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

Abstract

BackgroundPreclinical and translational evidence suggest BRAF/MEK inhibitors modulate the tumor microenvironment (TME), providing rationale for combination with immunotherapy.MethodsThis 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 endpointsobjective 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.ResultsPatients 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.ConclusionsTriple therapy with vemurafenib, cobimetinib and pembrolizumab is associated with high response rates but significant adverse events, leading to early study closure.

A phase 1 trial of the MEK inhibitor selumetinib in combination with pembrolizumab for advanced or metastatic solid tumors

“…The second interim analysis of the IMspire150 study showed no significant improvement in OS with triplet therapy (atezolizumab, cobimetinib, and vemurafenib) compared with MEK/BRAF kinase inhibition alone [ 12 ] and, in the phase 3 COMBI-i study, the addition of the PD-1 inhibitor spartalizumab to trametinib plus dabrafenib did not significantly improve PFS and led to increased toxicity compared with trametinib plus dabrafenib [ 22 ]. In a phase 1 study, DLTs of dermatitis (n = 5), QTc prolongation (n = 1), and arthralgias (n = 1) were reported among 5 patients treated with the triplet combination of pembrolizumab, cobimetinib, and vemurafenib, and the safety findings led to early closure of the study [ 23 ].…”

The fusion of light and immunity: Advancements in photoimmunotherapy for melanoma

“…PIT is advantageous as it is administered to a single, localized tumor region, minimizing the chances of detrimental off‐target toxicity, immune‐related adverse events, or cutaneous adverse events, all of which are challenges faced by the systemic therapies used for melanoma treatment, such as chemotherapy, targeted therapy, or immunotherapy 44 . Due to the significant adverse events of combining targeted therapy and ICB, a phase I clinical trial has faced early closure, 45 and another phase II trial experienced grade 3–5 treatment‐related adverse effects in 70% of the combined treatment arm patients 46 . Further, chemotherapy is notorious for immunosuppression, making it a poor candidate to be combined with ICB 47 and, due to poor response rates, chemotherapy has not been the recommended standard for melanoma management since the development of targeted and immunotherapy options 48 .…”

Efficacy of Pembrolizumab in Advanced Melanoma: A Narrative Review

“…There were two groups treated with pembrolizumab/vemurafenib and pembrolizumab/ vemurafenib/cobimetinib, respectively. The median OS was 23.8 months for vemurafenib/pembrolizumab, while the triple combination did not allow the calculation of the OS as it was discontinued due to the occurrence of side effects, leading to the closure of the study [23]. BRAF inhibitors (BRAFi) appear to be able to modulate the tumor microenvironment (TME).…”

“…BRAF inhibitors (BRAFi) appear to be able to modulate the tumor microenvironment (TME). In fact, on the one hand, the administration of a BRAFi in a BRAF-mutant melanoma model resulted in increased expression of CD40 ligand and interferon-gamma on tumor-infiltrating CD4+ lymphocytes (TILs) and decreased T-reg and myeloid cells on the other hand, suggesting antitumor modulation of the TME [23]. Furthermore, an increase in the T-cell exhaustion markers TIM-3 and PD1 was correlated with BRAFi in patients with metastatic melanoma [23].…”

“…In fact, on the one hand, the administration of a BRAFi in a BRAF-mutant melanoma model resulted in increased expression of CD40 ligand and interferon-gamma on tumor-infiltrating CD4+ lymphocytes (TILs) and decreased T-reg and myeloid cells on the other hand, suggesting antitumor modulation of the TME [23]. Furthermore, an increase in the T-cell exhaustion markers TIM-3 and PD1 was correlated with BRAFi in patients with metastatic melanoma [23]. However, the triple therapy proposed in this study did not allow the progression of the trial due to significant adverse events, such as dermatitis (n = 8), hepatitis (n = 1), arthralgias (n = 1), and QTc prolongation (n = 1).…”