Abstract 6403: Molecular correlates of clinical benefit from circulating tumor DNA (ctDNA): Analysis of the COLUMBUS study
Authors: Dummer Reinhard , Pathan Nuzhat , Zhu Zhou , Robert Caroline , Arance Ana , de Groot Jan Willem B. , Garbe Claus , Gogas Helen J. , Gutzmer Ralf , Krajsová Ivana , Liszkay Gabriella , Loquai Carmen , Mandala Mario , Schadendorf Dirk , Yamazaki Naoya , Edwards Michelle , Cantey-Kiser Jean , di Pietro Alessandra , Deng Shibing , Ascierto Paolo A. , Flaherty Keith 
Published: June 2022

Abstract
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&lt;0.0001) in the enco + bini arm. Treatment with enco + bini and enco sharply reduced BRAF V600 VAF (P&lt;0.0001). Decrease in BRAF V600 VAF was more pronounced in responders than in non-responders. Greater clinical benefit was observed in pts with complete ctDNA clearance at C2D1, among whom 12% and 58% had a complete or partial response, respectively, vs 9% and 48%, respectively, for those without complete ctDNA clearance. In the enco + bini arm, high tumor mutational burden (≥10 per megabase) at C2D1, but not at baseline, was associated with shorter PFS (P&lt;0.0001) and OS (P=0.0151). The most frequently detected alterations at baseline were BRAF (79%), TERT (53%), LRP1B (21%), TP53 (17%), and PREX2 (14%). BRAF gene had the most significant decrease from baseline to C2D1 (51.6% difference; P&lt;0.0001), followed by TERT (41.6% difference; P&lt;0.0001), GRIN2A (16.3% difference; P=0.0152), and ROS1 (12.2% difference; P=0.0437) in pts who received enco + bini. FGFR1 mutations were found to be most associated with a lack of BRAF V600 clearance (P=0.0005). Further analyses of molecular correlates of response and resistance are underway.
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.