Cancer and Metastasis Reviews

, Volume 36, Issue 1, pp 43–50 | Cite as

Combining forces: the promise and peril of synergistic immune checkpoint blockade and targeted therapy in metastatic melanoma

  • David J. Hermel
  • Patrick A. OttEmail author


Both immune checkpoint inhibitors and molecularly targeted agents have dramatically improved clinical outcomes for patients with metastatic melanoma. These two therapeutic approaches harness distinct mechanistic pathways—on the one hand, monoclonal antibodies against the immune checkpoints CTLA-4 and PD-1/PD-L1 stimulate the T cell mediated host immune response, while targeted inhibitors of the proto-oncogenes BRAF and MEK disrupt constitutive kinase activity responsible for tumor growth. The prospect of combining these two treatment modalities has been proposed as a potential way to increase overall response rate, extend durability of the anti-tumor response, and circumvent the immune-mediated resistance to targeted therapy. This review explores the preclinical rationale—building upon a wealth of in vitro and in vivo studies—for improved anti-tumor efficacy from combined immune checkpoint inhibition and targeted therapy. In the process, we detail the early clinical trials that have assessed the compatibility of combining these two therapies and the unexpected challenges faced from studies showing increased toxicity from these regimens. Ultimately, with more clinical data expected to mature and accrue in the near future, we elucidate a potentially novel and promising strategy for patients with advanced melanoma.


Melanoma Immune checkpoint inhibitors Targeted therapy Combination strategies Melanoma BRAF MEK CTLA-4 PD-1 PD-L1 


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Resident PhysicianUniversity of Southern CaliforniaLos AngelesUSA
  2. 2.Melanoma Disease Center and Center for Immuno-OncologyDana-Farber Cancer Institute/Harvard Medical SchoolBostonUSA

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