune response.1 The CTLA-4 inhibitor ipilimumab improved overall survival in two randomised trials leading to its regulatory approval for the treatment of advanced melanoma in many countries.2, 3 However, when disease progresses on or after ipilimumab, and BRAF inhibitor-based therapy if disease is BRAFV600 mutated (observed in approximately 40–50% of melanomas4), standard systemic treatment options are limited to cytotoxic chemotherapy or interleukin 2.

Research in context

Evidence before this study

Throughout the writing process and most recently on April 30, 2015, we did an extensive search of PubMed for studies of PD-L1 and PD-1 in advanced cancers, including melanoma. This search was not limited by date. Search terms were “PD-1 OR PD-L1 OR MK-3475 OR lambrolizumab OR nivolumab OR BMS-936558 OR MPDL3280A OR BMS-936559”. Two studies (Weber et al, 2015, and Robert et al, 2015) report findings for nivolumab that corroborate our data. We also searched PubMed to identify treatment options for ipilimumab-refractory melanoma, without any language restrictions. Apart from cytotoxic chemotherapy, we identified no standard treatment options for ipilimumab-refractory melanoma. Although some studies have shown efficacy for other anti-PD-1 and PD-L1 inhibitors after ipilimumab, these were not controlled and the sample sizes were small.

Added value of this study

Our study is, to the best of our knowledge, the largest reported randomised, controlled trial of an anti-PD-1 or anti-PD-L1 drug for ipilimumab-refractory melanoma. Results of this study confirm the efficacy and safety of pembrolizumab and the absence of a significant difference in outcomes between pembrolizumab doses of 2 mg/kg and 10 mg/kg given once every 3 weeks, as observed in an earlier phase 1b study of patients with ipilimumab-refractory melanoma. More important, the study shows the superiority of pembrolizumab over cytotoxic chemotherapy, the current standard-of-care therapy, to improve progression-free survival in ipilimumab-refractory melanoma. Our data are arguably of greater clinical relevance than are the data reported for nivolumab in this population because our study included patients with BRAFV600-mutant melanoma and we report progression-free survival and patient-reported outcomes data.

Implications of all the available evidence

Overall, these findings establish pembrolizumab as a new standard of care for melanoma and support the accelerated approval granted by the US Food and Drug Administration for the use of pembrolizumab 2 mg/kg once every 3 weeks by patients with unresectable or metastatic melanoma whose disease progressed after ipilimumab and, if BRAFV600 mutant-positive, a BRAF inhibitor.

When T cells infiltrate tumours, they produce interferon-mediated signals that lead cells in the tumour microenvironment to express PD-L1, which inhibits T cells through engagement of the PD-1 receptor.5 Preclinical studies provided the rationale for the use of antibodies that block PD-1 or PD-L1 to treat cancer.6, 7 Studies have provided clinical evidence of anti-tumour activity in melanoma, renal cell carcinoma, and lung and bladder cancer, among others.8, 9, 10, 11, 12, 13

In a phase 1b trial, the anti-PD-1 antibody pembrolizumab (formerly MK-3475 and lambrolizumab) showed anti-tumour activity and a manageable safety profile in patients with advanced melanoma, including those with disease refractory to ipilimumab and, when indicated, BRAF inhibitors.10, 11 Here, we present results of KEYNOTE-002, the definitive assessment of pembrolizumab in this population.

Section snippets

Study design and participants

KEYNOTE-002 is an international, randomised, controlled, phase 2 clinical trial comparing two pembrolizumab doses with investigator-choice chemotherapy. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed unresectable stage III or stage IV melanoma not amenable to local therapy; confirmed disease progression14 within 24 weeks of the last ipilimumab dose (minimum two doses, 3 mg/kg once every 3 weeks); previous BRAF or MEK inhibitor therapy or both (if

Results

Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients from 73 sites in 12 countries (full site list available in the appendix). We randomly allocated patients to pembrolizumab 2 mg/kg (n=180), pembrolizumab 10 mg/kg (n=181), or chemotherapy (n=179 [42 patients to paclitaxel plus carboplatin, 28 to paclitaxel, 13 to carboplatin, 45 to dacarbazine, and 43 to temozolomide; eight did not receive treatment]; figure 1). Patient characteristics were well balanced across study groups (table 1

Discussion

In this population of patients with advanced melanoma that progressed on ipilimumab and, in many cases, on chemotherapy or MAPK pathway inhibitors, pembrolizumab reduced the risk of disease progression or death compared with investigator-choice standard-of-care chemotherapy. Although median progression-free survival values were similar, around the time of the first scheduled tumour assessment at week 12 in all treatment groups, the Kaplan-Meier curves separated dramatically thereafter,

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