A phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with advanced melanoma.
Authors: Shaikh Saba , Zang Yan , Hanmer Janel , Wang Hong , Lin Yan , Davar Diwakar , Zarour Hassane M. , Kirkwood John M. , Najjar Yana G. 
Published: June 2021

e21506

Background: Management of patients (pts) with advanced melanoma includes anti-PD1 with or without anti-CTLA4, and for pts with a BRAF mutation, the additional option of targeted therapy. Preclinical and translational evidence suggest BRAF/MEK inhibitors (i) modulate the tumor microenvironment, providing rationale for combination with immune checkpoint inhibitors. Phase 3 IMspire data reported improved progression-free survival (PFS) with triplet therapy (atezolizumab/vemurafenib/cobimetinib), yielding regulatory approval. However, 79% of pts experienced grade 3/4 adverse events (AE) in the triplet arm. Methods: This is an investigator-initiated, phase I trial of pembrolizumab (pembro) plus vemurafenib (vem) and cobimetinib (cobi) for pts with advanced melanoma in the first line setting. The first 4 pts received vem/pembro. The protocol was subsequently amended, and the next 5 pts received vem/cobi/pembro. Vem/cobi had an escalating dosing regimen. Pembro was 200 mg q3 weeks. Primary endpoints: safety and maximum tolerated dose of vem/cobi when administered with pembro. Secondary endpoints: overall response rate (ORR), PFS, overall survival (OS), and quality of life (QoL). We planned to accrue 30 pts; however, the trial was closed after enrollment of 9 pts due to dose-limiting toxicity (DLT). This study NCT02818023 was approved by the IRB, and all pts provided informed consent. Results: Pts received a median of 6 cycles of triplet therapy. 8 of 9 pts experienced drug-related grade 3/4 AEs, most commonly dermatitis (89%). In the vem/pembro group, DLTs included hepatitis (n = 1), dermatitis (n = 3), and arthralgias (n = 1). In the vem/cobi/pembro group, DLTs included dermatitis (n = 5), QTc prolongation (n = 1), and arthralgias (n = 1). QoL assessments identified a clinically significant decrease in average health utility at 1 year compared to baseline (0.38 v 0.43). Median PFS was 20.7 months and median OS was 23.8 months for vem/pembro, and neither was reached for vem/cobi/pembro. Overall, 4 pts had ongoing responses at the time of data analysis. 2 pts experienced a complete response, 5 had a partial response, 1 had stable disease, and 1 had progressive disease at first restaging. Peripheral blood flow cytometry identified significantly decreased PD1 expression on CD4+ T-cells at 3 and 9 weeks compared to baseline. This did not correspond to clinical response. PD-L1 testing was also performed on 6 paired tumor samples, and no significant association was identified between PD-L1 expression and clinical outcomes. Conclusions: Despite preclinical and translational evidence for tumor immunomodulation with BRAF/MEKi and improved PFS noted in IMspire150, toxicity incurred with the triplet is challenging from a practical standpoint. Our study highlights clinical efficacy of the combination and adds additional toxicity data for triplet therapy, with 8 of 9 pts experiencing at least a grade 3 AE. Clinical trial information: NCT02818023.