Review Article | Published:

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Nature Reviews Clinical Oncology volume 14, pages 463482 (2017) | Download Citation

Abstract

Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints. These changes in the treatment landscape have dramatically improved patient outcomes, with the median overall survival of patients with advanced-stage melanoma increasing from approximately 9 months before 2011 to at least 2 years — and probably longer for those with BRAF-V600-mutant disease. Herein, we review the clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. Mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies are discussed, and the contrasting clinical benefits and limitations of these therapies are explored. We summarize the state of the field and outline a rational approach to frontline-treatment selection for each individual patient with BRAF-mutant melanoma.

Key points

  • Clinical therapeutics for advanced-stage melanoma have improved dramatically with the development of BRAF and MEK inhibitors, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell-death protein 1 (PD-1) blocking antibodies, and a modified oncolytic herpes virus that is delivered intratumourally

  • The overall survival of patients with advanced-stage melanoma has improved from 9 months before 2011 to an as yet undefined timeframe, with a subset of patients having ongoing long-term tumour control

  • Melanoma, particularly cutaneous melanoma, is amendable to immunotherapy for various reasons, including extensive tumour infiltration by T cells, a high mutational load, and crosstalk between oncogenic signalling pathways and immunobiology

  • Resistance mechanisms to BRAF-targeted treatments and immunotherapies are being elucidated; reactivation of the MAPK pathway is common after BRAF inhibition, whereas the effectiveness of both approaches might be limited by loss of tumour antigen presentation and T-cell trafficking

  • To move the field of clinical therapeutics forward, a greater focus on specific patient populations (based on serum lactose dehydrogenase levels, ECOG performance status, and number of metastases), as well as on landmark progression-free and overall survival measures, will be required in clinical trials

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Acknowledgements

J.J.L. has received funding from the Paul Calabresi Career Development in Clinical Oncology Award (NIH 1K12CA139160-05) and the Arthur J Schreiner Family Melanoma Research Fund.

Author information

Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, University of Chicago Comprehensive Cancer Center, 5841 South Maryland Avenue MC2115, Chicago, Illinois 60637, USA.

    • Jason J. Luke
  2. Department of Medicine, Harvard Medical School, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Keith T. Flaherty
  3. Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles Jonsson Comprehensive Cancer Center, 10833 Le Conte Avenue, Los Angeles, California 90024, USA.

    • Antoni Ribas
  4. Melanoma Institute Australia, The University of Sydney, and The Mater Hospital, Rocklands Road, North Sydney, New South Wales 2060, Australia.

    • Georgina V. Long
  5. Royal North Shore Hospital, Reserve Road, St Leonards, New South Wales 2065, Australia.

    • Georgina V. Long

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Contributions

All authors made substantial contributions to researching data for the article, discussions of content, and writing and reviewing/editing of the manuscript before submission.

Competing interests

J.J.L. has acted as a consultant for Amgen, Array, AstraZeneca, BeneVir, Bristol-Myers Squibb, CheckMate, EMD Serono, Gilead, Novartis, and Merck (non-paid). K.T.F. has been a consultant for Amgen, BMS, Merck, Novartis, and Roche. A.R. has acted as a consultant for Amgen, Array, BMS, Genentech-Roche, Merck MSD, and Novartis, and is a stock holder in Advaxis, Compugen, CytomX, Five Prime Therapeutics, and Kite Pharma. G.V.L. has been a consultant for Amgen, Array, BMS, Merck MSD, Novartis, Pierre-Fabre, and Roche.

Corresponding author

Correspondence to Jason J. Luke.

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DOI

https://doi.org/10.1038/nrclinonc.2017.43

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