Outcomes of BRAF mutant metastatic melanoma (MM) patients (pts) after cessation of targeted therapy (TT) with BRAF or BRAF/MEK inhibitor(i).
Authors: Jackson Natalie , Rodgers Theresa , John Ida , Milton Denai R. , Haydu Lauren Elaine , Amaria Rodabe Navroze , Diab Adi , McQuade Jennifer Leigh , Patel Sapna Pradyuman , Tawbi Hussein Abdul-Hassan , Wong Michael K.K. , Davies Michael A. , Glitza Isabella Claudia 
Published: June 2021

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Background: Since their introduction into the clinic a decade ago, BRAF and BRAF/MEKi have dramatically changed the outcomes of pts with BRAF mutant MM. While typically, these agents are administered until progression (PD), other reasons for stopping TT include unacceptable toxicity, complete response to treatment, or pt/physician decision or preference. The outcomes for MM pts that stop TT for reasons other than PD are largely unknown. Here we report the clinical features and outcomes of the largest cohort of MM pts who stopped TT for reasons other than PD to date. Methods: Under an institutionally approved database, we identified MM pts treated at the MD Anderson Cancer Center with BRAF±MEK inhibitors, and their records were reviewed to identify pts that stopped TT for reasons other than PD. Pts demographics, treatment information and clinical outcomes were recorded. Overall survival (OS) time was computed from three start dates (initial diagnosis, initial unresectable stage III melanoma, 1st dose of TT) to last known vital sign. Pts alive at the last follow-up date were censored. Time to recurrence was computed from date of 1st dose of TT to recurrence. Pts who did not experience disease recurrence were censored The Kaplan-Meier method was used to estimate OS and time to recurrence. Results: A total of 58 pts were identified, 32 (55%) were male. Most pts had a BRAF V600E (n = 49) or V600K (n = 6) mutation. At TT initiation median age was 59.5 years (range 29- 95), LDH was within normal range in 46 (85%), median number of prior systemic therapies was 1 (range 0-5), with 50% of pts receiving prior systemic therapy. Most (n = 33; 57%) pts were treated with single agent BRAFi (12 with dabrafenib, 11 vemurafenib). Among pts treated with combination TT (n = 25), most received dabrafenib with trametinib (n = 21; 84%). Median TT treatment duration was 9.5 months (range 0.03-80.5 months). Reasons for TT discontinuation were unacceptable toxicity (n = 29; 50%) and pt or physician decision/preference in responding patients (n = 23; 40%). At time of TT discontinuation, 48% of pts had achieved a complete response (CR), 28% a partial response (PR), and 22% stable disease (SD), 1 patient had unknown disease status. With standard follow-up, after stopping TT, 40 pts (69%) have recurred or experienced PD, with a median time to recurrence of 14.9 months (95% CI:7.8-26.3 months). At PD, 32 (76%) of pts had new metastatic sites. After PD 26 pts (63%) pts received BRAF/MEKi, 11 (44%) achieved a CR and 6 (24%) a PR, and 5 (20%) for a response rate of 88%; while 3 (12%) pt had PD as best response and 1 was unknown. For the full cohort, the median OS from time of 1st dose of TT was 6.4 years. Conclusions: Among MM pts who stopped TT for reasons other than PD, the majority of pts recurred, but most responded to re-introduction of TT. This information can help to inform discussion with pts regarding cessation of, or re-challenge with, TT.