Efficacy and safety of immune checkpoint inhibition combined with concurrent chemoradiotherapy in patients with stage III unresectable non-small cell lung cancer: A systematic review and meta-analysis

Background: In patients with unresectable, stage III non-small cell lung cancer (NSCLC), durvalumab maintenance after concurrent chemoradiotherapy (cCRT) was shown to improve survival over placebo. As subgroup analyses indicated better outcomes with earlier start of durvalumab, several trials evaluated concomitant checkpoint inhibition (CPI) with cCRT. However, this may introduce an increased risk of treatment-related pulmonary toxicity. Methods: We conducted a systematic review and meta-analysis of clinical trials of combined cCRT plus CPI followed by CPI maintenance in patients with stage III NSCLC. Endpoints included incidence of pneumonitis by any cause, objective response rate (ORR), progression-free (PFS), and overall survival (OS). Results: A total of 7 trials comprising 653 patients were included. In trials of single-agent CPI with cCRT, pneumonitis occurred in 33 % of patients (95 % confidence interval [CI], 28-39) with 7 % (5-9) having CTCAE grade 3-5. In one trial, double CPI (PD-1 and CTLA4) plus cCRT was associated with excessive pneumonitisrelated mortality of 16 % (4-40). Across all trials, ORR was 69 % (63-76). Median PFS and OS were 16.3 (95 % CI, 14.0-20.5) and 39.5 months (35.3-45.9), respectively. Three-year PFS and OS were 36.8 % (95 % CI, 32.7-41.4) and 53.1 % (49.1-57.4). Sensitivity analysis showed that induction chemoimmunotherapy prior cCRT plus CPI was associated with improved PFS of 48.0 % at 3 years (95 % CI, 40.7-56.7) in one trial. Discussion: Addition of single-agent CPI to cCRT is manageable in selected patients with stage III NSCLC. Efficacy outcomes appear to be in line with previous data of cCRT followed by CPI maintenance.