Phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with metastatic melanoma

Saba S Shaikh; Yan Zang; Janel Hanmer; Hong Wang; Yan Lin; Diwakar Davar; Hassane M Zarour; John M Kirkwood; Yana G Najjar

doi:10.3389/fonc.2022.1022496

Phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with metastatic melanoma

Front Oncol. 2022 Nov 23:12:1022496. doi: 10.3389/fonc.2022.1022496. eCollection 2022.

Authors

Saba S Shaikh^{1

2}, Yan Zang², Janel Hanmer³, Hong Wang⁴, Yan Lin⁴, Diwakar Davar², Hassane M Zarour², John M Kirkwood², Yana G Najjar²

Affiliations

¹ Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States.
² Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Medical Center Hillman Cancer Centet, Pittsburgh, PA, United States.
³ Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.
⁴ University of Pittsburgh, School of Public Health, Pittsburgh, PA, United States.

Abstract

Background: Preclinical and translational evidence suggest BRAF/MEK inhibitors modulate the tumor microenvironment (TME), providing rationale for combination with immunotherapy.

Methods: This investigator-initiated, phase I trial evaluated pembrolizumab, vemurafenib, and cobimetinib in patients with untreated, BRAFV600E/K mutant advanced melanoma. The first 4 patients received vemurafenib with pembrolizumab, and the next 5 patients received vemurafenib and cobimetinib with pembrolizumab. Primary endpoints: safety and maximum tolerated dose of the triplet.

Secondary endpoints: objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and quality of life (QoL). The trial was closed after enrollment of 9 (planned 30) patients due to dose-limiting toxicity (DLT). Study NCT02818023 was approved by the IRB, and all patients provided informed consent.

Results: Patients received a median of 6 cycles of therapy. 8 of 9 experienced drug-related grade 3/4 AEs. DLTs included dermatitis (n=8), hepatitis (n=1), QTc prolongation (n=1), and arthralgias (n=1 each). QoL assessments identified a clinically significant decrease in self assessed QoL 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 vemurafenib with pembrolizumab. Median PFS and OS were not reached for patients receiving triple therapy. ORR in the overall cohort was 78% (7/9). 2 patients experienced a complete response, 5 had a partial response, 1 had stable disease, and 1 had progressive disease. 4 patients had ongoing responses at data analysis. Peripheral blood flow cytometry identified significantly decreased PD1 expression on CD4+ T-cells at 3 and 9 weeks compared to baseline, not corresponding to clinical response.

Conclusions: Triple therapy with vemurafenib, cobimetinib and pembrolizumab is associated with high response rates but significant adverse events, leading to early study closure.

Keywords: BRAF; clinical trial; immune checkpoint inhibitor; immunotherapy; melanoma; metastatic; targeted therapy; triplet therapy.