Anti-PD-1 and PD-L1 antibodies in metastatic melanoma.

Abstract

“ Genetic mutations and dysregulation of the immune system may be related in some patients and may have an important impact on the efficacy of therapies. ” The advent of monoclonal antibodies that target CTLA-4 (ipilimumab) or PD-1 checkpoints (nivolumab and pembrolizumab) has increased hopes of improved outcomes in advanced melanoma. However, resistance remains an important issue. Genetic mutations and dysregulation of the immune system may be related in some patients and may have an important impact on the efficacy of therapies. Another explanation may be that patients who progressed in the chemotherapy arm may then have received pembrolizumab. In the CheckMate 066 study in patients with previously untreated BRAF wild-type advanced melanoma, ORR was also higher with first-line nivolumab compared with chemotherapy (dacarbazine; 40 vs 13.9%) [3] . Median OS of patients treated with nivolumab was not reached [4] . The other approved anti-PD-1, pembrolizumab, has shown a similar benefit as nivolumab. The Phase I KEYNOTE 001 study showed a median OS of 20 months for all studied doses and was 28 months in ipilimumab-naive patients. Similar results were seen at 3 years [5] . The Phase II KEYNOTE 002 study showed the benefit of pembrolizumab compared with chemotherapy in patients previously treated with ipilimumab and a BRAF or MEK inhibitor, with an ORR of 22.2 and 27.6% for pembrolizumab 2 and 10 mg / kg, respectively, compared with 4.5% with chemotherapy. Median progression-free survival (PFS) at 2 years was significantly prolonged with pembrolizumab at both doses, but median OS was only significantly improved in patients treated with pembrolizumab 10 mg / kg (14.7 vs. 11 months with chemotherapy; p = 0.01; hazard ratio = 0.74) [6] . In the KEYNOTE 006 Phase III trial, first- or second-line pembrolizumab in BRAF mutant or wild-type melanoma patients had a higher response rate compared with ipilimumab. OS at 2 years with pembrolizumab was 55 versus 43% with ipilimumab [7] . At median follow-up of nearly 3 years, 33-month OS and PFS rates with pembrolizumab compared with ipilimumab were 50 versus 39% and 31 versus 14%, respectively [8] . Moreover, responses were durable in 104 patients who stopped pembrolizumab treatment after 2 years as per the study protocol; at a median follow-up of at 9.7 months after completing 2 years of