Purpose: Preclinical data indicate that fianlimab (anti-lymphocyte activation gene-3) plus cemiplimab (anti-programmed cell death-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies. Experimental Design: Adult patients received fianlimab 1−40 mg/kg ± cemiplimab 350 mg every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were rate of dose-limiting toxicities, adverse events (including immune-mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of response, and antidrug antibody variables. Results: Seventy-eight patients were enrolled (fianlimab + cemiplimab, n = 47; fianlimab monotherapy, n = 31). One patient treated with 3 mg/kg fianlimab + cemiplimab experienced dose-limiting toxicities, including increased blood creatine phosphokinase and myasthenic syndrome. No maximum tolerated dose was reached. Any-grade treatment-emergent adverse events occurred in 90% of patients with fianlimab monotherapy, 87% with fianlimab + cemiplimab, and 87% who transitioned from monotherapy to combination therapy. Fianlimab pharmacokinetics were dose-proportional, and similar in monotherapy and combination therapy. Across patients who received fianlimab + cemiplimab, five achieved a partial response; three of whom experienced a response after transitioning from monotherapy to combination therapy. Fianlimab 1600 mg Q3W (20 mg/kg in an 80 kg individual) is the selected dose for phase 2 and 3 studies. Conclusions: Fianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent with previous reports of cemiplimab.

中文翻译：

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抗淋巴细胞活化基因 3 抗体 Fianlimab 与 Cemiplimab 在晚期恶性肿瘤患者中的首次人体剂量递增研究


目的：临床前数据表明，fianlimab （抗淋巴细胞活化基因-3） 加 cemiplimab （抗程序性细胞死亡-1） 可增强抗肿瘤活性。在这里，我们报告了 fianlimab 作为单一疗法和与 cemiplimab 联合治疗晚期恶性肿瘤患者的首次人体 1 期研究 （NCT03005782） 剂量递增部分的预先指定最终分析。实验设计： 成年患者接受 fianlimab 1-40 mg/kg ± cemiplimab 350 mg 每 3 周 （Q3W） 各种剂量递增方案。主要目标是剂量限制性毒性、不良事件 （包括免疫介导） 、死亡、实验室异常和药代动力学的发生率。次要结局是客观缓解率、最佳总体缓解、缓解持续时间和抗药抗体变量。结果： 纳入 78 例患者 （fianlimab + cemiplimab，n = 47;fianlimab 单药治疗，n = 31）。1 例接受 3 mg/kg fianlimab + cemiplimab 治疗的患者出现剂量限制性毒性，包括血肌酸磷酸激酶升高和肌无力综合征。未达到最大耐受剂量。90% 的 fianlimab 单药治疗患者、87% 的 fianlimab + cemiplimab 患者以及 87% 的从单药治疗过渡到联合治疗的患者发生了任何级别治疗中出现的不良事件。Fianlimab 的药代动力学是剂量比例的，在单药治疗和联合治疗中相似。在接受 fianlimab + cemiplimab 治疗的患者中，5 例达到部分缓解;其中 3 例在从单一疗法过渡到联合疗法后出现了反应。Fianlimab 1600 mg Q3W（80 kg 个体中为 20 mg/kg）是 2 期和 3 期研究的选择剂量。 结论： Fianlimab 作为单药治疗和与 cemiplimab 联合治疗显示出可接受的安全性和初步的抗肿瘤活性，这与 cemiplimab 的既往报道基本一致。