Combination of immune checkpoint inhibitors with multi-targeted tyrosine kinase inhibitors for second- or later-line therapy of non-small cell lung cancer: a systematic review and meta-analysis.

Background: Second- or later-line therapy for patients with advanced non-small cell lung cancer (NSCLC) is highly individualized. Combining immune checkpoint inhibitors (ICIs) with multi-targeted tyrosine kinase inhibitors (multi-TKIs) has emerged as a chemotherapy-free option for these patients. We aim to provide a comprehensive overview of the efficacy and safety of the treatment. Methods: We systematically searched four databases for studies evaluating ICIs combined with multi-TKIs in second- or later-line therapy for NSCLC. Data were extracted and study quality was assessed using the Canadian Institute of Health Economics tool for case series. A systematic review and meta-analysis were conducted for efficacy outcomes. Results: Twenty studies (10 prospective and 10 retrospective) were included from 155 retrieved articles. Nineteen studies were conducted in China, with programmed death receptor 1 (PD-1) antibodies and anlotinib as the most frequently used combination. The single-arm meta-analysis showed that the pooled median progression-free survival (mPFS) was 5.74 months [95% confidence interval (CI): 4.65-6.84], and the median overall survival was 15.41 months (95% CI: 13.40-17.41). The objective response rate was 26.35% (95% CI: 19.52-33.18%), and the disease control rate was about 80.73% (95% CI: 75.59-85.86%). For patients with EGFR/ALK/ROS1 mutations, the mPFS was 3.17 months (95% CI: 2.54-3.79). The most commonly reported severe adverse events across the included studies were hypertension, fatigue, hepatic dysfunction, urinary abnormalities, and hand-foot syndrome. Conclusions: The combination of ICIs and multi-TKIs offers an alternative chemotherapy-free treatment option for patients with advanced NSCLC in the second- or later-line setting.