Treatment management forBRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG

Haist, Maximilian

; Stege, Henner ; Rogall, Friederike ; Tan, Yuqi

; von Wasielewski, Imke ; Klespe, Kai Christian ; Meier, Friedegund

; Mohr, Peter ; Kähler, Katharina C ; Weichenthal, Michael

; Hauschild, Axel ; Schadendorf, Dirk ; Ugurel, Selma ; Lodde, Georg ; Zimmer, Lisa ; Gutzmer, Ralf ; Debus, Dirk ; Schilling, Bastian ; Kreuter, Alexander ; Ulrich, Jens ; Meiss, Frank

; Herbst, Rudolf ; Forschner, Andrea ; Leiter, Ulrike ; Pfoehler, Claudia ; Kaatz, Martin ; Ziller, Fabian ; Hassel, Jessica C ; Tronnier, Michael ; Sachse, Michael ; Dippel, Edgar ; Terheyden, Patrick ; Berking, Carola ; Heppt, Markus V ; Kiecker, Felix ; Haferkamp, Sebastian ; Gebhardt, Christoffer

; Simon, Jan Christoph ; Grabbe, Stephan ; Loquai, Carmen

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Background Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant (BRAFmut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy.Methods For this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments.Results Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004).Conclusions BRAFmut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT.

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