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Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients

Ryan J Sullivan1, Omid Hamid2, Rene Gonzalez3

  • 1Massachusetts General Hospital Cancer Center, Boston, MA, USA. rsullivan7@mgh.harvard.edu.

Nature Medicine
|June 8, 2019
PubMed

Insights

This study shows that combining atezolizumab (anti-PD-L1) with cobimetinib and vemurafenib offers a high response rate for BRAF-mutated melanoma. The triple therapy demonstrated manageable toxicity and a durable response in patients with advanced melanoma.

Area of Science:

  • Oncology
  • Immunotherapy
  • Targeted Therapy

Background:

  • Recent advances in melanoma treatment include immune checkpoint inhibitors (PD-1/PD-L1, CTLA-4) and BRAF/MEK inhibitors for BRAF-mutated tumors.
  • BRAF/MEK inhibitors can modulate the tumor microenvironment, suggesting potential synergy with PD-1/PD-L1 inhibitors.

Purpose of the Study:

  • To evaluate the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor) or cobimetinib (MEK inhibitor) plus vemurafenib.
  • To assess the effects of combination therapy on the tumor microenvironment and immune cell populations.

Main Methods:

  • Phase Ib study (NCT01656642) in patients with BRAF V600-mutated metastatic melanoma.
  • Investigated triple combination therapy: atezolizumab + cobimetinib + vemurafenib, following a 28-day run-in with cobimetinib + vemurafenib.
  • Exploratory biomarker analysis of immune cells (CD4+ T-helper, T-regulatory cells).

Main Results:

  • Triple combination therapy exhibited substantial but manageable toxicity.
  • Confirmed objective response rate was 71.8% (95% CI 55.1-85.0).
  • Median duration of response was 17.4 months, with 39.3% of patients ongoing response at 29.9 months follow-up.

Conclusions:

  • The combination of atezolizumab, cobimetinib, and vemurafenib shows promising anti-tumor activity and a manageable safety profile in BRAF V600-mutated metastatic melanoma.
  • The run-in period with cobimetinib + vemurafenib was associated with increased proliferating CD4+ T-helper cells.
  • Further investigation in a phase III trial is warranted.

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