Objectives

Both combinations of the PARP inhibitor veliparib plus platinum doublet chemotherapy (CT), and the programmed death receptor-1 (PD-1) inhibitor nivolumab plus CT have demonstrated encouraging efficacy for treatment of non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study (NCT02944396) evaluated the quadruple combination of veliparib with nivolumab and doublet CT in patients with unresectable advanced/metastatic NSCLC.

Materials and methods

Patients were enrolled into five dosing cohorts: patients received veliparib 120 mg twice daily (BID) combined with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and paclitaxel 200 mg/m² (C/PAC) or veliparib 80/120/200/240 mg BID in combination with nivolumab 360 mg, carboplatin AUC 6 mg/mL∙min, and pemetrexed 500 mg/m² (C/PEM). Primary objective was to identify the recommended phase 2 dose (RP2D) of veliparib + nivolumab + CT. Safety, tolerability, and efficacy of this combination were also assessed.

Results

Twenty-five patients were enrolled: 6 patients received veliparib 120 mg BID + nivolumab + C/PAC and 19 received veliparib (80–240 mg BID) + nivolumab + C/PEM. No dose-limiting toxicities were reported, and the RP2Ds were veliparib 120 mg BID + nivolumab + C/PAC, and veliparib 240 mg BID + nivolumab + C/PEM. The most common any-grade adverse events (AEs) were fatigue (56%), nausea (52%), and anemia (48%). Grade 3/4 AEs included anemia (32%) and neutropenia (24%), and the most frequent serious AE was malignant neoplasm progression (12%). Veliparib exhibited approximately dose proportional kinetics in the dose range 80–240 mg BID combined with nivolumab and C/PEM, with no effects on pemetrexed pharmacokinetics. Overall, the confirmed objective response rate was 40%, and best overall response was 64%.

Conclusion

Veliparib combined with nivolumab and platinum doublet CT was tolerated in patients with advanced/metastatic NSCLC, and no evidence of drug–drug interaction was observed. Although preliminary, this quadruple therapy may have promising antitumor activity.

中文翻译：

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Veliparib 和 nivolumab 联合铂类双药化疗治疗转移性或晚期非小细胞肺癌：一项 1 期剂量递增研究

目标

PARP 抑制剂 veliparib 加铂双药化疗 (CT) 和程序性死亡受体-1 (PD-1) 抑制剂纳武单抗加 CT 的两种组合在治疗非小细胞肺癌 (NSCLC) 方面都表现出令人鼓舞的疗效。这项 1 期剂量递增研究 (NCT02944396) 在不可切除的晚期/转移性 NSCLC 患者中评估了 veliparib 与纳武单抗和双联 CT 的四联组合。

材料和方法

患者被纳入五个给药队列：患者接受 veliparib 120 mg 每天两次 (BID) 联合 nivolumab 360 mg、卡铂 AUC 6 mg/mL∙min 和紫杉醇 200 mg/m ² (C/PAC) 或 veliparib 80/120 /200/240 mg BID 与 nivolumab 360 mg、卡铂 AUC 6 mg/mL∙min 和培美曲塞 500 mg/m ² (C/PEM) 组合。主要目标是确定 veliparib + nivolumab + CT 的推荐 2 期剂量 (RP2D)。还评估了这种组合的安全性、耐受性和有效性。

结果

25 名患者入组：6 名患者接受 veliparib 120 mg BID + nivolumab + C/PAC，19 名患者接受 veliparib (80–240 mg BID) + nivolumab + C/PEM。未报告剂量限制性毒性，RP2D 为 veliparib 120 mg BID + nivolumab + C/PAC 和 veliparib 240 mg BID + nivolumab + C/PEM。最常见的任何级别的不良事件 (AE) 是疲劳 (56%)、恶心 (52%) 和贫血 (48%)。3/4 级 AE 包括贫血 (32%) 和中性粒细胞减少 (24%)，最常见的严重 AE 是恶性肿瘤进展 (12%)。Veliparib 在 80-240 mg BID 的剂量范围内表现出近似的剂量比例动力学，联合纳武单抗和 C/PEM，对培美曲塞的药代动力学没有影响。总体而言，确认的客观反应率为 40%，最佳总体反应率为 64%。

结论

Veliparib 联合纳武单抗和铂双联 CT 在晚期/转移性 NSCLC 患者中是耐受的，并且没有观察到药物相互作用的证据。尽管是初步的，但这种四联疗法可能具有有希望的抗肿瘤活性。