Melanoma Institute Australia, The University of Sydney, North Sydney, New South Wales, Australia.
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
J Immunother Cancer. 2022 Jul;10(7). doi: 10.1136/jitc-2022-004610.
Patients with V600BRAF mutant metastatic melanoma have higher rates of progression-free survival (PFS) and overall survival (OS) with first-line anti-PD1 (PD1]+anti-CTLA-4 (IPI) versus PD1. Whether this is also true after BRAF/MEKi therapy is unknown. We aimed to determine the efficacy and safety of PD1 versus IPI +PD1 after BRAF/MEK inhibitors (BRAF/MEKi).
Patients with V600BRAF mutant metastatic melanoma treated with BRAF/MEKi who had subsequent PD1 versus IPI+PD1 at eight centers were included. The endpoints were objective response rate (ORR), PFS, OS and safety in each group.
Of 200 patients with V600E (75%) or non-V600E (25%) mutant metastatic melanoma treated with BRAF/MEKi (median time of treatment 7.6 months; treatment cessation due to progressive disease in 77%), 115 (57.5%) had subsequent PD1 and 85 (42.5%) had IPI+PD1. Differences in patient characteristics between PD1 and IPI+PD1 groups included, age (med. 63 vs 54 years), time between BRAF/MEKi and PD1±IPI (16 vs 4 days), Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥1 (62% vs 44%), AJCC M1C/M1D stage (72% vs 94%) and progressing brain metastases at the start of PD1±IPI (34% vs 57%). Median follow-up from PD1±IPI start was 37.8 months (95% CI, 33.9 to 52.9). ORR was 36%; 34% with PD1 vs 39% with IPI+PD1 (p=0.5713). Median PFS was 3.4 months; 3.4 with PD1 vs 3.6 months with IPI+PD1 (p=0.6951). Median OS was 15.4 months; 14.4 for PD1 vs 20.5 months with IPI+PD1 (p=0.2603). The rate of grade 3 or 4 toxicities was higher with IPI+PD1 (31%) vs PD1 (7%). ORR, PFS and OS were numerically higher with IPI+PD1 vs PD1 across most subgroups except for females, those with <10 days between BRAF/MEKi and PD1±IPI, and those with stage III/M1A/M1B melanoma. The combination of ECOG PS=0 and absence of liver metastases identified patients with >3 years OS (area under the curve, AUC=0.74), while ECOG PS ≥1, progressing brain metastases and presence of bone metastases predicted primary progression (AUC=0.67).
IPI+PD1 and PD1 after BRAF/MEKi have similar outcomes despite worse baseline prognostic features in the IPI+PD1 group, however, IPI+PD1 is more toxic. A combination of clinical factors can identify long-term survivors, but less accurately those with primary resistance to immunotherapy after targeted therapy.
与 PD1 相比，V600BRAF 突变转移性黑色素瘤患者接受一线抗 PD1（PD1]+抗 CTLA-4（IPI）治疗具有更高的无进展生存期（PFS）和总生存期（OS）。在 BRAF/MEKi 治疗后是否也是如此尚不清楚。我们旨在确定 PD1 与 BRAF/MEKi 后 PD1 与 IPI+PD1 的疗效和安全性。
纳入在 8 个中心接受 BRAF/MEKi 治疗的 V600BRAF 突变转移性黑色素瘤患者，随后接受 PD1 与 IPI+PD1 治疗。终点是每组的客观缓解率（ORR）、PFS、OS 和安全性。
在 200 名接受 BRAF/MEKi 治疗的 V600E（75%）或非 V600E（25%）突变转移性黑色素瘤患者中（中位治疗时间为 7.6 个月；77%因疾病进展而停止治疗），115 名（57.5%）患者随后接受 PD1 治疗，85 名（42.5%）患者接受 IPI+PD1 治疗。PD1 和 IPI+PD1 组之间患者特征的差异包括年龄（中位数 63 岁 vs 54 岁）、BRAF/MEKi 与 PD1±IPI 之间的时间（16 天 vs 4 天）、东部合作肿瘤学组表现状态（ECOG PS）≥1（62% vs 44%）、AJCC M1C/M1D 期（72% vs 94%）和开始 PD1±IPI 时进展性脑转移（34% vs 57%）。从 PD1±IPI 开始的中位随访时间为 37.8 个月（95%CI，33.9 至 52.9）。ORR 为 36%；PD1 为 34%，IPI+PD1 为 39%（p=0.5713）。中位 PFS 为 3.4 个月；PD1 为 3.4 个月，IPI+PD1 为 3.6 个月（p=0.6951）。中位 OS 为 15.4 个月；PD1 为 14.4 个月，IPI+PD1 为 20.5 个月（p=0.2603）。IPI+PD1 的 3 级或 4 级毒性发生率高于 PD1（31% vs 7%）。除女性、BRAF/MEKi 与 PD1±IPI 之间<10 天和 III/M1A/M1B 期黑色素瘤患者外，IPI+PD1 与 PD1 相比，ORR、PFS 和 OS 在大多数亚组中均较高。ECOG PS=0 且无肝转移可识别出 OS 超过 3 年的患者（曲线下面积，AUC=0.74），而 ECOG PS≥1、进展性脑转移和存在骨转移可预测原发性进展（AUC=0.67）。
尽管 IPI+PD1 组的基线预后特征较差，但与 BRAF/MEKi 后 IPI+PD1 和 PD1 相比，两者具有相似的结果，但 IPI+PD1 毒性更大。临床因素的组合可以识别出长期存活者，但对靶向治疗后免疫治疗原发性耐药的患者的识别准确性较低。
