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Background: In the randomized, two-part, phase 3 COLUMBUS study (NCT01909453), encorafenib (enco) + binimetinib (bini) and enco alone improved 5-year progression-free survival (PFS) and overall survival (OS) vs vemurafenib (vem) in patients (pts) with advanced BRAF V600E/K-mutant melanoma. ctDNA offers a less invasive alternative to tissue biopsy for identifying mutations in pts with advanced melanoma and may have prognostic value. We evaluated whether ctDNA from pts enrolled in COLUMBUS Part 1 correlate with pts’ efficacy outcomes. Methods: In COLUMBUS Part 1, 577 pts were randomized 1:1:1 to enco + bini, enco, or vem. 650 plasma samples were collected at baseline (Cycle 0 or Cycle 1 Day 1; all arms) and during treatment (Cycle 2 Day 1 [C2D1]; enco + bini and enco arms); 426 samples from COLUMBUS Part 1 were successfully analyzed using the GuardantOMNI assay. Analyses were exploratory with no multiplicity adjustments. Results: Survival outcomes in the biomarker cohort were similar to those in the intent-to-treat population. ctDNA was detected in 279 (96%) pts at baseline and 107 (79%) pts at C2D1. 92% concordance was observed between two plasma genomics assays (Inostics and Guardant) and 75% between tumor and plasma with respect to BRAF mutation status. BRAF V600 variant allele frequency (VAF) at baseline was prognostic for PFS and OS (P Conclusions: These exploratory analyses of Part 1 of the COLUMBUS study suggested that treatment with enco + bini significantly reduced BRAF V600 VAF, which was prognostic for PFS and OS at both baseline and C2D1. ctDNA provides a powerful tool for understanding the molecular basis for response and resistance to treatment and may impact future treatment decisions. Citation Format: Reinhard Dummer, Nuzhat Pathan, Zhou Zhu, Caroline Robert, Ana Arance, Jan Willem B. de Groot, Claus Garbe, Helen J. Gogas, Ralf Gutzmer, Ivana Krajsová, Gabriella Liszkay, Carmen Loquai, Mario Mandala, Dirk Schadendorf, Naoya Yamazaki, Michelle Edwards, Jean Cantey-Kiser, Alessandra di Pietro, Shibing Deng, Paolo A. Ascierto, Keith Flaherty. Molecular correlates of clinical benefit from circulating tumor DNA (ctDNA): Analysis of the COLUMBUS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6403. |
