Commenting on the SECOMBIT trial was Omid Hamid, MD, Chief of Translational Research and Immunotherapy at The Angeles Clinic & Research Institute, a Cedars-Sinai Affiliate, and Co-Director, Cutaneous Malignancy Program, Cedars-Sinai Cancer. Dr. Hamid said SECOMBIT addresses an important question from clinicians about treating BRAF-mutated metastatic melanoma: whether targeted therapy or combination immunotherapy should be the initial therapy in the metastatic setting.
Omid Hamid, MD
“As we have seen the approval of combinatorial BRAF and MEK inhibitors—together showing improved progression-free survival and overall survival over single-agent BRAF inhibitors—we’ve also seen an explosion of immunotherapy, with combination CTLA-4 and PD-1 blockade. These approaches have given us two viable options for our patients with BRAF-mutated disease, so there’s always been this debate: which one is the right one to start with?” Dr. Hamid said.
Two trials have been working to answer this question in stage III–IV BRAF V600–mutant melanoma: phase II SECOMBIT1 and phase III ECOG 6134 (ie, DREAMseq; ClinicalTrials.gov identifier NCT02224781).
SECOMBIT randomly assigned 251 patients to one of three arms: immunotherapy first with ipilimumab/nivolumab followed in the second line by targeted therapy with encorafenib/binimetinib; the targeted agents first followed by combination immunotherapy second; or a sandwich strategy of targeted therapy for 8 weeks, then immunotherapy for 8 weeks, with targeted therapy given again in the second line. DREAMseq randomly assigned 300 patients to dabrafenib/trametinib followed by ipilimumab/nivolumab, or the opposite.
As reported at the ESMO Congress 2021 by Paolo Ascierto, MD, SECOMBIT showed a strong trend toward improved overall survival with immunotherapy given first (hazard ratio [HR] = 0.73 vs targeted therapy first); some benefit was also shown for the sandwich approach (HR = 0.81 vs targeted therapy first). “The hazard ratios were inclined to favor these arms, but the confidence intervals crossed 1, and they were not statistically significant. We did see a trend toward the best sequential approach being immunotherapy first,” Dr. Hamid said.
The melanoma research community were recently notified by the Clinical Trials Support Unit that DREAMseq met its primary endpoint: patients starting therapy with immunotherapy experienced a significant improvement in overall survival vs those starting on targeted therapy, he said. Enrollment for the trial has closed.
“These data are the best we have now, and we look forward to seeing them presented at an upcoming meeting,” Dr. Hamid commented. Based on these two important trials, he said: “Unless there’s a contraindication to starting immunotherapy, clinicians should consider starting with combination immunotherapy.”
Since surveys have shown that community oncologists tend to use targeted therapy first, he added, these two studies together will be practice-changing. Looking ahead, their correlative findings will be very important in refining treatment selection—will circulating tumor DNA, for example, have predictive value? “But as a whole,” he concluded, “we have already come to an answer from the randomized phase II and III trials that everyone wanted.”
DISCLOSURE: Dr. Hamid has received honoraria from Array BioPharma, Bristol Myers Squibb, Novartis, and Sanofi/Regeneron; has served as a consultant or advisor to Aduro, Akeso Biopharma, Amgen, Array BioPharma, BeiGene, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Immunocore, Incyte, Janssen, Merck, NextCure, Novartis, Regeneron, Roche, Sanofi, Seattle Genetics, Tempus, and Zelluna; has participated in a speakers bureau for Array BioPharma, Bristol Myers Squibb, Novartis, and Sanofi/Regeneron; has received institutional research funding from Aduro Biotech, Akeso Biopharma, Amgen, Arcus Biosciences, Array BioPharma, AstraZeneca, Bristol Myers Squibb, CytomX Therapeutics, Exelixis, Genentech, GlaxoSmithKline, Immunocore, Incyte, Iovance Biotherapeutics, MedImmune, Merck, Merck Serono, Moderna Therapeutics, NextCure, Novartis, Pfizer, Regeneron, Roche, Sanofi, Seattle Genetics, Torque, and Zelluna.
Reference
1. Ascierto PA, Mandala M, Ferrucci PF, et al: SECOMBIT: The best sequential approach with combo immunotherapy (ipilimumab/nivolumab) and combo target therapy (encorafenib/binimetinib) in patients with BRAF mutated metastatic melanoma: A phase II randomized study. ESMO Congress 2021. Abstract LBA40. Presented September 20, 2021.
