Phase III Randomised Trial Shows Pembrolizumab Superiority When Compared to Ipilimumab in Patients with Advanced Melanoma

KEYNOTE-006 study compared PD-1 inhibition with CTLA-4 blockade

A randomised phase III study comparing two immune checkpoint inhibitors showed that pembrolizumab, as compared with ipilimumab, significantly prolonged progression-free survival (PFS) and overall survival (OS) with fewer high-grade toxicities in patients with advanced melanoma. The results are published online on 20 April in The New England Journal of Medicine by Dr Caroline Robert as a corresponding author and colleagues and reported by Dr Antoni Ribas simultaneously at AACR Annual Meeting 2015 (18-22 April, Philadelphia, USA).

KEYNOTE-006 study was randomised, controlled, phase III study, in which 834 patients with advanced melanoma were assigned in a 1:1:1 ratio to receive pembrolizumab at a dose of 10 mg per kilogram of body weight every 2 weeks or every 3 weeks or four doses of ipilimumab at 3 mg per kilogram every 3 weeks. The study primary endpoints were PFS and OS.

Response was assessed at week 12 and every 6 weeks thereafter according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, on the basis of central radiologic review and immune-related response criteria by investigator review.

Among enrolled patients, 65.8% had received no previous systemic treatment for advanced melanoma, 68.7% had an ECOG performance status of 0, 65.3% had stage M1c disease, and 32.4% had elevated lactate dehydrogenase (LDH) levels. BRAF V600 mutations were observed in 36.2% of patients, and of these, approximately 50% had received previous BRAF inhibitor treatment; 80.5% of patients had PD-L1–positive tissue samples.

The estimated 6-month PFS rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; p < 0.001 for both pembrolizumab regimens versus ipilimumab).

Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63, p = 0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69, p = 0.0036).

The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (p < 0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups.

The most common treatment-related adverse events of any grade occurring in the pembrolizumab were fatigue (20.9% in the 2-week group and 19.1% in the 3-week group), diarrhoea (16.9% and 14.4%, respectively), rash (14.7% and 13.4%, respectively), and pruritus (14.4% and 14.1%, respectively); all events were of grade 3 to 4 severity in less than 1% of patients, except diarrhoea (2.5% and 1.1%, respectively).

For ipilimumab, the most frequent adverse events were pruritus (25.4%), diarrhoea (22.7%), fatigue (15.2%), and rash (14.5%); these events were of grade 3 to 5 severity in less than 1% of patients, except for diarrhoea (3.1%) and fatigue (1.2%).

The adverse events of special interest on the basis of the likely autoimmune or immune-related mechanism most frequently observed with pembrolizumab were hypothyroidism (10.1% in the 2-week group and 8.7% in the 3-week group) and hyperthyroidism (6.5% and 3.2%, respectively). Grade 3 to 4 events that were reported in more than 1% of pembrolizumab-treated patients were colitis (1.4% and 2.5%, respectively) and hepatitis (1.1% and 1.8%, respectively).

In the ipilimumab group, the most common adverse event of special interest was colitis, which occurred in 8.2% of patients. Grade 3 to 4 events that were reported in more than 1% of ipilimumab-treated patients were colitis (7.0%) and hypophysitis (1.6%).

Although exposure to treatment was approximately 3 times as long with pembrolizumab as with ipilimumab, which may account for an increase in the cumulative number of adverse events, the incidence of grade 3 to 5 events attributed to treatment was lower with pembrolizumab than with ipilimumab, as was the incidence of permanent discontinuation for an adverse event.

Improving survival in patients with advanced melanoma

In the study background, the authors explained that two therapeutic strategies have improved survival for patients with advanced melanoma in recent years: immunotherapy with checkpoint inhibitors and targeted therapies blocking BRAF and MEK. BRAF and MEK inhibitors are indicated for the approximately 40 to 50% of patients with BRAF V600 mutations, whereas immunotherapies are effective independently of BRAF mutational status.

Ipilimumab, which blocks CTLA-4, is approved for treating advanced melanoma on the basis of its survival benefit. However, grade 3 or 4 adverse events, mostly immune-related, are observed in 23% of patients. Pembrolizumab is approved by FDA as second-line therapy for patients with metastatic melanoma whose tumours no longer respond to ipilimumab or BRAF inhibitors. However, pembrolizumab is still not on the market in Europe, except in the context of an expanded access programme after failure to ipilimumab. Two monoclonal antibodies directed against PD-1, pembrolizumab and nivolumab are approved in the United States for use in patients who had disease progression after receiving ipilimumab and, in those with the BRAF V600 mutation, BRAF-targeted therapy.

Pembrolizumab vs. ipilimumab

Because the OS results at the second interim analysis in the KEYNOTE-006 study crossed the prespecified efficacy boundary, the trial was stopped for efficacy and the results were unblinded. The study will continue safety and survival follow-up until the final analysis. Responses appeared to be durable in all groups, with ongoing responses in 93.0% of patients in the combined pembrolizumab groups and 87.8% of those in the ipilimumab group at the time of data cut-off.

Subgroup analyses showed that the PFS and OS benefits provided by pembrolizumab extended to most subgroups that were assessed. Similar hazard ratios were observed for PFS and OS with the two pembrolizumab regimens across all patient subgroups except for OS in patients with PD-L1–negative melanoma, a finding that reinforces the superiority of pembrolizumab over ipilimumab and the lack of an effect for pembrolizumab according to regimen. For PD-L1 expression, the sample size was too small (less than 20% of patients) to draw a definite conclusion on relative efficacy.

This study did not enroll patients with BRAF V600 mutations who did not receive previous anti-BRAF targeted therapy if they had high LDH levels and symptomatic or rapidly progressive disease, because targeted anti-BRAF agents can have a rapid clinical benefit in this population of patients.

The treatment of patients with BRAF V600 mutations and, in particular, the most effective sequence of immunotherapy and BRAF or MEK inhibitors remains one of the most critical, yet unanswered, questions. Although this question cannot be addressed without randomised, controlled trials, BRAF V600 status did not seem to affect the benefit of pembrolizumab over ipilimumab in this study.

Other important areas of clinical investigation include the role of combination immunotherapy and the treatment of patients who have minimal disease progression or mixed responses.

The study was supported by Merck Sharp & Dohme.

Reference

Robert C, Schachter J, Long G, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. NEJM 2015; Online First April 19. DOI: 10.1056/NEJMoa1503093.