What is the role of medical therapy in the treatment of melanoma?

Updated: Jun 28, 2021
  • Author: Jonathan B Heistein, MD; Chief Editor: Gregory Gary Caputy, MD, PhD, FICS  more...
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Medical therapy is used as adjuvant treatment in advanced stages of unresectable or metastatic melanoma and, most recently, for resected, advanced-stage disease. Approvals from the US Food and Drug Administration (FDA) include trametinib (Mekinist), dabrafenib (Tafinlar), ipilimumab (Yervoy), vemurafenib (Zelboraf), pembrolizumab (Keytruda), and nivolumab (Opdivo). Trametinib is a MEK inhibitor indicated for melanoma with BRAF V600E or V600K mutations. Dabrafenib is a BRAF protein kinase inhibitor indicated for melanoma with BRAF V600E mutation. Ipilimumab is a targeted T-cell antibody that binds to CTLA-4. Vemurafenib is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E. Pembrolizumab and nivolumab are monoclonal antibodies to programed cell death-1 (PD-1) protein. They block the interaction between PD-1 and its ligands (ie, PD-L1 and PD-L2). [18, 19]

The combination of binimetinib (Mektovi), a MEK inhibitor, plus encorafenib (Braftovi), a BRAF inhibitor, was approved by the FDA in June 2018 for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Approval followed the success of the phase 3 COLUMBUS trial, in which, compared with treatment with vemurafenib alone, binimetinib/encorafenib therapy led to double the median progression-free survival time (7.3 mo vs 14.9 mo, respectively). [20]

A study by Hecht et al indicated that patients with BRAF-mutated melanoma have better overall survival and experience less toxicity when vemurafenib treatment is interrupted during radiotherapy instead of administered concomitantly. For patients who underwent interrupted treatment, median overall survival from the start of radiotherapy and from the beginning of vemurafenib treatment was 10.1 and 13.1 months, respectively, compared with 6.6 and 10.9 months, respectively, for the group that received concomitant therapy. Moreover, there was a greater incidence of skin toxicity of grade 2 or higher (based on Common Terminology Criteria for Adverse Events [CTCAE]) in the concomitant patients than in the interrupted group. [21]

In October 2015, the FDA approved talimogene laherparepvec (Imlygic), a genetically modified, live attenuated herpes simplex virus programmed to replicate within tumors and manufacture granulocyte-macrophage colony-stimulating factor (GM-CSF), an immunostimulatory protein. The first oncolytic viral therapy approved by the FDA, talimogene laherparepvec is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in cases of postsurgery melanoma recurrence. It is administered by injection into lesions that are visible, palpable, or detectable by ultrasonographic guidance. [22]

Approval was based on results from OPTiM (OncoVEX [GM-CSF] Pivotal Trial in Melanoma), a randomized, controlled study conducted in 436 adults with unresectable regionally or distantly metastatic melanoma. In the trial, 295 patients were treated with talimogene laherparepvec, while 141 patients received with GM-CSF. Those who were treated with talimogene laherparepvec had a 16.3% durable response rate (the rate of complete response plus partial response beginning within the first 12 months and lasting continuously for ≥6 months), compared with 2.1% in patients given GM-CSF. A complete response was obtained in 32 patients (10.8%) treated with talimogene laherparepvec, versus just one patient (0.7%) who received GM-CSF. [22, 23]

A retrospective study by Wang et al indicated that patients with advanced BRAF-mutated melanoma have better brain metastasis–free survival (BMFS) and greater overall survival with first-line immunotherapy than with first-line targeted therapy. Patients who underwent first-line immunotherapy had a median BMFS of 41.9 months, compared with 11.0 months for first-line targeted therapy patients, while median overall survival was 48.3 and 13.8 months, respectively. Moreover, first-line targeted therapy was associated with a larger cumulative incidence of brain metastases than was first-line immunotherapy (P <0.001).<ref>24</ref>

Adjuvant treatment for resected melanoma

In addition to its use against unresectable or metastatic melanoma, in December 2017 nivolumab received FDA approval as an adjuvant therapy for patients who have undergone complete resection of melanoma with lymph node involvement or metastatic disease. Approval stemmed from the CheckMate-238 trial. In that study, investigators found that in completely resected patients with stage IIIB/C or IV melanoma, those treated with nivolumab had a higher 12-month recurrence-free survival rate than did patients treated with ipilimumab (70.5% vs 60.8%, respectively). [25]

Pembrolizumab gained FDA approval in February 2019 for adjuvant treatment of resected, high-risk stage 3 melanoma. Approval was based on data from a phase 3, double-blind trial showing the rate of 1-year recurrence-free survival to be significantly greater with pembrolizumab than with placebo (75.4% vs 61%, respectively). [26]

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