背景:免疫检查点抑制剂(CPI)或BRAF/MEK定向靶向治疗(TT)的辅助治疗可改善晚期患者的无复发生存率(RFS),BRAFV600-突变体(BRAFmut)切除的黑色素瘤。然而,这些患者中有40%会在5年内发生远处转移(DM),这需要全身治疗。很少有数据指导糖尿病患者选择前期辅助治疗或治疗管理。这项研究评估了前期辅助治疗后肿瘤复发后后续治疗的疗效。
方法:对于这项多中心队列研究,我们确定了515例接受PD-1抑制剂(抗PD1)或TT辅助治疗的切除III期黑色素瘤的BRAFmut患者.疾病特征,治疗方案,肿瘤复发的细节,后续治疗管理,和生存结果在预期范围内收集,真实世界的皮肤癌注册ADOReg.主要终点包括DM后的无进展生存期(PFS)和对一线(1L)治疗的最佳肿瘤反应。
结果:在515名符合条件的患者中,273名患者接受了辅助抗PD1和242辅助TT。中位随访21个月,54.6%的抗PD1患者和36.4%的TT患者复发,39.6%(抗PD1)和29.3%(TT)发展为DM。与抗PD1相比,接受TT治疗的患者的复发风险显着降低(校正HR0.52;95%CI0.40至0.68,p<0.001)。同样,接受TT治疗的患者的中位RFS明显更长(31vs17个月,p<0.001)。与辅助CPI相比,局部复发后接受TT作为第二辅助治疗的患者具有更长的RFS2(41vs6个月,p=0.009)。在辅助TT后在远处复发的患者在转换为1Lipilimumab+nivolumab(ipi+nivo)后表现出良好的应答率(42.9%)。在抗PD1辅助治疗期间,DM患者在转换为1LTT后的反应率为58.7%,1Lipi+nivo的反应率为35.3%。总的来说,转换治疗IV期疾病的患者的中位PFS明显更长(中位PFS9vs5个月,p=0.004)。
结论:BRAFmut黑色素瘤患者在前期辅助治疗后发展为DM,在IV期疾病一线转用治疗方式后获得了良好的肿瘤控制和延长的PFS。局部复发的患者受益于完全切除复发,然后进行第二次TT辅助治疗。
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.