Department of Dermatology, University Hospital Essen & German Cancer Consortium (DKTK), Partner Site Essen, Germany.
Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, Germany.
Eur J Cancer. 2022 May;167:32-41. doi: 10.1016/j.ejca.2022.02.023. Epub 2022 Mar 30.
OBJECTIVES: Forty to sixty percent of patients with advanced melanoma show primary resistance to PD-1-based immunotherapy, 30-40% of initial responders also progress. Here, we evaluated the outcome of second-line targeted therapy (TT) after progression on PD-1-based immune checkpoint inhibition (ICI) in BRAFV600-mutated melanoma. In addition, we report data on the activity of re-exposure with PD-1-based regimes. METHODS: Patients with advanced (non-resectable stage III or IV, AJCC 2017, 8th edition) melanoma progressing on PD-1-based ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line BRAF plus MEK inhibition were identified from the prospective multicenter skin cancer registry ADOREG. RESULTS: We identified 108 patients with unresectable stage III or stage IV melanoma progressing on first-line ICI (nivolumab, pembrolizumab or ipilimumab plus nivolumab) and receiving second-line combined BRAF/MEK inhibition. Seventy-three percent of the cohort presented with primary PD-1 resistant disease. Median progression-free survival (PFS) on ICI was 2.6 (95% CI 2.2-2.9) months. Median PFS on subsequent TT was 6.6 (95% CI 5.4-7.8) months. Median OS from start of second-line TT was 16.0 (95% CI 11.2-20.8) months. The 3-year PFS and OS rates on second-line TT were 16% and 30%. The objective response rate (ORR) and disease control rate (DCR) to TT were 42.6% and 55.6%. In patients with brain metastases, the ORR and DCR were 31.4% and 43.1%. Patients without brain metastases showed an ORR and DCR of 52.6% and 66.7%, respectively. Response to first-line ICI was associated with a numerically higher ORR and DCR to second-line TT and improved OS on TT. Twenty-three patients received third-line ICI of whom two patients showed an objective response. CONCLUSIONS: BRAF plus MEK inhibition shows meaningful activity and outcome in patients with advanced melanoma resistant to anti-PD-1-based immunotherapy. Rates of long-term benefit and survival in our study were similar to those reported for treatment-naïve patients receiving first-line MAPKi.
目的：40%至 60%的晚期黑色素瘤患者对 PD-1 为基础的免疫治疗表现出原发性耐药，30%至 40%的初始应答者也会进展。在这里，我们评估了 PD-1 为基础的免疫检查点抑制（ICI）治疗后进展的 BRAFV600 突变黑色素瘤患者二线靶向治疗（TT）的结果。此外，我们还报告了重新使用 PD-1 为基础方案治疗的疗效数据。
方法：从前瞻性多中心皮肤癌登记处 ADOREG 中确定了进展期（不可切除的 III 或 IV 期，AJCC 2017 第 8 版）黑色素瘤患者，这些患者接受 PD-1 为基础的 ICI（nivolumab、pembrolizumab 或 ipilimumab 加 nivolumab）治疗后进展，并接受二线 BRAF 加 MEK 抑制治疗。
结果：我们确定了 108 例不可切除的 III 期或 IV 期黑色素瘤患者，这些患者在接受一线 ICI（nivolumab、pembrolizumab 或 ipilimumab 加 nivolumab）治疗后进展，并接受二线联合 BRAF/MEK 抑制治疗。该队列中有 73%的患者表现为原发性 PD-1 耐药疾病。ICI 治疗的中位无进展生存期（PFS）为 2.6（95%CI 2.2-2.9）个月。随后 TT 的中位 PFS 为 6.6（95%CI 5.4-7.8）个月。二线 TT 开始后中位 OS 为 16.0（95%CI 11.2-20.8）个月。二线 TT 的 3 年 PFS 和 OS 率分别为 16%和 30%。TT 的客观缓解率（ORR）和疾病控制率（DCR）分别为 42.6%和 55.6%。在有脑转移的患者中，ORR 和 DCR 分别为 31.4%和 43.1%。无脑转移的患者的 ORR 和 DCR 分别为 52.6%和 66.7%。一线 ICI 的缓解与二线 TT 的更高的 ORR 和 DCR 以及 TT 的 OS 改善相关。23 例患者接受了三线 ICI 治疗，其中 2 例患者有客观缓解。
结论：BRAF 加 MEK 抑制在抗 PD-1 为基础免疫治疗耐药的晚期黑色素瘤患者中具有显著的疗效和结局。在我们的研究中，长期获益和生存的比例与接受一线 MAPKi 治疗的初治患者相似。
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Zotero 插件