Safety and efficacy of multi-target TKI combined with nivolumab in check-point inhibitor-refractory patients with advanced NSCLC: a prospective, single-arm, two-stage study
Bo Zhang,
Hongyu Liu,
Chunlei Shi,
Zhiqiang Gao,
Runbo Zhong,
Aiqin Gu,
Tianqing Chu,
Huimin Wang,
Liwen Xiong,
Wei Zhang,
Xueyan Zhang,
Bo Yan,
Jiajun Teng,
Weimin Wang,
Hao Bai,
Rong Qiao,
Lei Cheng,
Yanbin Kuang,
Ruiying Zhao,
Hua Zhong,
Baohui Han
Affiliations
Bo Zhang
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Hongyu Liu
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Chunlei Shi
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Zhiqiang Gao
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Runbo Zhong
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Aiqin Gu
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Tianqing Chu
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Huimin Wang
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Liwen Xiong
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Wei Zhang
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Xueyan Zhang
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Bo Yan
Clinical Research Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Jiajun Teng
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Weimin Wang
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Hao Bai
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Rong Qiao
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Lei Cheng
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Yanbin Kuang
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Ruiying Zhao
Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Hua Zhong
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Baohui Han
Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine
Abstract Background Resistance to immune checkpoint inhibitors (ICIs) represents a major unmet medical need in non-small cell lung cancer (NSCLC) patients. Vascular endothelial growth factor (VEGF) inhibition may reverse a suppressive microenvironment and recover sensitivity to subsequent ICIs. Methods This phase Ib/IIa, single-arm study, comprised dose-finding (Part A) and expansion (Part B) cohorts. Patients with ICIs-refractory NSCLC were enrolled to receive anlotinib (a multi-target tyrosine kinase inhibitor) orally (from days 1 to 14 in a 21-day cycle) and nivolumab (360 mg every 3 weeks, intravenously) on a 21-day treatment cycle. The first 21-day treatment cycle was a safety observation period (phase Ib) followed by a phase II expansion cohort. The primary objectives were recommended phase 2 dose (RP2D, part A), safety (part B), and objective response rate (ORR, part B), respectively. Results Between November 2020 and March 2022, 34 patients were screened, and 21 eligible patients were enrolled (6 patients in Part A). The RP2D of anlotinib is 12 mg/day orally (14 days on and 7 days off) and nivolumab (360 mg every 3 weeks). Adverse events (AEs) of any cause and treatment-related AEs (TRAEs) were reported in all treated patients. Two patients (9.5%) experienced grade 3 TRAE. No grade 4 or higher AEs were observed. Serious AEs were reported in 4 patients. Six patients experienced anlotinib interruption and 4 patients experienced nivolumab interruption due to TRAEs. ORR and disease control rate (DCR) was 19.0% and 76.2%, respectively. Median PFS and OS were 7.4 months (95% CI, 4.3-NE) and 15.2 months (95% CI, 12.1-NE), respectively. Conclusion Our study suggests that anlotinib combined with nivolumab shows manageable safety and promising efficacy signals. Further studies are warranted. Trial registration NCT04507906 August 11, 2020.
