Therapeutic combinations of immune checkpoint blockade with targeted, oncolytic, or antiangiogenic approaches are promising for patients with cutaneous melanoma, according to a study published in Cancers.1

Researchers sought to summarize the current therapies and emerging agents and regimens for the treatment of  cutaneous melanoma.

Current immune checkpoint inhibitors (ICIs) for skin cancer treatment include cytokines that target the IL-2 and IFNAR 1/2 pathways such as aldesleukin and interferon/peginterferon alfa-2b, PD-1 inhibitors including pembrolizumab and nivolumab; PD-L1 inhibitors such as atezolizumab; and ipilimumab, the first clinically approved monoclonal antibody for cutaneous melanoma that targets CTLA-4.

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Although combination therapies with an ICI can be beneficial, they can also increase the incidence and severity of immune-mediated adverse effects. Some regimens that are being investigated include new immunomodulators and treatments that combine an ICI with targeted therapy such as atezolizumab, vemurafenib, and cobimetinib.

In BRAF-mutant metastatic melanoma, BRAF and MEK inhibitors have led to improved survival, although a number of patients develop resistance within a year. BRAF and MEK inhibitors are also associated with toxicity.

A recent randomized, double-blind, phase 3 trial ( Identifier: NCT02908672) of patients with stage III-IV BRAFV600-positive melanoma examined atezolizumab use in combination with vermurafenib and cobimetinib.2 Progression-free survival was significantly increased from 10.6 months in controls to 15.1 months in the atezolizumab group, with similar overall response rates (65% vs 66%, respectively).

A landmark phase 3, randomized clinical study( identifier: NCT03434379) in which patients with unresectable hepatocellular carcinoma were treated with a combination of a PD-L1 inhibitor (atezolizumab) and a vascular endothelial growth factor inhibitor (bevacizumab) found a significantly improved overall and progression-free survival compared with participants who received the standard-of-care protein kinase inhibitor, sorafenib.3

A pair of phase 1 trials of pembrolizumab plus angiopoietin-1/-2-neutralizing peptibody, AMG386, and tremelimumab plus antiangiopoietin-2 antibody, MEDI3617, are under way.

“The development of patient-centered approaches for targeted treatment will be one of the main challenges in cutaneous melanoma care in the next decade,” stated the researchers .

Innovative optical and acoustic technology-based techniques, including confocal laser-scanning microscopy, optical coherence tomography (OCT), photoacoustic/ultrasound/OCT, multiphoton excited fluorescence imaging, and stepwise 2-photon excited fluorescence, also may improve the diagnostic accuracy in noninvasive melanoma.

Future research must address emerging noncutaneous and cutaneous adverse events as well as treatment interventions that combine different modes of action while minimizing toxicity, the study authors concluded.

Disclosures: Several study authors reported affiliations with the pharmaceutical industry. Please see the original references for full lists of authors’ disclosures.


  1. Kasakovski D, Skrygan M, Gambichler T, Susok L. Advances in targeting cutaneous melanoma. Cancers (Basel). 2021;13(9):2090. doi:10.3390/cancers13092090
  2. Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020;395(10240):1835-1844. doi:10.1016/S0140-6736(20)30934-X
  3. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745