Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial.
Paolo Antonio AsciertoMilena CasulaJenny BulgarelliMarina PisanoClaudia PiccininiLuisa PiccinAntonio CossuMario MandalaPier Francesco FerrucciMassimo GuidoboniPiotr Lukasz RutkowskiVirginia FerraresiAna M AranceMichele GuidaEvaristo MaielloHelen GogasErika RichtigMaria Teresa FierroCeleste LebbèHildur HelgadottirPaola QueiroloFrancesco SpagnoloMarco TucciMichele Del VecchioMaria Gonzales CaoAlessandro Marco MinisiniSabino De PlacidoMiguel F SanmamedDomenico MallardoMiriam PaoneMaria Grazia VitaleIgnacio Melero BermejoAntonio M GrimaldiDiana GiannarelliReinhard DummerVanna Chiarion SileniGiuseppe PalmieriPublished in: Nature communications (2024)
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.
Keyphrases
- free survival
- phase ii
- wild type
- open label
- clinical trial
- phase iii
- placebo controlled
- dna damage
- double blind
- metastatic colorectal cancer
- small cell lung cancer
- squamous cell carcinoma
- ejection fraction
- newly diagnosed
- pi k akt
- cell cycle
- end stage renal disease
- study protocol
- randomized controlled trial
- current status
- small molecule
- prognostic factors
- big data
- immune response
- peripheral blood
- deep learning
- basal cell carcinoma
- patient reported
- combination therapy