Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

Abstract

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

Local and Systemic Management Options for Melanoma Brain Metastases

“…Updated 4-year OS data from SECOMBIT trial continue to show superior survival benefit with first-line combination immunotherapy with or without an initial induction course of targeted therapy. 32…”

“…However, the “sandwich approach,” which includes an initial induction course of targeted therapy followed by immunotherapy maintenance, could be used in patients with rapidly progressing disease and was shown to be of clinical benefit in the SECOMBIT trial. Updated 4-year OS data from SECOMBIT trial continue to show superior survival benefit with first-line combination immunotherapy with or without an initial induction course of targeted therapy 32 …”

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

“…The best-known examples include sun-induced melanomas with high tumor mutation burden and BRAF V600E mutations, smoking-related lung carcinomas with KRAS G12C substitutions, and microsatelliteunstable colorectal tumors with kinase-activating genetic alterations, which are potentially sensitive both to immune therapy and to inhibitors of the MAPK pathway [37,98,156]. For example, clinical studies on BRAF V600E mutant melanomas revealed that the overall survival is higher in patients who received BRAFi/MEKi after disease progression during immune therapy when compared to subjects treated with BRAFi/MEKi upfront and ICIs as a second-line [157,158]. Furthermore, combined administration of BRAFi/MEKi and ICIs seems feasible in patients who developed resistance to these drugs previously given as sequential treatment [159].…”

Nivolumab and Ipilimumab Acting as Tormentors of Advanced Tumors by Unleashing Immune Cells and Associated Collateral Damage

“…The combination of immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) has demonstrated heightened efficacy in advanced melanoma, albeit with notable side effects. Comparative studies of ipilimumab plus nivolumab, nivolumab alone, and ipilimumab alone reveal superior outcomes for the combination and nivolumab alone, emphasizing improved response rates, progression-free survival, and overall survival [ 85 , 86 , 87 , 88 , 89 ]. Sequential immunotherapy followed by targeted therapy proves to be beneficial in untreated BRAFV600-mutant metastatic melanoma, highlighting the potential for tailored treatment sequences.…”