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:

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

Nature Medicine volume 25, pages 936–940 (2019)Cite this article

Subjects

A Publisher Correction to this article was published on 02 July 2019

This article has been updated

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 BRAF V600-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 BRAF V600-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 BRAF V600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.

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
Buy now

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

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).

Similar content being viewed by others

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.

Change history

  • 02 July 2019

    This sentence was originally included in the legend for Extended Data Fig. 1: "*Nominal time after first dose. N denotes number of patients with samples for pharmacokinetic analysis." The sentence was deleted as no asterisk appeared in that figure.

References

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

    Article  Google Scholar 

  2. 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 

  3. Robert, C. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30–39 (2015).

    Article  Google Scholar 

  4. 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 

  5. 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 

  6. Hu-Lieskovan, S. et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF V600E melanoma. Sci. Transl. Med. 7, 279ra41 (2015).

    Article  Google Scholar 

  7. Akbani, R. et al. Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015).

    Article  Google Scholar 

  8. Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507–2516 (2011).

    Article  CAS  Google Scholar 

  9. Hauschild, A. et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380, 358–365 (2012).

    Article  CAS  Google Scholar 

  10. 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 

  11. 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 

  12. 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 

  13. Long, G. V. et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J. Clin. Oncol. 29, 1239–1246 (2011).

    Article  Google Scholar 

  14. Shi, H. et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 4, 80–93 (2014).

    Article  CAS  Google Scholar 

  15. Van Allen, E. M. et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 4, 94–109 (2014).

    Article  CAS  Google Scholar 

  16. Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).

    Article  Google Scholar 

  17. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  CAS  Google Scholar 

  18. Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    Article  CAS  Google Scholar 

  19. Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).

    Article  CAS  Google Scholar 

  20. Daud, A. I. et al. Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma. J. Clin. Oncol. 34, 4102–4109 (2016).

    Article  CAS  Google Scholar 

  21. 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 

  22. 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 

  23. Chen, P. L. et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov. 6, 827–837 (2016).

    Article  Google Scholar 

  24. Vilain, R. E. et al. Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin. Cancer Res. 23, 5024–5033 (2017).

    Article  CAS  Google Scholar 

  25. K EYTRUDA ® (Pembrolizumab) for Injection, for Intravenous Use (Merck Sharp & Dohme Corp., 2019).

  26. T afinlar 50 mg Hard Capsules (Novartis Europharm, 2015).

  27. M EKINIST (Trametinib) Tablets, for Oral Use (GlaxoSmithKline, 2018).

  28. 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 

  29. Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

    Article  Google Scholar 

  30. 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 

  31. Schachter, J. et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390, 1853–1862 (2017).

    Article  CAS  Google Scholar 

  32. Ribas, A. et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J. Clin. Oncol. 33, 3003 (2015).

    Article  Google Scholar 

  33. Lyle, S. et al. Human hair follicle bulge cells are biochemically distinct and possess an epithelial stem cell phenotype. J. Investig. Dermatol. Symp. Proc. 4, 296–301 (1999).

    Article  CAS  Google Scholar 

  34. Nuckols, J. D., Shea, C. R., Horenstein, M. G., Burchette, J. L. & Prieto, V. G. Quantitation of intraepidermal T-cell subsets in formalin-fixed, paraffin-embedded tissue helps in the diagnosis of mycosis fungoides. J. Cutan. Pathol. 26, 169–175 (1999).

    Article  CAS  Google Scholar 

  35. Kim, D., Langmead, B. & Salzberg, S. L. HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12, 357–360 (2015).

    Article  CAS  Google Scholar 

  36. Anders, S., Pyl, P. T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

    Article  CAS  Google Scholar 

  37. Grasso, C. S. et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov. 8, 730–749 (2018).

    Article  CAS  Google Scholar 

  38. Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

    Article  CAS  Google Scholar 

Download references

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

Authors and Affiliations

  1. University of California, Los Angeles, Los Angeles, CA, USA

    Antoni Ribas, Jennifer Tsoi & Catherine S. Grasso

  2. Massachusetts General Hospital, Boston, MA, USA

    Donald Lawrence

  3. Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, Queensland, Australia

    Victoria Atkinson

  4. Indiana University Health Goshen Center for Cancer Care, Goshen, IN, USA

    Sachin Agarwal

  5. Segal Cancer Centre, Montreal, Quebec, Canada

    Wilson H. Miller Jr

  6. Jewish General Hospital, Montreal, Quebec, Canada

    Wilson H. Miller Jr

  7. McGill University, Montreal, Quebec, Canada

    Wilson H. Miller Jr

  8. Westmead Hospital, Sydney, New South Wales, Australia

    Matteo S. Carlino

  9. Blacktown Hospital, Sydney, New South Wales, Australia

    Matteo S. Carlino

  10. The University of Sydney, Sydney, New South Wales, Australia

    Matteo S. Carlino & Georgina V. Long

  11. Melanoma Institute Australia, Sydney, New South Wales, Australia

    Matteo S. Carlino & Georgina V. Long

  12. Auckland District Health Board, Auckland, New Zealand

    Rosalie Fisher

  13. Royal North Shore Hospital, Sydney, New South Wales, Australia

    Georgina V. Long

  14. Mater Hospital, Sydney, New South Wales, Australia

    Georgina V. Long

  15. Dana-Farber Cancer Institute, Boston, MA, USA

    F. Stephen Hodi

  16. Novartis, East Hanover, NJ, USA

    Bijoyesh Mookerjee

  17. Merck & Co., Inc., Kenilworth, NJ, USA

    Qing Zhao, Razi Ghori, Blanca Homet Moreno & Nageatte Ibrahim

  18. The Angeles Clinic and Research Institute, Los Angeles, CA, USA

    Omid Hamid

Authors
  1. Antoni Ribas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donald Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victoria Atkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sachin Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wilson H. Miller Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matteo S. Carlino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rosalie Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Georgina V. Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F. Stephen Hodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jennifer Tsoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Catherine S. Grasso
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Bijoyesh Mookerjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Qing Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Razi Ghori
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Blanca Homet Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Nageatte Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Omid Hamid
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Antoni Ribas.

Ethics declarations

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.

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 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.

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ribas, A., Lawrence, D., Atkinson, V. et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat Med 25, 936–940 (2019). https://doi.org/10.1038/s41591-019-0476-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-019-0476-5

This article is cited by

Search

Advanced 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