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Nat Med. 2019 Jun;25(6):929-935. doi: 10.1038/s41591-019-0474-7. Epub 2019 Jun 6.

Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients.

Author information

1
Massachusetts General Hospital Cancer Center, Boston, MA, USA. rsullivan7@mgh.harvard.edu.
2
The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
3
University of Colorado Cancer Center, Aurora, CO, USA.
4
Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
5
Sarah Cannon Research Institute/Florida Cancer Specialists & Research Institute, Sarasota, FL, USA.
6
Dana-Farber Cancer Institute, Boston, MA, USA.
7
MD Anderson Cancer Center, Houston, TX, USA.
8
Genentech, Inc., South San Francisco, CA, USA.

Abstract

Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAFV600 mutations1-9. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors10-20. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAFV600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1-85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6-25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.

PMID:
31171876
DOI:
10.1038/s41591-019-0474-7
[Indexed for MEDLINE]

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