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Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma

Abstract

Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial (NCT02130466), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60) or placebo (doublet; n = 60). The primary end point of progression-free survival 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 (95% confidence interval, 10.1–22.1) and 12.5 months (95% confidence interval, 6.0–14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, 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. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.

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Fig. 1: Kaplan–Meier estimates of progression-free survival and duration of response.
Fig. 2: Best percentage reduction in the line length of the target lesion compared to baseline.

Data availability

Merck Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized patient-level data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. The company is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The process includes submission of data requests to the MSD data-sharing website (available at: http://engagezone.msd.com/ds_documentation.php). Data will be made available for request after product approval in the United States and European Union or after product development is discontinued. There are circumstances that may prevent MSD from sharing the requested data.

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Acknowledgements

We thank the patients and their families; S. Ebbinghaus for clinical study design, oversight and initiation of this collaborative study with Novartis; S. Diede for clinical study design and oversight; M. Bucci, J. Siegel and N. Cote for data acquisition; J. Anderson for statistical analysis and study oversight; and R. Yadav Baddula for data analysis. Medical writing and/or 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. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Study drug was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Novartis. A.R. is supported by the Parker Institute for Cancer Immunotherapy and NIH grants R35 CA197633 and P01 CA168585. The sponsor collaborated with academic advisors to design the study, acquire and analyze data, and interpret the results. All authors had access to all study data and reviewed and approved the final version of the manuscript for publication.

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P.A.A., B.M., N.I., B.H.M. and A.R. conceived, designed or planned the study. P.F.F., R.F., M.D.V., V.A., H.S., P.Q., G.V.L., I.M.S., M.L., G.B.-S., F.C., R.G., B.H.M. and A.R. acquired the data. P.A.A., P.F.F., R.G., N.I., B.H.M. and A.R. analysed the data. P.A.A., P.F.F., M.D.V., V.A., H.S., J.S., P.Q., G.V.L., A.M.D.G., G.B.-S., B.M., N.I., B.H.M. and A.R. interpreted the results. P.A.A., P.F.F., M.D.V., N.I., B.H.M. and A.R. drafted the manuscript with contributions from all authors; the first draft was written by P.P.A., P.F.F. and A.R. P.A.A., P.F.F., R.F., V.A., H.S., J.S., P.Q., G.V.L., A.M.D.G., I.M.S., G.B.-S., B.M., R.G., N.I., B.H.M. and A.R. reviewed or revised the manuscript for important intellectual content. P.A.A., R.F., M.D.V., J.S., G.V.L., I.M.S. and M.L. contributed to the provision of study materials or patient data. G.V.L. provided administrative, logistical or technical support. All authors reviewed the interim drafts and the final version of the manuscript and agreed with its content and submission. All authors had access to all 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.

Corresponding authors

Correspondence to Paolo Antonio Ascierto or Pier Francesco Ferrucci or Antoni Ribas.

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Competing interests

P.A.A. reports receiving research funds and fees for serving on advisory boards of Bristol-Myers Squibb, Roche-Genentech and Array Biopharma and fees for serving on advisory boards of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Amgen, Novartis, Merck Serono, Pierre Fabre, Incyte, Genmab, Newlink Genetics, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera and Ultimovacs. P.F.F. reports receiving fees for serving on advisory boards of Bristol-Myers Squibb, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Pierre Fabre and Roche. R.F. reports receiving a honorarium for speaking engagement from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. M.D.V. reports receiving fees for serving on advisory boards of Bristol-Myers Squibb, Novartis and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. V.A. reports receiving fees for serving on advisory boards, speaker fees, travel support from Bristol-Myers Squibb, speaker fees and fees for serving on advisory boards of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono and Novartis and fees for serving on advisory boards of Pierre Fabre. H.S. reports receiving research funds from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, personal fees and non-financial support from Bristol-Myers Squibb and personal fees from Roche, Incyte and Novartis. J.S. reports no competing interests. P.Q. reports receiving fees for serving on advisory boards of Roche, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Bristol-Myers Squibb and Novartis. G.V.L. reports receiving fees for serving on advisory boards of Aduro, Amgen, Array Biopharma, Bristol-Myers Squibb, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Oncosec and Pierre Fabre. A.M.D.G. reports receiving personal fees for educational activities for Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and fees for serving on advisory boards of Bristol-Myers Squibb, Incyte and Pierre Fabre. I.M.S. reports receiving honoraria for teaching and serving on advisory board of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, fees for serving on advisory board and non-financial support for conference participation from Novartis. M.L. reports receiving consulting fees from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Bristol-Myers Squibb. G.B.-S. reports receiving grants from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. F.C. reports no competing interests. B.M. reports stock options and employment at Novartis and stocks at GlaxoSmithKline and AstraZeneca. R.G. reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. N.I. reports stock ownership at GlaxoSmithKline and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. B.H.M. reports employment at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. A.R. reports receiving honoraria for consulting at Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Amgen, Bristol-Myers Squibb, Chugai, Genentech and Roche and participation in scientific advisory board and stock ownership in Advaxis, Arcus, Bioncotech, Compugen, CytomX, Five Prime, FLX-Bio, ImaginAb, Isoplexis, Kite-Gilead, Merus, Rgenix, Lutris, PACT Pharma and Tango Therapeutics.

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Extended Data

Extended Data Fig. 1 Patient flow diagram.

Reasons for ineligibility: 60 patients were ineligible because they did not meet at least one inclusion and/or exclusion criterion. Most common causes of ineligibility were not meeting the inclusion criterion regarding the provision of a biopsy sample (n = 15); exclusion criterion regarding absence of active central nervous system metastases (n = 11); inclusion criteria regarding histologically confirmed diagnosis of advanced unresectable stage III or metastatic stage IV melanoma (n = 8); inclusion criterion regarding provision of informed consent (n = 7); inclusion criterion regarding BRAF mutation status (n = 5); inclusion criterion regarding adequate organ function (n = 4). Detailed inclusion and exclusion criteria are provided in the study protocol. BID, twice daily; QD, once daily; Q3W, every 3 weeks.

Extended Data Fig. 2 Subgroup analysis of progression-free survival in patients treated with pembrolizumab, dabrafenib and trametinib (triplet) or with placebo, dabrafenib and trametinib (doublet).

Events are shown for the number of patients with progression (n) out of the total number of patients (N).

Extended Data Fig. 3 Kaplan–Meier estimate of overall survival.

Hazard ratios and 95% confidence intervals are based on a Cox regression model with treatment as a covariate stratified by ECOG performance status (0 or 1) and LDH (LDH >1.1× ULN or ≤1.1× ULN); owing to the small number of patients in the ECOG performance status 1 and LDH ≤1.1× ULN strata, these strata were combined. P value is one-sided and based on stratified log-rank test. ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; ULN, the upper limit of normal.

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Ascierto, P.A., Ferrucci, P.F., Fisher, R. et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med 25, 941–946 (2019). https://doi.org/10.1038/s41591-019-0448-9

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