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  • Review Article
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Targeted agents and immunotherapies: optimizing outcomes in melanoma

Nature Reviews Clinical Oncology volume 14, pages 463–482 (2017)Cite this article

Subjects

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

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.

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Figure 1: Timeline charting the seminal, practice-changing clinical trials in advanced-stage melanoma.
Figure 2: Frequency and overlap of alterations in driver and tumour-suppressor genes associated with melanoma.
Figure 3: Summary of overall survival by Kaplan–Meier analysis across seminal clinical trials in patients with advanced-stage melanoma.
Figure 4: Molecular signalling and immunological interactions relevant to the clinical treatment of melanoma.
Figure 5: Factors associated with overall survival in patients with melanoma treated with dabrafenib and trametinib.

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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.

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Authors and Affiliations

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

    Jason J. Luke

  2. Department of Medicine, Harvard Medical School, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, 02114, Massachusetts, 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, 90024, California, USA

    Antoni Ribas

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

    Georgina V. Long

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

    Georgina V. Long

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

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Correspondence to Jason J. Luke.

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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.

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Luke, J., Flaherty, K., Ribas, A. et al. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol 14, 463–482 (2017). https://doi.org/10.1038/nrclinonc.2017.43

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