Background: phase III RCT included 834 patients with unresectable stage III/IV melanoma who received up to one previous systemic therapy. Previous anti-CTLA-4, PD-1, or PD-L1 agents, ocular melanoma, brain mets, autoimmune disease were excluded.

Arm A: pembrolizumab 10mg/kg q2wk x2yr or POD, intolerable toxicity, CR, withdrawal
Arm B: pembrolizumab same dose but q3wk
Arm C: ipi3: ipilimumab 3mg/kg q3wk x4

Primary end point:mOS
mFollow up: 22.9mo

mOS: not reached in pembrolizumab groups (q2wk or q3wk) vs 16.0mo for ipi3 with HR 0.68, 95%CI 0.53-0.87 for pembro q2wk; P=.0009 and 0.68, 0.53-0.86 for pembro q3wk P=.0008)
2yr OS: 55% vs 55% vs 43% for pembro q2wk vs pembro q3wk vs ipi3, respectively.

STUDY UPDATE
(Robert C et al, Lancet Onc, 2019; PMID:31345627)

M-Follow up: 57.7mo
mOS: 32.7mo vs 15.9mo; combined pembrolizumab groups vs ipilimumab respectively with HR 0.73, 95%CI 0.61-0.88, P=.00049
mPFS: 8.4mo vs 3.4mo; combined pembrolizumab groups vs ipilimumab respectively with HR 0.57, 95%CI 0.48-0.67, P<.0001
4-yr OS: 42.3% vs 30.0%

Main adverse events. Grade 3-4 in 17% vs 20% in combined pembrolizumab groups vs ipilimumab,most common colitis 2% vs 6%

Conclusions: pembrolizumab provides significantly better OS and PFS over ipilimumab. In this trial pembrolizumab 10mg/kg was used, this dose was previously compared to pembrolizumab 2mg/kg and chemotherapy in KEYNOTE-002 (Hamid O and Puzanov I et al, EJC, 2017, PMID:28961465) where both doses produced similar results, therefore FDA approved only 2mg/kg dose. Later, pembrolizumab dose was updated to 200mg q3wk or 400mg q6w.

Summarized by Veli Bakalov, MD

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