Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Final results and exploratory biomarker analysis from the phase 2 TRICOTEL study.

Reinhard Dummer University Hospital Zurich, Zurich, Switzerland info_outline Reinhard Dummer, Mitchell Levesque, Elisa Bellini, Marissa Chen, Youyou Hu, Tiffany Wong, Katja Stassen, Pauline Duhard, Yibing Yan, Hussein A. Tawbi

Authors Reinhard Dummer University Hospital Zurich, Zurich, Switzerland info_outline Reinhard Dummer, Mitchell Levesque, Elisa Bellini, Marissa Chen, Youyou Hu, Tiffany Wong, Katja Stassen, Pauline Duhard, Yibing Yan, Hussein A. Tawbi Organizations University Hospital Zurich, Zurich, Switzerland, University of Zürich Hospital, Zürich, Switzerland, ISS AG, Integrated Scientific Services, Biel, Switzerland, Genentech, South San Francisco, CA, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Genentech Inc, South San Francisco, CA, SOTIO Biotech, Basel, Switzerland, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX Abstract Disclosures Research Funding F. Hoffmann-La Roche Ltd. Background: Primary analysis results from the phase 2 TRICOTEL study showed intracranial activity with the triplet combination of A + C + V in pts with BRAF V600 -mutated melanoma with CNS mets (1). Here, we report final analysis results and exploratory biomarker analyses for pts with BRAF V600 -mutated melanoma in the triplet combination cohort from TRICOTEL. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Tumor tissue and circulating tumor DNA (ctDNA) samples collected at baseline (cycle 1, day 1) and ctDNA at the time of progressive disease (PD) were profiled for mutations using next-generation sequencing. Tumor tissue was profiled using a pipeline programmed for MelArray, and ctDNA was measured based on the tissue genetic profile. Results: A total of65 pts were enrolled in the triplet combination cohort. At final analysis, median follow-up was 12.4 mo. Per independent review committee (IRC) assessment, intracranial ORR (confirmed by assessments ≥4 wk apart) was 38% (95% CI, 27–51) and median intracranial PFS was 5.1 mo (95% CI, 3.7–6.9) (Table). Median OS was 13.4 mo (95% CI, 10.7–16.9). No new safety signals were observed since primary analysis. Mutations were detected in baseline ctDNA samples of 60 pts (5 pts not reported) and showed high prevalence of NF1 , NRAS , and GNAI2 mutations; relative to tumor tissue, 11 additional BRAF mutations were detected in ctDNA at baseline. Acquired mutations in AKT1 were detected in ctDNA at PD. Median OS shortened in pts with >2 versus ≤2 mutated MAPK pathway genes in ctDNA at baseline (9.1 vs 14.5 mo; hazard ratio, 2.0 [95% CI, 1.0–3.7]; p<0.05). In tumor tissue, baseline mutations in PIK3C2A and PLEKHG4 were enriched in nonresponders, while RAD51B mutations were enriched in responders. Conclusions: Combination A + C + V had clinical intracranial activity in pts with BRAF V600 -mutated melanoma with CNS mets. Exploratory biomarker analyses in this small cohort demonstrate the presence of ctDNA in pts with melanoma and CNS mets and provide insight into mutations associated with response and resistance to the triplet combination. 1. Dummer R et al, Lancet Oncol 2023. Clinical trial information: NCT03625141. Outcomes at final analysis (N=65). Intracranial (IRC) Intracranial (investigator) Extracranial (investigator) Overall (investigator) ORR, % (95% CI) 38 (27–51) 49 (37–62) 57 (44–69) 52 (40–65) Median duration of response, mo (95% CI) 6.2 (4.8–9.4) 6.7 (5.6–9.5) 11.6 (9.2–13.0) 7.4 (5.5–9.5) Median PFS, mo (95% CI) 5.1 (3.7–6.9) 5.8 (5.4–7.4) 10.7 (7.9–13.7) 5.5 (5.1–7.4)

Clinical