Letter | Published:

Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma

Abstract

Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year1,2,3. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity4,5,6, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab (NCT02130466). Eleven 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 antibody or the targeted therapy combination. Eleven patients (73%; 95% confidence interval = 45–92%) had an objective response, and six (40%; 95% confidence interval = 16–68%) continued with a response at a median follow-up of 27 months (range = 10.3–38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.

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Data availability

To protect the privacy and confidentiality of the 22 patients in this small study, RNA-Seq and WES data supporting the GEP and TMB analyses have not been made publicly available in a repository and are instead provided in the Supplementary Material linked to this article. Patient BRAF mutation status, GEP and TMB scores, and available RNA-Seq and WES data are listed in Supplementary Table 10, and anonymized patient-level somatic mutation data are provided in Supplementary Table 11. Requests for access to patient-level clinical data from the KEYNOTE trial in this study can be submitted through the EngageZone site (http://engagezone.msd.com/ds_documentation.php) or via email (dataaccess@merck.com) per Merck’s data-sharing policy. Research proposals involving predictive biomarker data should include statistical analysis plans that describe a prespecified hypothesis and accompanying statistical power calculation. Studies of de novo biomarker discovery must additionally include descriptions of independent training and validation sets.

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Acknowledgements

Funding for this research was provided by Merck Sharpe & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The authors thank the patients and their families, all primary investigators and site personnel for participation in the study. The authors thank S. Ebbinghaus and S. Diede for study design and oversight, M. Bucci, J. Siegel and N. Cote for data acquisition, A. L. Webber for biomarker analysis, M. Nebozhyn for GEP analysis, R. Cristescu for WES analysis; Y. Cui for CD8 analysis, and R. Mogg for biomarker analysis. Editorial assistance was provided by D. Mitra of the ApotheCom pembrolizumab team. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. A.R., J.T. and C.S.G. were funded by NIH grants R35 CA197633 and P01 CA168585, and by the Parker Institute for Cancer Immunotherapy.

Author information

A.R., O.H., G.V.L., B.M. and B.H.M. conceived, designed or planned the study. V.A., B.H.M., M.S.C., O.H., F.S.H., G.V.L., N.I. and A.R. acquired the data. Q.Z., B.H.M., F.S.H., G.V.L., B.M., N.I. and A.R. analyzed the data. V.A., B.H.M., M.S.C., F.S.H., G.V.L., B.M., N.I. and A.R. interpreted the results. J.T. and C.S.G., together with R.G., analyzed the genomic data. A.R. wrote the first draft of the manuscript, with contributions from Q.Z., V.A., B.H.M., O.H. and N.I. M.S.C., O.H., F.S.H., G.V.L., B.M., N.I. and A.R. critically reviewed or revised the manuscript for important intellectual content. All authors reviewed the interim drafts and final version of the manuscript, and agreed with its content and submission. All authors had access to all of the relevant study data and related analyses, and vouch for the completeness and accuracy of the presented data. All authors agree to be accountable for all aspects of the work and will ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Competing interests

A.R. received personal fees for consulting from Amgen, Bristol-Myers Squibb, Chugai, Genentech–Roche, Merck–MSD and Novartis, and is on the scientific advisory board of, and holds stock in, Advaxis, Apricity, Arcus, Bioncotech, Compugen, CytomX, Five Prime, FLX Bio, ImaginAb, Isoplexis, Kite-Gilead, Merus, Rgenix, Lutris, PACT Pharma and Tango Therapeutics. V.A. received personal fees and non-financial support from Bristol-Myers Squibb and Merck Sharpe & Dohme, and personal fees only from Merck Serono, Novartis and Pierre Fabre. W.H.M. received personal fees from Bristol-Myers Squibb, Novartis, GlaxoSmithKline, Amgen and Roche. M.S.C. received personal fees from Merck Sharpe & Dohme, Novartis, Bristol-Myers Squibb and Pierre Fabre. R.F. received personal fees from Merck Sharpe & Dohme. G.V.L. received personal fees from Aduro, Amgen, Array, Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis, Oncosec and Pierre Fabre. F.S.H. reports receiving personal fees from Merck, Bristol-Myers Squibb, EMD Serono, Celldex, Sanofi, and Novartis; other from Merck to his institution and he has a patent on MICA related disorders for which he receives royalties. B.M. reports employment and stock options at Novartis and stock options at GlaxoSmithKline. B.H.M., Q.Z., R.G. and N.I. report employment at Merck Sharp & Dohme. N.I. also holds stocks in Merck & Co. and GlaxoSmithKline. O.H. reports personal fees from Merck, during the conduct of the study; personal fees from Amgen, Novartis, Roche, Bristol-Myers Squibb, Genenetch, and contracted institutional support from AstraZeneca, Bristol-Myers Squibb, Celldex, Genentech, Immunocore, Incyte, Merck, MerckSerono, MedImmune, Novartis, Pfizer, Rinat and Roche. All other authors have no competing interests.

Correspondence to Antoni Ribas.

Extended data

Extended Data Fig. 1 Pharmacokinetic concentration-time profiles of pembrolizumab, dabrafenib and trametinib.

Pharmacokinetic concentration-time profiles of (a) pembrolizumab, (b) dabrafenib and (c) trametinib following administration of 2 mg/kg pembrolizumab intravenously administered together with multiple oral administrations dabrafenib 150 mg twice daily and trametinib 2 mg daily. Individual concentrations/profiles are presented as colored lines for pembrolizumab and open circles for dabrafenib and trametinib. Arithmetic mean concentration-time profiles (±standard error) are presented as dotted black bold lines. *Nominal time after first dose. N denotes number of patients with samples for pharmacokinetic analysis.

Extended Data Fig. 2 Dosing of pembrolizumab in part 2: dose expansion.

Pembrolizumab 2 mg/kg Q3W, trametinib 2 mg QD, and dabrafenib 150 mg BID in the dose expansion phase. BID, twice daily; Q3W, every 3 weeks; QD, once daily.

Extended Data Fig. 3 Kaplan-Meier estimates of progression-free survival and overall survival.

(a) Progression-free survival and (b) overall survival.

Supplementary information

Supplementary Information

Supplementary Tables 1–10 and Supplementary Protocol 1

Reporting Summary

Supplementary Table 11

Anonymized somatic mutation data of patients

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Fig. 1: Antitumor activity of combined dabrafenib, trametinib and pembrolizumab.
Fig. 2: Analyses of biopsy specimens from patients treated with dabrafenib, trametinib, and pembrolizumab (patients with available data per Supplementary Table 9).
Extended Data Fig. 1: Pharmacokinetic concentration-time profiles of pembrolizumab, dabrafenib and trametinib.
Extended Data Fig. 2: Dosing of pembrolizumab in part 2: dose expansion.
Extended Data Fig. 3: Kaplan-Meier estimates of progression-free survival and overall survival.