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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.

SUBMITTER: Ascierto PA

PROVIDER: S-EPMC10761671 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Ascierto Paolo A PA Casula Milena M Bulgarelli Jenny J Pisano Marina M Piccinini Claudia C Piccin Luisa L Cossu Antonio A Mandalà Mario M Ferrucci Pier Francesco PF Guidoboni Massimo M Rutkowski Piotr P Ferraresi Virginia V Arance Ana A Guida Michele M Maiello Evaristo E Gogas Helen H Richtig Erika E Fierro Maria Teresa MT Lebbe Celeste C Helgadottir Hildur H Queirolo Paola P Spagnolo Francesco F Tucci Marco M Del Vecchio Michele M Cao Maria Gonzales MG Minisini Alessandro Marco AM De Placido Sabino S Sanmamed Miguel F MF Mallardo Domenico D Paone Miriam M Vitale Maria Grazia MG Melero Ignacio I Grimaldi Antonio M AM Giannarelli Diana D Dummer Reinhard R Sileni Vanna Chiarion VC Palmieri Giuseppe G

Nature communications 20240102 1

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 ...[more]

PMID: 38167503

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Project description:ImportancePrognostic models may provide insight into clinical trial results and inform the clinical management of patients with BRAF V600-mutated metastatic melanoma.ObjectiveTo identify subgroups with distinct survival outcomes based on clinical and genomic characteristics and to assess survival in identified prognostic subgroups across cohorts treated with dacarbazine, vemurafenib, or cobimetinib plus vemurafenib.Design, setting, and participantsThis retrospective and exploratory recursive partitioning analysis (RPA) modeled associations between prespecified covariates and survival outcomes using pooled data from the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies.InterventionsDacarbazine, vemurafenib, or cobimetinib plus vemurafenib.Main outcomes and measuresProgression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method.ResultsThe RPA included 1365 patients (783 men; 57.4%). Of these, 1032 (75.6%) were older than 65 years; 310 received cobimetinib plus vemurafenib; 717, vemurafenib alone; and 338, dacarbazine. Median follow-up was 14.1 months (interquartile range, 6.3-28.3 months). In the RPA that included all patients, baseline lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group performance status (ECOG PS), presence or absence of liver metastases, and baseline sum of longest diameters of target lesions (SLDs) were significant prognostic factors for PFS: Median PFS was longest in patients with lower LDH (≤2 × upper limit of normal [ULN]), ECOG PS 0, and shorter SLD (≤44 mm) (11.1 months; 95% CI, 7.0-18.4 months), and shortest in those with elevated LDH (>2 × ULN) (3.5 months; 95% CI, 3.0-3.8 months). The subgroup with normal baseline LDH and no liver metastases had the longest median OS (22.7 months; 95% CI, 20.3-27.2 months). Similar PFS trends were observed when these prognostic subgroups were applied to the cobimetinib plus vemurafenib, vemurafenib alone, and dacarbazine cohorts. Baseline LDH, ECOG PS, and SLD were significant prognostic factors for OS: Median OS was longest in patients with normal LDH and shorter SLD (≤45 mm) (27.2 months; 95% CI, 22.1-32.1 months) and shortest in those with elevated LDH (>2 × ULN) (6.0 months; 95% CI, 5.3-6.8 months). Among patients in the most favorable subgroup (normal LDH and SLD ≤45 mm), 3-year OS rates were 53.3% (95% CI, 39.5%-67.1%) in the cobimetinib plus vemurafenib cohort, 35.6% (95% CI, 27.4%-43.8%) in the vemurafenib cohort, and 35.6% (95% CI, 24.8%-46.4%) in the dacarbazine cohort. Among patients with available gene expression data, RPA identified gene signature as a significant prognostic factor for PFS in those with normal LDH; 3-year PFS rates were 21.9%, (95% CI, 15.4%-28.4%) and 8.8% (95% CI, 3.6%-14.1%) in immune and cell cycle signature, respectively. The RPA for OS did not identify gene signature as a significant factor.Conclusions and relevanceBaseline LDH, ECOG PS, disease burden, and gene signature appear to be key determinants of survival outcomes in patients with BRAF V600-mutated metastatic melanoma treated with BRAF and/or MEK inhibitors. These results are consistent with survival benefits of cobimetinib plus vemurafenib over vemurafenib alone observed in the coBRIM study.

Dataset Information

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

Publications

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

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