Background: In ORIENT-11, addition of sintilimab to first-line chemotherapy demonstrated improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in Chinese patients with AMnsqNSCLC. This SLR and NMA compared the efficacy and safety of sintilimab+pemetrexed+platinum versus FDA-approved and NCCN-recommended immune checkpoint inhibitor combinations (ICIs) for first-line treatment of AMnsqNSCLC.

Methods: SLR followed the PRISMA guideline. Eligible studies were phase 2 and 3 RCTs published in English between 1991 and September 2021 comparing efficacy or safety of ICIs with other treatments for AMnsqNSCLC without EGFR/ALK mutations. Bayesian fixed and random effects NMA with independent baseline models were used, and chemotherapy was the common comparator. PFS, OS, ORR, and exposure-adjusted adverse events(AEs) were the key outcomes analyzed. Hazard ratios(HR)<1.0, odds ratios(OR)>1.0, and median exposure-adjusted rate difference(D)>0 favored the reference treatment, sintilimab+pemetrexed+platinum.

Results: After screening 6,418 records, 11 RCTs involving a total of 4,979 eligible patients regardless of PD-L1 status were included in the primary evidence network. ICIs with chemotherapy were generally superior to chemotherapy alone. For PFS, pembrolizumab+pemetrexed+platinum(HR 0.96 [95% Credible Interval: 0.71-1.30]) and atezolizumab+bevacizumab+platinum+nab-paclitaxel(0.83 [0.57-1.19]) were not significantly different to sintilimab+pemetrexed+platinum. Sintilimab+pemetrexed+platinum had significantly better PFS compared to atezolizumab+platinum+nab-paclitaxel(0.57[0.40-0.82]) and nivolumab+ipilimumab+pemetrexed+platinum(0.66[0.48-0.92]). Sintilimab+pemetrexed+platinum was not significantly different for OS: atezolizumab+bevacizumab+platinum+nab-paclitaxel(0.85[0.59-1.23]), atezolizumab+platinum+nab-paclitaxel(0.81[0.56-1.17]), pembrolizumab+pemetrexed+platinum(1.08[0.79-1.47]), nivolumab+ipilimumab+pemetrexed+platinum(0.95[0.67-1.34]), and nivolumab+ipilimumab(0.83[0.61-1.13]). Rate of Grade≥3 AEs(D range:-0.35-0.84) and ORR(OR range:0.73-1.91) were comparable across ICIs.

Conclusions: This NMA showed that sintilimab+pemetrexed+platinum was associated with comparable efficacy and safety versus standard-of-care ICIs in the US, further supporting the favorable benefit/risk profile of ICI versus chemotherapy among patients with previously untreated AMnsqNSCLC and no EGFR or ALK mutations. The results may aid clinical decision-making and future cost-effectiveness evaluation of ICIs in the absence of head-to-head evidence from RCTs.