Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Luke, J. J., Flaherty, K. T., Ribas, A. & Long, G. V. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat. Rev. Clin. Oncol. 14, 463–482 (2017).

    Article  CAS  Google Scholar 

  2. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    Article  CAS  Google Scholar 

  3. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    Article  CAS  Google Scholar 

  4. Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).

    Article  CAS  Google Scholar 

  5. NCCN Clinical Practice Guidelines in Oncology - Melanoma version 3.2018 (National Comprehensive Cancer Network, 2018).

  6. Long, G. V. et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386, 444–451 (2015).

    Article  CAS  Google Scholar 

  7. Robert, C. et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Eur. J. Cancer 51, S663 (2015).

    Article  Google Scholar 

  8. Larkin, J. et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 371, 1867–1876 (2014).

    Article  Google Scholar 

  9. Johnson, D. B. et al. Combined BRAF (dabrafenib) and MEK inhibition (trametinib) in patients with BRAF V600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J. Clin. Oncol. 32, 3697–3704 (2014).

    Article  CAS  Google Scholar 

  10. Long, G. V. et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 371, 1877–1888 (2014).

    Article  Google Scholar 

  11. Schadendorf, D. et al. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur. J. Cancer 82, 45–55 (2017).

    Article  CAS  Google Scholar 

  12. Ascierto, P. A. & Dummer, R. Immunological effects of BRAF+MEK inhibition. OncoImmunology 7, e1468955 (2018).

    Article  Google Scholar 

  13. Wilmott, J. S. et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin. Cancer Res. 18, 1386–1394 (2012).

    Article  CAS  Google Scholar 

  14. Deken, M. A. et al. Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma. OncoImmunology 5, e1238557 (2016).

    Article  Google Scholar 

  15. Homet Moreno, B., Mok, S., Comin-Anduix, B., Hu-Lieskovan, S. & Ribas, A. Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma. OncoImmunology 5, e1052212 (2016).

    Article  Google Scholar 

  16. Hu-Lieskovan, S. et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF V600E melanoma. Sci. Transl. Med. 7, 279ra241 (2015).

    Article  Google Scholar 

  17. Frederick, D. T. et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 19, 1225–1231 (2013).

    Article  CAS  Google Scholar 

  18. Ribas, A., Hodi, F. S., Callahan, M., Konto, C. & Wolchok, J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368, 1365–1366 (2013).

    Article  CAS  Google Scholar 

  19. Hall-Jackson, C. A. et al. Paradoxical activation of Raf by a novel Raf inhibitor. Chem. Biol. 6, 559–568 (1999).

    Article  CAS  Google Scholar 

  20. Su, F. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 366, 207–215 (2012).

    Article  CAS  Google Scholar 

  21. Vella, L. J. et al. MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells. Cancer Immunol. Res. 2, 351–360 (2014).

    Article  CAS  Google Scholar 

  22. Ebert, P. J. R. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016).

    Article  CAS  Google Scholar 

  23. Ribas, A. et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat. Med. (in the press).

  24. Dummer, R. et al. Preliminary findings from part 1 of COMBI-i: a phase III study of anti-PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma. J. Clin. Oncol. 36, 189 (2018).

    Article  Google Scholar 

  25. Long, G. V. et al. Overall survival and durable responses in patients with BRAF V600-mutant metastatic melanoma receiving dabrafenib combined with trametinib. J. Clin. Oncol. 34, 871–878 (2016).

    Article  CAS  Google Scholar 

  26. Weide, B. et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin. Cancer Res. 22, 5487–5496 (2016).

    Article  CAS  Google Scholar 

  27. Long, G. V. et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 17, 1743–1754 (2016).

    Article  CAS  Google Scholar 

  28. Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    Article  CAS  Google Scholar 

  29. Ribas, A. et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. J. Am. Med. Assoc. 315, 1600–1609 (2016).

    Article  CAS  Google Scholar 

  30. Long, G. V. et al. Long-term follow-up of standard-dose pembrolizumab (pembro) plus reduced-dose ipilimumab (ipi) in 153 patients (pts) with advanced melanoma (MEL): KEYNOTE-029 1B. In Proc. 2018 Congress Society for Melanoma Research (2018).

  31. Rozeman, E. A. et al. Phase II study comparing pembrolizumab (PEM) with intermittent/short‐term dual MAPK pathway inhibition plus PEM in patients harboring the BRAFV600 mutation (IMPemBra). Ann Oncol. 29, mdy424.056 (2018).

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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, Pier Francesco Ferrucci or Antoni Ribas.

Ethics declarations

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.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Supplementary information

Supplementary Information

Supplementary Tables 1–6 and Supplementary Methods

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-019-0448-9

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing