Triple Combined Therapy in BRAF-Mutated Melanoma

Combinations of immune checkpoint inhibitor and targeted therapies show tolerability and promising efficacy

The combination of immune checkpoint inhibitor with BRAF and MEK inhibition is tolerable and has promising efficacy in BRAF-mutated melanoma according to findings from three articles published on 6 June 2019 in the Nature Medicine. Such triple combination therapy warrants further investigation.

Targeted therapy with BRAF and MEK inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately one year. Anti-PD-1 therapy produces lower response rates but with long response duration. BRAF/MEK combination targeted therapies have effects on the tumour microenvironment that support their combination with PD-1/PD-L1 inhibitors.

First paper reports the findings from a first-in-human clinical trial which show that triple therapy combining BRAF and MEK inhibitors with immune checkpoint blockade may benefit a subset of patients with BRAFV600-mutated metastatic melanoma. In second paper, a randomised phase II trial testing triple combination of BRAF, MEK and PD-1 inhibition as first-line therapy in patients with BRAF-mutated melanoma shows durable responses and encouraging progression-free survival (PFS). In third paper, treatment with BRAF and/or MEK inhibitors followed by addition of anti-PD-L1 in BRAF-mutated melanoma patients shows to be safe and with promising antitumour activity.

Testing dabrafenib and trametinib together with the pembrolizumab in BRAF-mutated melanoma

Antoni Ribas of the University of California, Los Angeles, CA, USA and colleagues explain in study background that preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade improves antitumour activity, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. Such rationale prompted the study team to initiate a first-in-human clinical trial (NCT02130466) of dabrafenib, trametinib and pembrolizumab.

The study team enrolled 15 patients with BRAFV600-mutated metastatic melanoma from whom 11 patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 treatment or the targeted therapy combination.

Eleven patients (73%) had an objective response, and six (40%) continued with a response at a median follow-up of 27 months for all patients.

Paolo Antonio Ascierto of the Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Naples, Pier Francesco Ferrucci of the European Institute of Oncology IRCCS, Milan, Italy and Antoni Ribas of the University of California, Los Angeles, CA, USA reported in second article findings from the randomised phase II portion of same study. Patients with treatment-naive BRAFV600E/K-mutated, advanced melanoma received dabrafenib and trametinib together with pembrolizumab (triplet therapy; n = 60) or placebo (doublet therapy; n = 60).

The primary endpoint of PFS was numerically improved in the triplet group, 16.0 months compared with 10.3 months in the doublet group (hazard ratio, 0.66; p = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement.

Median duration of response was 18.7 months and 12.5 months; 59.8% and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatments, respectively.

Grade 3–5 treatment-related adverse events occurred in 58.3% and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis.

The NCT02130466 was funded by Merck Sharpe & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Testing atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients

Ryan J. Sullivan of the Massachusetts General Hospital Cancer Center, Boston, MA, USA and colleagues reported the results from phase Ib study (NCT01656642). The study evaluated safety and antitumour activity of combining anti-PD-L1 antibody atezolizumab with BRAF inhibitor, vemurafenib or MEK inhibitor, cobimetinib plus vemurafenib in patients with BRAFV600-mutated metastatic melanoma.

Triple combination therapy with atezolizumab plus cobimetinib plus vemurafenib, after a 28 days run-in period with cobimetinib plus vemurafenib, had substantial but manageable toxicity.

Exploratory biomarker data show that the cobimetinib plus vemurafenib run-in was associated with an increase in proliferating CD4-positive 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%. The estimated median duration of response was 17.4 months with ongoing response in 39.3% of patients after 29.9 months of follow-up.

Further investigation in a phase III trial is underway.

The NCT01656642 was funded by F. Hoffmann-La Roche Ltd.



Ribas A, Lawrence D, Atkinson V, et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nature Medicine; Published online 6 June 2019. doi: 10.1038/s41591-019-0476-5.

Ascierto PA, Ferrucci PF, Fisher R, et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nature Medicine; Published online 6 June 2019. doi: 10.1038/s41591-019-0448-9.

Sullivan RJ, Hamid O, Gonzalez R, et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nature Medicine; Published online 6 June 2019. doi: 10.1038/s41591-019-0474-7.