‘Better biomarkers are needed’ as treatment options for advanced melanoma increase
Click Here to Manage Email Alerts
Approvals of BRAF-targeted therapies and immune checkpoint inhibitors have greatly expanded the melanoma treatment landscape during the past decade, according to a speaker at Chemotherapy Foundation Symposium.
“It’s important to remember that melanoma is a genetic disease,” Ryan J. Sullivan, MD, associate professor of medicine at Harvard Medical School and associate professor of hematology/oncology at Massachusetts General Hospital, said during a presentation. “About half our patients [with advanced melanoma] have activating mutations in BRAF and another quarter have activating mutations in NRAS.”
One model for optimal treatment selection depends upon blood or tissue genotyping and availability of targeted therapy for specific genotypes, with selection of immunotherapy left to default or gestalt.
Sullivan presented a summary of 5-year clinical trial data that showed longer PFS and OS with anti-PD-1 antibody vs. BRAF and MEK inhibitor combination strategies. Randomized trial data evaluating such strategies will be released soon, he said.
The phase 2 SECOMBIT trial compared various sequences of therapy, including “sandwich” treatment with the BRAF inhibitor encorafenib (Braftovi, Array Biopharma) and MEK inhibitor binimetinib (Mektovi, Array Biopharma/Pfizer Oncology), followed by the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) plus the anti-PD-1 antibody nivolumab (Opdivo, Bristol Myers Squibb), and then encorafenib and binimetinib again at progression. Results suggest early use of the checkpoint inhibitor combination is associated with better outcomes, Sullivan said.
Two randomized phase 3 trials investigated combinations of BRAF/MEK plus either PD-1 or PD-L1 inhibitors.
The IMspire150 study showed the addition of the anti-PD-L1 antibody atezolizumab (Tecentriq, Genentech) to the MEK inhibitor cobimetinib (Cotellic, Genentech) and BRAF inhibitor vemurafenib (Zelboraf, Genentech) resulted in slightly higher toxicity but significantly longer PFS among patients with BRAF V600 mutation-positive advanced melanoma. The data led to FDA approval of the triplet regimen.
The COMBI-i trial, designed to evaluate the addition of the investigational PD-1 inhibitor spartalizumab (PDR001, Novartis) to the BRAF inhibitor dabrafenib (Tafinlar, Novartis) and the MEK1/2 inhibitor trametinib (Mekinist, Novartis), did not meet its primary endpoint of improved PFS among patients with previously untreated, unresectable or metastatic BRAF V600-mutant melanoma. In addition, toxicity was higher with the three-drug combination.
“The preferred therapy for [patients with BRAF-mutant advanced melanoma] is anti-PD-1-based therapy, either as a single agent or in combination with ipilimumab,” Sullivan said.
For patients with BRAF wild-type disease, ipilimumab plus nivolumab “numerically looks better” than front-line pembrolizumab or nivolumab in terms of overall response rate and 5-year rates of PFS and OS, Sullivan said. However, combination anti-PD-1 and anti-CTLA-4 therapy is toxic, with more than half of patients experiencing grade 3 or grade 4 adverse events, he said. Ipilimumab plus nivolumab may be considered for patients with melanoma brain metastases, in whom it has demonstrated durable benefit vs. single-agent PD-1 inhibitors.
Combination anti-PD-1 and anti-lymphocyte-activation gene 3 (LAG-3) therapy represents a new potential regimen, Sullivan said. In the RELATIVITY-047 study, presented at this year’s virtual ASCO Annual Meeting, the LAG-3 inhibitor relatlimab (BMS-986016, Bristol Myers Squibb) plus nivolumab conferred longer PFS compared with nivolumab alone as first-line treatment for patients with advanced melanoma.
“Emerging data with anti-PD-1 and anti-LAG-3 may change the treatment landscape in the near future,” he said. “It’s clear that better biomarkers are needed to help select front-line immunotherapy, particularly when we’re going to have three choices likely in the near future.”
References:
Ascierto PA, et al. Abstract LBA45. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
Lipson TJ, et al. Abstract 9503. Presented at: ASCO Annual Meeting; June 4-8, 2021 (virtual meeting).
McArthur GA, et al. Abstract CT012. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Sullivan RJ. Individualized management of advanced melanoma: 2021 Updates. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
Collapse
Sullivan RJ. Individualized management of advanced melanoma: 2021 Updates. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
Click Here to Manage Email Alerts