Liquid biopsy and radiological response predict outcomes following discontinuation of targeted therapy in patients with BRAF mutated melanoma.

Abstract

BACKGROUND\nOutcomes of patients with metastatic melanoma discontinuing BRAF-targeted therapy for cumulative toxicity after sustained response are unknown.\n\n\nPATIENTS AND METHODS\nThis retrospective case series analysis conducted at a single Cancer Center in Italy included patients with BRAF mutated metastatic melanoma treated with a BRAF inhibitor as a single agent or in combination with a MEK inhibitor between June 1, 2011 and January 1, 2020 and interrupting treatment after achieving complete response (CR) or long-lasting partial response (PR - i.e. >\u200912 months) due to cumulative toxicity.\n\n\nRESULTS\nWe included 24 patients with a median treatment duration of 59.4 months (95%CI 55.4-63.4 - range 12-88). CR and PR were achieved in 71% and 29% of patients, respectively. At a median follow-up after treatment discontinuation of 37.8 months (95%CI 33.7-41.9), 12-months progression free survival after discontinuation (dPFS) rate was 70.8% (95%CI 54.8 - 91.6) and 24-months dPFS rate was 58.3% (95%CI 41.6 - 81.8). Baseline patients and tumor characteristics as well as treatment duration and best response did not significantly impact on dPFS. Patients with CR and negative circulating tumor DNA (ctDNA) at time of discontinuation had a significantly improved dPFS compared to patients with either radiological residual disease or ctDNA positivity (P =\u20090.007). No patient in CR with undetectable ctDNA experienced progression.\n\n\nCONCLUSION\nThe risk of progression is high even in patients with sustained sensitivity to BRAF/MEK inhibitors. Integration of liquid biopsy in clinical trials investigating optimal management of patients with sustained sensitivity to BRAF/MEK inhibitors is warranted.\n\n\nIMPLICATIONS FOR PRACTICE\nOutcomes of patients with metastatic melanoma discontinuing BRAF-targeted therapy for cumulative toxicity are unknown. We analyzed patients with sustained responses (median treatment duration 59.4 months). Twelve and 24-months progression free survival following discontinuation were 70.8% and 58.3% respectively. Complete response and negative ctDNA at time of discontinuation are promising prognostic biomarkers in this setting.