Efficacy and safety of sintilimab in combination with chemotherapy in previously untreated advanced or metastatic nonsquamous or squamous NSCLC: two cohorts of an open-label, phase 1b study

Haiping Jiang, Yulong Zheng, Jiong Qian, Chenyu Mao, Xin Xu, Ning Li, Cheng Xiao, Huan Wang, Lisong Teng, Hui Zhou, Shuyan Wang, Donglei Zhu, Tao Sun, Yingying Yu, Wenying Guo, Nong Xu, Haiping Jiang, Yulong Zheng, Jiong Qian, Chenyu Mao, Xin Xu, Ning Li, Cheng Xiao, Huan Wang, Lisong Teng, Hui Zhou, Shuyan Wang, Donglei Zhu, Tao Sun, Yingying Yu, Wenying Guo, Nong Xu

Abstract

Combining chemotherapy with immunotherapy improves the therapeutic outcome for first-line (1L) patients with advance nonsmall-cell lung cancer (NSCLC). Two cohorts of a phase 1b study (NCT02937116) aimed to evaluate the safety and efficacy of sintilimab, a PD-1 inhibitor, plus chemotherapy in 1L patients with nonsquamous and squamous NSCLC (nsqNSCLC/sqNSCLC); and to identify potential biomarkers for treatment response. Treatment-naïve patients with nsqNSCLC were enrolled and intravenously given sintilimab (200 mg), pemetrexed (500 mg/m2), and cisplatin (75 mg/m2), every 3 weeks (Q3W) for 4 cycles in cohort D. Treatment-naïve patients with sqNSCLC were enrolled and intravenously given sintilimab (200 mg), gemcitabine (1250 mg/m2), and cisplatin (75 mg/m2), Q3W, for 6 cycles in cohort E. The primary objective was to evaluate the safety and efficacy of the treatment. The additional objective was to explore biomarkers for the treatment efficacy. Twenty-one patients with nsqNSCLC, and 20 patients with sqNSCLC were enrolled in cohort D and cohort E, respectively. By the data cutoff (April 17, 2019), 8 (38.1%) patients in cohort D and 17 (85.0%) patients in cohort E experienced grade 3-4 adverse events. The median follow-up duration was 16.4 months (14.8-23.0) in cohort D and 15.9 months (11.7-17.7) in cohort E. The objective response rate was 68.4% (95% CI 43.4%, 87.4%) in cohort D and 64.7% (95% CI 38.3%, 85.8%) in cohort E. Neither PD-L1 expression nor tumor mutation burden value was significantly associated with an improved treatment response. Sintilimab plus chemotherapy exhibited manageable toxicity and an encouraging antitumor activity in patients with nsqNSCLC and sqNSCLC.

Keywords: First line; NSCLC; Sintilimab; TCR; TMB.

Conflict of interest statement

HZ, SYW, and DLZ are employees of Innovent Biologics. TS, YYY, and WYG are staff of Hangzhou ImmuQuad Biotechnologies. The other authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Waterfall plot of the best response to sintilimab-chemo combination therapy. a Cohort D, b Cohort E. PR partial remission, SD stable disease, PD progressive disease, TMB tumor mutation burden
Fig. 2
Fig. 2
Kaplan-Meier curves of progression-free survival. a Cohort D, b Cohort E
Fig. 3
Fig. 3
Response and duration for the patients receiving sintilimab-chemo combination therapy with different PD-L1 expressions and TMB values. a Cohort D, b Cohort E. PR partial remission, PD progressive disease, TMB tumor mutation burden
Fig. 4
Fig. 4
Association of CD8+ T cell receptor (TCR) and treatment efficacy. a TCRCclonality (the ratio of TCR clonality index post- and pre-treatment) between disease control (DC) group and progressive disease (PD) group; b TCRCdiversity (the ratio of TCR diversity index post- and pre-treatment) between DC and PD groups; c TCR clonality tracking within the treatment of every patient; d, e progression-free survival (PFS) and overall survival (OS) stratified by TCRCclonality (> 1 vs. < 1); F and G, PFS and OS stratified by TCRCdiversity (> 1 vs. < 1)

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