9512 Background: BRAF/MEK-inhibitor combinations have a central role in the treatment of BRAF V600–mutant melanoma based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). Because of these meaningful improvements in outcome, mature landmark analyses of PFS and OS, as well as analyses of some prognostic subgroups, require long-term follow-up. Here we report an updated analysis of OS and other endpoints from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 patients with advanced/metastatic BRAF V600‒mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to ENCO 450 mg QD + BINI 45 mg BID (COMBO450) vs VEM 960 mg BID (VEM) or ENCO 300 mg QD (ENCO300). An updated analysis including PFS, OS, objective response rate (ORR), safety and tolerability, and analyses of results by prognostic subgroups including elevated lactate dehydrogenase (LDH) and degree of organ involvement was conducted after an additional 12 months’ follow-up. Results: At data cutoff, there were 116, 113, and 138 deaths in the COMBO450, ENCO300, and VEM treatment arms, respectively. Across arms, median follow-up for OS was 48.6 months (mo), with median OS of 33.6 mo (95% CI, 24.4–39.2) for COMBO450, 23.5 mo (95% CI, 19.6–33.6) for ENCO300, and 16.9 mo (95% CI, 14.0–24.5) for VEM. Compared to VEM, COMBO450 decreased the risk of death by 39% (HR, 0.61 [95% CI, 0.48–0.79). Updated median PFS was COMBO450, 14.9 mo (95% CI, 11.0–20.2), ENCO300, 9.6 mo (95% CI, 7.4–14.8), and VEM, 7.3 mo (95% CI, 5.6–8.2). PFS was longer for COMBO450 vs VEM (HR, 0.52 [95% CI, 0.40–0.67). Landmark OS and PFS results, as well as subgroup analyses and updated safety and tolerability, will be presented. Conclusions: Updated PFS and OS results for COMBO 450 from the COLUMBUS trial continue to represent new benchmarks for combined BRAF/MEK-inhibitor combinations for treatment of BRAF V600‒mutated melanoma. Clinical trial information: NCT01909453.

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<0.0001) in the enco + bini arm. Treatment with enco + bini and enco sharply reduced BRAF V600 VAF (P<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<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<0.0001), followed by TERT (41.6% difference; P<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.

Background Recent real–world studies have reported significant improvements in the survival of malignant melanoma in the past few years, mainly as a result of modern therapies. However, long–term survival data from Central Eastern European countries such as Hungary are currently lacking. Methods This nationwide, retrospective study examined melanoma survival in Hungary between 2011–2019 using the databases of the National Health Insurance Fund (NHIF) and Central Statistical Office (CSO) of Hungary. Crude overall survival and age–standardized 5–year net survival as well as the association between age, sex, and survival were calculated. Results Between 2011 and 2019, 22,948 newly diagnosed malignant melanoma cases were recorded in the NHIF database (47.89% male, mean age: 60.75 years (SD: ±16.39)). 5–year overall survival was 75.40% (women: 80.78%; men: 69.52%). Patients diagnosed between 2017–2019 had a 20% lower risk of mortality compared to patients diagnosed between 2011–2012 (HR 0.80, 95% CI 0.73– 0.89; p<0.0001). Age-standardized 5–year net survival rates in 2011–2014 and 2015–2019 were 90.6% and 95.8%, respectively (women: 93.1% and 98.4%, men: 87.8% and 92.7%, respectively). The highest age–standardized 5–year net survival rates were found in the 0–39 age cohort (94.6% in the 2015–2019 period). Conclusion Hungary has similar melanoma survival rates to Western European countries. Based on net survival, the risk of dying of melanoma within 5 years was cut by more than half (55%) during the study period, which coincides with the successful implementation of awareness campaigns and the wide availability of modern therapies.