Atezolizumab, cobimetinib, and vemurafenib as first-line treatment for unresectable metastatic BRAF V600 mutated melanoma

ABSTRACT

Introduction

The treatment of metastatic melanoma has been revolutionized by the introduction of immune checkpoint inhibitors and BRAF/MEK inhibition. Nevertheless, almost half of patients will progress or show primary resistance to treatment. The combination of BRAF/MEK and immune checkpoint inhibition might achieve higher response rates and improve long-term disease control. The IMspire150 trial investigated the combination of atezolizumab, cobimetinib and vemurafenib versus cobimetinib and vemurafenib alone.

Areas covered

This review covers the efficacy and safety of atezolizumab, cobimetinib and vemurafenib for patients with advanced or metastatic BRAF mutant melanoma. The combination is compared with the current standard of care including BRAF/MEK inhibition and treatment with immune checkpoint inhibitors.

Expert Opinion

Atezolizumab plus cobimetinib and vemurafenib showed superior progression-free survival in metastatic melanoma compared to cobimetinib and vemurafenib alone. Triplet therapy might be an option in situations of urgent need for disease control, when oncologists choose BRAF/MEK inhibition over immune checkpoint inhibition as first line treatment. At this time results are not mature yet, and longer follow-up including overall survival data is needed. The future role of this combination will also be determined by a comparison with the combination of ipilimumab and nivolumab.

KEYWORDS:

• Advanced melanoma
• atezolizumab
• braf inhibitor
• cobimetinib
• immunotherapy
• MEK inhibitor
• vemurafenib

Declaration of interest

AM Schmitt has received support for conference attendance from Novartis and an educational grant from Janssen-Cilag AG.

JMG Larkin is a consultant advisor for Iovance, Boston Biomedical, Pfizer, BMS, GSK, Novartis, Incyte, Immunocore, YKT Global, iOnctura, Apple Tree. He has received institutional research support: BMS, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, Aveo. He has received grants from Achilles, BMS, MSD, Nektar, Novartis, Pfizer, Roche, Immunocore, Aveo, Pharmacyclics. JMG Larkin has received honorarium from Roche, Novartis, iOnctura, BMS, Pfizer, Incyte, Dynavax, CRUK, GSK, Eisai, Merck, touchIME, touchExperts. JMG Larkin has received speaker fees of BMS, Pfizer, Incyte, Roche, Pierre Fabre, AstraZeneca, Novartis, EUSA Pharma, MSD, Ervaxx, Merck, GSK, Ipsen, Aptitude, Eisai, Calithera, Ultimovacs, Seagen.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• Preclinical data suggest that the combination of checkpoint inhibitors and BRAF/MEK inhibitors might have synergistic effects with improved response rates and survival.

• BRAF/MEK inhibition might induce favorable changes in the tumor microenvironment, including increased expression of antigens and CD8 positive T-cell infiltration, and upregulation of PD-L1.

• Treatment with atezolizumab, cobimetinib, and vemurafenib significantly improved progression-free survival compared to cobimetinib and vemurafenib alone.

• The triplet treatment did not achieve higher response rates compared to BRAF/MEK inhibition alone.

• More mature data, including results on overall survival, will be needed to determine the role of the triplet therapy in the treatment of advanced BRAF mutated melanoma.