KEYNOTE-006

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Robert C, et al. "Pembrolizumab versus Ipilimumab in Advanced Melanoma". The New England Journal of Medicine. 2015. 372(26):2521-2532.
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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 [1] 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. [2] 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%) [3]

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

Further Reading

  1. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. Hodi FS, et al. NEJM 2010. 363:711-723.
  2. 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. Weber JS. Lancet Onc. 2014. 16(4): 375-384.
  3. Ipilimumab and its toxicities: a multidisciplinary approach. Fecher LA, et al. Oncologist. 2013 Jun;18(6):733-43.