Department of Biomedical Sciences, Humanitas University, Milan, Italy.
Department of Oncology and Hematology, IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Via Manzoni 56, Rozzano-Milan, 20089, Italy.
BMC Cancer. 2024 Oct 24;24(1):1307. doi: 10.1186/s12885-024-12841-2.
BACKGROUND: Despite promising outcomes of treatment with anti-programmed cell death (PD)-1/PD-ligand (L)1 agents in combination with platinum-doublet chemotherapy (PDC) in the first-line setting, a significant unmet medical need remains in patients with PD-L1-unselected non-small cell lung cancer (NSCLC). METHODS: This multicenter, open-label, phase 1b study comprising dose-confirmation and dose-expansion parts investigated the combination of spartalizumab and various PDC regimens, with or without canakinumab, in treatment-naïve patients with PD-L1-unselected, metastatic NSCLC. The primary objectives were to determine maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of spartalizumab, with or without canakinumab, in combination with PDC in the dose-confirmation part and antitumor activity of spartalizumab in the dose-expansion part. RESULTS: The MTD/RDE of spartalizumab was 300 mg every 3 weeks (Q3W) when administered with either gemcitabine (1250 mg/m)/cisplatin (75 mg/m) (group A; no dose-limiting toxicities [DLTs]), pemetrexed (500 mg/m)/cisplatin (group B; 2 DLTs: grade 2 posterior reversible encephalopathy syndrome and grade 4 hyponatremia), or paclitaxel (200 mg/m)/carboplatin area under the curve 6 min*mg/mL (group C; 1 DLT: grade 4 neutropenic colitis). The RDE of canakinumab combined with spartalizumab and pemetrexed/cisplatin (group E; no DLTs) was 200 mg Q3W (no dose-expansion part was initiated). No new safety signals were identified. In groups A, B, C, and E, the overall response rates were 57.6%, 55.3%, 51.5%, and 57.1%, respectively. Group B compared with other groups had the longest median progression-free survival (10.4 months vs. 6.2-7.5 months), overall survival (29.7 months vs. 16.1-21.0 months), and duration of response (30.1 months vs. 6.0-8.2 months). CONCLUSIONS: The combination of spartalizumab and PDC, with or without canakinumab, was well tolerated across treatment groups. The antitumor activity across treatment groups was comparable with that of pembrolizumab and pemetrexed combination. Canakinumab did not appear to improve the antitumor activity when combined with spartalizumab, pemetrexed and cisplatin. TRIAL REGISTRATION: The trial was registered in Clinicaltrials.gov with identifier no. NCT03064854. Date of Registration: 06 February 2017.
背景：尽管在一线治疗中，抗程序性死亡（PD）-1/PD-配体（L）1 药物联合铂类双联化疗（PDC）在治疗上取得了有前景的结果，但 PD-L1 未选择的非小细胞肺癌（NSCLC）患者仍存在显著未满足的医疗需求。
方法：本研究为多中心、开放标签、1b 期剂量确证和扩展部分研究，评估了 spartalizumab 联合不同 PDC 方案（有或无 canakinumab）在 PD-L1 未选择的转移性 NSCLC 初治患者中的疗效。主要目的是确定 spartalizumab 联合 PDC 在剂量确证部分的最大耐受剂量（MTD）和/或扩展剂量（RDE），以及 spartalizumab 在剂量扩展部分的抗肿瘤活性。
结果：在剂量确证部分，当与吉西他滨（1250 mg/m）/顺铂（75 mg/m）（A 组；无剂量限制毒性[DLT]）、培美曲塞（500 mg/m）/顺铂（B 组；2 例 DLT：2 级后部可逆性脑病综合征和 4 级低钠血症）或紫杉醇（200 mg/m）/卡铂 AUC6min*mg/mL（C 组；1 例 DLT：4 级中性粒细胞结肠炎）联合使用时，spartalizumab 的 MTD/RDE 为 300mg，每 3 周（Q3W）一次。在联合培美曲塞/顺铂时，canakinumab 的 RDE 为 200mg，每 3 周（Q3W）一次（无剂量扩展部分）。未发现新的安全性信号。在 A、B、C 和 E 组中，总缓解率分别为 57.6%、55.3%、51.5%和 57.1%。B 组与其他组相比，中位无进展生存期（10.4 个月比 6.2-7.5 个月）、总生存期（29.7 个月比 16.1-21.0 个月）和缓解持续时间（30.1 个月比 6.0-8.2 个月）最长。
结论：spartalizumab 联合 PDC（有或无 canakinumab）在各治疗组中均具有良好的耐受性。各治疗组的抗肿瘤活性与 pembrolizumab 和 pemetrexed 联合治疗相当。当与 spartalizumab、培美曲塞和顺铂联合使用时，canakinumab 似乎并未提高抗肿瘤活性。
试验注册：该试验在 Clinicaltrials.gov 上注册，注册号为 NCT03064854。注册日期：2017 年 2 月 6 日。
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