Background: Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need. Methods: This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375). Results: In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was <3 months. Following a relapse of the disease during the first adjuvant treatment, the median progression-free survival (PFS2) was only 6.6 months; outcomes were particularly poor for relapses that were unresectable (median PFS2 3.9 months) or occurred within the first 2 months (median PFS2 2.7 months). A second adjuvant treatment for patients with resectable relapses still showed efficacy (median RFS2 43.7 months). Elevated LDH levels in patients with an unresectable relapse was correlated with a strong reduction in OS2 (HR 9.84,p= 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78,p< 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64,p= 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65,p< 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62,p= 0.026), affected OS2. Conclusion: Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment.
背景：免疫检查点抑制剂（ICIs）和BRAF/MEK抑制剂（BRAF/MEKi）已显著改变了晚期黑色素瘤患者在可切除/辅助治疗和不可切除/转移性治疗中的预后。在这项真实世界数据的后续分析中，我们旨在调查瑞士一家三级转诊中心在ICIs和BRAF/MEKi引入临床使用约十年后，对晚期黑色素瘤患者的临床管理和治疗结果。此外，我们旨在将结果与关键的3期临床试验进行比较，并确定临床需求未得到满足的领域。方法：这项单中心回顾性队列研究分析了瑞士苏黎世大学医院（一家三级癌症中心）的黑色素瘤登记数据，纳入了在可切除/辅助治疗（n = 331）或不可切除/转移性治疗（n = 375）中接受治疗的患者。结果：在可切除治疗中，辅助性抗PD1或BRAF/MEKi治疗分别显示出53%和67.6%的3年无复发生存率（RFS），总体中位RFS为50个月。在开始辅助治疗前已存在淋巴结加移行转移或远处转移的患者，其总生存期（OS）显著缩短。10.9%的患者因毒性而停止治疗，这并未影响RFS/OS，除非治疗持续时间<3个月。在首次辅助治疗期间疾病复发后，中位无进展生存期（PFS2）仅为6.6个月；对于不可切除的复发（中位PFS2 3.9个月）或在最初2个月内发生的复发（中位PFS2 2.7个月），预后尤其差。对于可切除复发的患者，第二次辅助治疗仍显示出疗效（中位RFS2 43.7个月）。不可切除复发患者中LDH水平升高与OS2的显著降低相关（HR 9.84, p=0.018）。在不可切除治疗中，一线抗PD1、抗CTLA4/PD1联合治疗或BRAF/MEKi治疗分别显示出46.5%、52.4%和49.2%的5年OS。在多变量分析中，LDH水平升高或存在脑转移显著缩短了OS（HR > 1.78, p < 0.035）。与抗PD1治疗相比，接受抗CTLA4/PD1治疗的患者生存期有改善趋势，但无统计学意义（HR 0.64, p=0.15）。在一线治疗进展后，中位OS2降至两年以下。LDH水平升高（HR 4.65, p<0.001）以及疾病广泛扩散至至少三个转移部位，特别是骨转移（HR 2.62, p=0.026），影响了OS2。结论：我们的研究提供了关于辅助治疗和不可切除治疗中晚期黑色素瘤患者临床管理、治疗模式和结果的真实世界见解。接受辅助治疗的患者早期复发构成了一个特殊挑战，但这些患者通常被排除在一线试验之外。已获批的一线转移性治疗在真实世界环境中非常有效，5年OS率约为50%。然而，对于存在脑转移或一线治疗失败的患者，预后仍然较差。
肿瘤(癌症)患者之家