Dr. Goyal is a house officer in the Department of Internal Medicine and Dr. Silberstein is a professor and chief of Hematology/Oncology, both at CHI Health Creighton University Medical Center in Omaha, Nebraska. Dr. Silberstein is also the chief of oncology at VA Nebraska-Western Iowa Healthcare System in Omaha.
References
In the 2012 KEYNOTE-002 clinical trial, a randomized phase 2 trial involving 540 patients with ipilimumab-refractory advanced melanoma, patients were randomized 1:1:1 to pembrolizumab 2 mg/kg or 10 mg/kg q3w or investigator-choice chemotherapy (control arm consisting of carboplatin plus paclitaxel, carboplatin, paclitaxel, dacarbazine, or temozolomide). The 6-month PFS was significantly improved with pembrolizumab (34% and 38% for pembrolizumab 2 mg/kg and 10 mg/kg, respectively) compared with 16% with chemotherapy. The ORR was significantly better with pembrolizumab (21% at 2 mg/kg, 25% at 10 mg/kg) compared with the control arm (4%). 21 These findings led to the approval of pembrolizumab by the FDA for treatment of patients with advanced melanoma who have progressed on ipilimumab. Pembrolizumab is generally well tolerated. The most common AEs include fatigue, pruritus, and rash.
Nivolumab was studied in a recent phase 1 trial in which 107 patients with previously treated advanced melanoma were treated with escalated doses every 2 weeks. 22 The 2-year and 3-year OS rates were 48% and 41%, respectively. Objective responses were seen in 32% of the patients. The median response duration was 23 months. 23
The first phase 3 trial was conducted in 418 patients with previously untreated metastatic melanoma BRAF mutation. Patients were randomized to receive either nivolumab or dacarbazine. The PFS and OS were significantly better with nivolumab compared with dacarbazine (PFS 5.1 months vs 2.2 months; OS 73% vs 42% at 1 year). 24 The AE profile of nivolumab is similar to pembrolizumab and includes lung, skin, endocrine, renal, and gastrointestinal tract toxicities.
Preliminary results of another phase 3 trial were presented at the European Society of Medical Oncology 2014 meeting. Patients with previously treated metastatic melanoma (ipilimumab or BRAF inhibitor) were randomized in a 2:1 ratio to receive either nivolumab or investigators’ choice chemotherapy (dacarbazine or carboplatin plus paclitaxel). The ORR was significantly better with nivolumab (32% vs 11%), and 95% of patients were still responding after 6 months. The nivolumab group showed a complete remission in 3% of the patients with 34% of the responses lasting ≥ 6 months. 25 This led to the recent approval of nivolumab for patients with metastatic melanoma with a BRAF mutation who have advanced on ipilimumab. In the phase 3 NCT01844505 trial patients are being randomized to receive ipilimumab, nivolumab, or both.
A newer PD-1 inhibitor, pidilizumab, was studied in a phase 2 trial that included 103 patients with metastatic melanoma, 51% of whom had received therapy with ipilimumab. The ORR in the study group was relatively lower (6%), but the OS at 1 year was 64.5%. 26 Further studies are underway to evaluate the role of this drug in metastatic melanoma.
The response with both nivolumab and pembrolizumab is durable as well as sustained, even after discontinuation of therapy. None of the deaths in the aforementioned studies were atributed to drug-related toxicities. As evidenced by current data, these 2 drugs hold a great promise for the management of patients who progress after therapy with anti-CTLA-4 antibodies.
Anti-PD-L1 Antibodies
The anti-PD-L1 monoclonal antibodies work in a similar way to the PD-1 inhibitors and block the interaction between the PD-1 and its ligand, PD-L1. This causes sustained activation of cytotoxic T cells and facilitates their antitumor activity. Two of PD-L1 inhibitors have shown clinical activity against metastatic melanoma.
