Objectives

This first-in-human phase I study (NCT03179436) investigated anti–cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti–programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab+pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non–small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy.

Materials and Methods

Patients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumors v1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints.

Results

Forty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7-33) among all patients, 7% (<1-34) for PD-L1–positive tumors (n=14), and 19% (5-42) for PD-L1–negative tumors (n=21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%.

Conclusions

Encouraging antitumor activity was observed with quavonlimab+pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1–positive and PD-L1–negative tumors. The combination was tolerable with manageable toxicities.

中文翻译：

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抗细胞毒性 T 淋巴细胞相关抗原 4 单克隆抗体 quavonlimab 联合派姆单抗：来自先前治疗的广泛期小细胞肺癌 I 期研究的安全性和有效性

目标

这项首次人体 I 期研究 (NCT03179436) 在晚期实体瘤患者中研究了抗细胞毒性 T 淋巴细胞相关蛋白 4 单克隆抗体 quavonlimab 和抗程序性死亡 1 单克隆抗体 pembrolizumab。该研究分两部分进行：剂量递增（第 1 部分）和剂量确认（第 2 部分）。quavonlimab + pembrolizumab 的一线治疗具有令人鼓舞的抗肿瘤活性（客观缓解率 [ORR]，28%-40%）并且总体耐受性良好（使用 quavonlimab 25 mg 每次治疗时，≥3 级的治疗相关不良事件 [TRAEs] 最低6 周 [Q6W] 为 30%，quavonlimab 75 mg Q3W 为 57%，在非小细胞肺癌中最高。我们提供了接受二线或后续治疗的广泛期小细胞肺癌 (SCLC) 患者的数据。

材料和方法

III/IV 期 SCLC 患者接受 quavonlimab 75 mg Q6W 加 p​​embrolizumab 200 mg Q3W ≤2 年。主要终点是安全性和耐受性；根据实体瘤中的反应评估标准 v1.1通过盲法独立中央审查评估的 ORR是次要终点。无进展生存期 (PFS)、总生存期 (OS) 以及反应与 PD-L1 表达的相关性是探索性终点。

结果

40 名广泛期 SCLC 患者接受了治疗；中位随访时间为 13 个月。4 名患者 (10%) 发生了剂量限制性毒性。80% 的患者发生了 TRAE；33% 的患者发生了 3 级事件，并且没有报告 4/5 级事件。所有患者中确认的 ORR (95% CI) 为 18% (7-33)，PD-L1 阳性肿瘤 ( n = 14)为 7% (<1-34)，PD 为19% (5-42) -L1-阴性肿瘤（n = 21）。反应持续时间从 2.9 到 19.1+ 个月不等。中位 PFS 为 2.0 个月；6 个月 PFS 率为 26%。中位 OS 为 11.0 个月；6 个月 OS 率为 66%。

结论

quavonlimab + pembrolizumab 在广泛期 SCLC 患者中观察到令人鼓舞的抗肿瘤活性；在 PD-L1 阳性和 PD-L1 阴性肿瘤中观察到反应。这种组合是可以忍受的，毒性可控。