KEYNOTE-006

In Review

Robert C, et al. "Pembrolizumab versus Ipilimumab in Advanced Melanoma". The New England Journal of Medicine. 2015. 372(26):2521-2532.
PubMed • Full text • PDF

Clinical Question

In patients with advanced melanoma, does pembrolizumab improve progression-free survival and overall survival compared to ipilimumab?

Bottom Line

Pembrolizumab outperformed ipilimumab in progression-free and overall survival for unresectable and metastatic melanoma.

Major Points

A major milestone in immunotherapy, ipilimumab became the first FDA-approved immune checkpoint inhibitor for melanoma treatment after a large 2010 trial demonstrated its survival benefit in patients with metastatic disease. Ipilimumab is a monoclonal antibody that binds CTLA-4, blocking an immunologic "brake pedal" leading to increased T cell activation, allowing for improved tumor recognition and clearance.

In 2012, BRAF inhibitors demonstrated survival benefit and good tolerability for metastatic melanoma patients with BRAF mutations, while ipilimumab remained a common option for the 50% of patients without BRAF mutations.

In 2015, phase 3 data provided strong support for a different checkpoint inhibitor target. Two anti-PD-1 agents, nivolumab and pembrolizumab, had several major trials being compared to CTLA-4 targeting in metastatic disease. In the CheckMate-037 trial, nivolumab provided additional survival benefit in patients who had failed CTLA-4 targeted therapy. Similarly, KEYNOTE-002 (a phase 2 study) supported benefit of pembrolizumab in ipilimumab-refractory melanoma over alternative therapies. The KEYNOTE-006 trial (phase 3) demonstrated improved survival outcomes with initiating pembrolizumab over ipilimumab for unresectable/metastatic melanoma, supporting its addition in the NCCN guidelines as first-line therapy. Since >96% of the patients in this study had metastatic melanoma, these results can not be easily generalized to patients with resectable melanoma and high risk of recurrence; trials are ongoing to examine pembrolizumab in that population.

Guidelines

NCCN Guidelines Melanoma (2016, adapted)

• For patients with metastatic or unresectable disease, anti PD-1 monotherapy with pembrolizumab or nivolumab constitute first-line systemic therapy, regardless of BRAF status
• For patients on BRAF targeted therapy with disease progression or maximal clinical benefit, anti PD-1 monotherapy with pembrolizumab or nivolumab are recommended options for subsequent therapy

Design

• Multicenter, randomized, controlled trial
• N=834
  • Pembrolizumab every 2 weeks (n=279)
  • Pembrolizumab every 3 weeks (n=277)
  • Ipilimumab (n=278)
• Setting: Multiple centers in 16 countries including France, USA, and UK
• Enrollment: September 2013 to March 2014
• Mean follow-up: 7.9 months
• Analysis: Intention-to-treat
• Blinding not clearly specified
• Primary outcome: Progression-free survival and overall survival

Population

Inclusion Criteria

• Unresectable Stage 3-4 Melanoma, histologically confirmed
• ECOG 0-1
• Known BRAF V600 mutational status and sample provided for PD-L1 expression analysis

Exclusion Criteria

• Ocular melanoma
• Active brain metastases
• Serious autoimmune disease
• Received prior CTLA-4 or PD-1 targeted therapy
• Received 2+ prior systemic therapies for advanced melanoma
• BRAF+ patients with evidence of rapidly progressing disease, significant tumor-related symptoms, or elevated LDH without prior BRAF targeted therapy

Baseline Characteristics

No significant differences

• Mean age: 62 years
• ECOG status of 0 (68.7%)
• Stage: M0 (3.8%), M1a (10.2%), M1b (18.8), M1c (65.3%)
• Number of prior systemic therapies: 0 (66%) vs 1 (34%)
• BRAF V600 mutation: 36%
• Prior BRAF targeted therapy: 18%

Interventions

• Randomized 1:1:1 to pembrolizumab (Q2wk) vs. pembrolizumab (Q3wk) vs. ipilimumab (Q3wk)
• Pembrolizumab dose was 10 mg/kg; ipilimumab was 3mg/kg
  • Randomization was stratified by ECOG status, PD-1L expression, and line of therapy (first vs. second)

Outcomes

Comparisons are pembrolizumab vs ipilimumab

Primary Outcomes

Progression-free survival at 6 months

47.3% vs 26.5% (HR 0.58; 95% CI 0.46-0.72; P<0.001) for 2-week regimen

46.4% vs 26.5% (HR 0.58; 95% CI 0.47-0.72; P<0.001) for 3-week regimen

Overall survival at 12 months

74.1% vs 58.2% (HR 0.63; 95% CI 0.47-0.83; P<0.0005) for 2-week regimen

68.4% vs 58.2% (HR 0.69; 95% CI 0.52-0.90; P<0.005) for 3-week regimen

Secondary Outcomes

Comparisons are pembrolizumab 2-weeks vs 3-weeks vs ipilimumab

Rate of complete response

5.0% vs 6.1% vs 1.4%

Rate of response

33.7% vs 32.9% vs 11.9% (P<0.001)

Time to response

85 vs. 86 vs. 87 days

Subgroup Analysis

- Pembrolizumab benefit for PFS was seen in all subgroups (regardless of PD-1L expression, BRAF mutation status, ECOG status)

- Pembrolizumab benefit for OS was seen in all subgroups except tumors negative for PD-1L expression (HR 0.91; HR 1.02)

Adverse Events

Rate of permanent discontinutation

4.0% vs 6.9% vs 9.4%

Severe adverse events

Grade 3-4 diarrhea: 2.5% vs 1.1% vs 3.1%

Grade 3-5 adverse events attributed to study drug: 13.3% vs 10.1% vs 19.9%

1 treatment-related death: in the ipilimumab group, from metabolic imbalances due to colitis leading to cardiac arrest

Common adverse events

Pembrolizumab: fatigue (19-21%), diarrhea (14-17%) rash (13-15%), pruritus (14-15%)

Ipilimumab: pruritus (25.4%), diarrhea (22.7%), fatigue (15.2%), rash (14.5%)

Criticisms

• Study was not powered to determine if PD-1L tumor expression predicts pembrolizumab response
• Blinding and masked allocation not clearly specified
• Statistical analysis, authorship, and treatment-attribution of adverse events had contribution from private funder

Funding

Merck (makers of pembrolizumab) funded study and provided statisticians and contributing authors, though all authors had full access to data