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Authors Saba Shaikh, Yan Zang, Janel Hanmer, Hong Wang, Yan Lin, Diwakar Davar, Hassane M. Zarour, John M. Kirkwood, Yana G. Najjar
Title A phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with advanced melanoma.
Journal Vol Issue Date Pages Journal Short Title
Journal of Clinical Oncology 39 no. 15_suppl
URL https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.e21506
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E melanoma no benefit Cobimetinib + Pembrolizumab + Vemurafenib Phase I Actionable In a Phase I trial, combination of Cotellic (cobimetinib), Zelboraf (vemurafenib), and Keytruda (pembrolizumab) resulted in unreached median progression-free survival and overall survival in patients with advanced melanoma harboring BRAF V600E or V600K mutations, however, the trial was closed due to high incidence of dose-limiting toxicity and decreased health utility at 1 year (J Clin Oncol 39, no. 15_suppl, abstract e21506; NCT02818023). detail...
BRAF V600K melanoma no benefit Cobimetinib + Pembrolizumab + Vemurafenib Phase I Actionable In a Phase I trial, combination of Cotellic (cobimetinib), Zelboraf (vemurafenib), and Keytruda (pembrolizumab) resulted in unreached median progression-free survival and overall survival in patients with advanced melanoma harboring BRAF V600E or V600K mutations, however, the trial was closed due to high incidence of dose-limiting toxicity and decreased health utility at 1 year (J Clin Oncol 39, no. 15_suppl, abstract e21506; NCT02818023). detail...