免疫检查点抑制剂（CPI）或BRAF/MEK定向靶向治疗（TT）的辅助治疗可提高携带BRAFV600突变（BRAFmut）的晚期切除黑色素瘤患者的无复发生存期（RFS）。然而，其中40％的患者在5年内将发生远处转移（DM），需要系统治疗。目前缺乏足够数据指导选择最初的辅助治疗或DM发生后的治疗管理。本研究评估了在最初辅助治疗后肿瘤复发时后续治疗的疗效。在这个多中心队列研究中，我们确定了515例在辅助治疗中接受PD-1抑制剂（anti-PD1）或TT的切除III期黑色素瘤患者。通过前瞻性的真实世界皮肤癌登记处ADOReg收集了疾病特点、治疗方案、肿瘤复发细节、后续治疗管理和生存结果。主要终点包括DM后的无进展生存期（PFS）和一线治疗的最佳肿瘤反应。在515名符合条件的患者中，273名患者接受了辅助anti-PD1治疗，242名接受了辅助TT治疗。在中位随访21个月的情况下，54.6％的anti-PD1患者和36.4％的TT患者发生了复发，而39.6％（anti-PD1）和29.3％（TT）的患者出现了DM。与anti-PD1相比，TT治疗组患者的复发风险显著降低（调整后风险比0.52；95％ CI 0.40 至 0.68，p<0.001）。同样，TT治疗组患者的中位RFS显著延长（31 vs 17个月，p<0.001）。在局部区域复发后接受TT作为第二辅助治疗的患者具有较长的RFS2，与辅助CPI相比（41 vs 6个月，p=0.009）。在接受辅助TT后出现远处转移的患者切换为1L ipilimumab+nivolumab（ipi+nivo）后具有良好的反应率（42.9％）。在辅助anti-PD1期间出现DM的患者切换为1L TT后达到58.7％的反应率，1L ipi+nivo的反应率为35.3％。总体而言，切换治疗的患者的中位PFS显著延长（9 vs 5个月，p=0.004）。在最初辅助治疗中发生DM的BRAFmut黑色素瘤患者在转换治疗方式后的第一线治疗中实现了良好的肿瘤控制和延长的PFS。局部区域复发的患者获益于完全切除复发并随后进行第二辅助治疗的TT。© 作者（或其雇主）2023。CC BY-NC下允许再使用。不允许商业再使用。由BMJ出版。

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.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.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).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.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.