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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.

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Massachusetts General Hospital Cancer Center, Boston, MA, USA.
The Angeles Clinic and Research Institute, Los Angeles, CA, USA.
University of Colorado Cancer Center, Aurora, CO, USA.
Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA.
Sarah Cannon Research Institute/Florida Cancer Specialists & Research Institute, Sarasota, FL, USA.
Dana-Farber Cancer Institute, Boston, MA, USA.
MD Anderson Cancer Center, Houston, TX, USA.
Genentech, Inc., South San Francisco, CA, USA.


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 (, 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.

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