目的:淋巴细胞活化基因-3(LAG-3)和PD-1受体的Coblockade可以为晚期黑色素瘤患者提供显着的临床益处。Fianlimab和cemiplimab是高亲和力的,人类,铰链稳定的IgG4单克隆抗体,分别靶向LAG-3和PD-1。我们报告了fianlimab和cemiplimab在包括晚期黑色素瘤在内的各种恶性肿瘤中的安全性和有效性的人类I期首次研究的结果。
方法:患有晚期黑色素瘤的患者有资格进入四个队列:三个患者为未患有晚期疾病的患者,一个患者为先前使用抗PD-1治疗的患者。患者每3周一次静脉注射fianlimab1,600mg和cemiplimab350mg,持续51周,如果有临床指征,可选择额外的51周。主要终点是根据RECIST1.1标准的客观缓解率(ORR)。
结果:抗PD-1初治黑色素瘤患者的ORR为63%(队列-6;n=40;中位随访20.8个月),63%用于全身治疗初治黑色素瘤患者(队列-15;n=40;11.5个月),曾接受过新/辅助治疗的黑色素瘤患者为56%(队列16;n=18,9.7个月)。合并队列的中位随访时间为12.6个月(6+15+16),ORR为61.2%,中位无进展生存期(mPFS)为13.3个月(95%CI,7.5~未估计[NE]).在以前接受过抗PD-1辅助治疗的患者(n=13)中,ORR为61.5%,mPFS为12个月(95%CI,NE为1.4)。先前接受过晚期疾病抗PD-1治疗的患者(n=15)的ORR为13.3%,mPFS为1.5个月(95%CI,1.3至7.7)。44%和22%的患者观察到治疗紧急和治疗相关的不良事件≥3级(G3)。分别。除了肾上腺功能不全的发生率增加(12%-G1-4,4%-G3-4),没有新的安全信号记录.
结论:目前的结果显示,fianlimab/cemiplimab联合治疗晚期黑色素瘤患者具有良好的获益-风险特征,包括那些以前在辅助治疗中抗PD-1的患者,但不是先进的,设置。
OBJECTIVE: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I
study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma.
METHODS: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria.
RESULTS: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded.
CONCLUSIONS: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.