Sequencing strategy of immunotherapy with chemoradiotherapy in stage III non–small cell lung cancer: A pooled analysis of prospective trials.

Abstract

e20041 Background: Consolidative immunotherapy(IO) after chemoradiotherapy (CRT) is the current standard of care for locally advanced stage III non–small cell lung cancer (NSCLC). Preclinical evidence supports synergistic antitumor effects of radiation and immunotherapy through tumor microenvironment modulation. Emerging clinical studies have demonstrated promising outcomes with combined CRT and IO in stage III NSCLC. However, the optimal sequencing strategy of IO and CRT to maximize survival benefit remains unclear. Methods: We conducted a systematic review of prospective clinical trials evaluating different sequencing strategies of IO combined with CRT in stage III NSCLC. Individual patient data were reconstructed from published Kaplan–Meier curves using a validated algorithm(IPDfromKM). Reconstructed patients were pooled across trials and categorized according to IO starting timing: before CRT(IO induction), concurrent with CRT(ICRT), after CRT(CRT-IO). Progression-free survival (PFS) and overall survival (OS) were analyzed using pooled Cox proportional hazards models. Results: Eleven phase II and III prospective clinical trials involving 2213 patients were included. The immunotherapy included PD-1 and PD-L1 inhibitors. PFS and OS time anchors differed across trials, with IO induction initiating earlier and CRT-IO initiating after completion of CRT. IO induction regimens showed significantly longer PFS than both CRT-IO (HR 0.66, 95% CI 0.56–0.78, p < 0.001) and ICRT (HR 0.65, 95% CI 0.55–0.78, p < 0.001); the median PFS was 31.71 months for IO induction, compared with 15.38 months for CRT-IO and 14.68 months for ICRT. This trend was consistent across IO subtypes. Both IO induction and CRT-IO regimens were associated with significantly better OS than ICRT (IO induction vs ICRT: HR 0.79, 95% CI 0.65–0.96, p = 0.017; CRT-IO vs ICRT: HR 0.82, 95% CI 0.71–0.95, p = 0.007). Median OS was 44.96 months for IO induction, 44.43 months for CRT-IO, and 37.88 months for ICRT. In sensitivity analyses excluding longer induction regimens, the PFS benefit with IO induction was preserved, while OS differences were directionally consistent but less stable. Conclusions: In data pooled across prospective trials, IO induction prior to CRT was associated with longer PFS and favorable OS compared with alternative sequencing strategies. Concurrent initiation of immunotherapy with CRT did not demonstrate survival benefit. Given the heterogeneity in trial design and endpoint anchoring difference, these findings are hypothesis-generating and support prospective evaluation of IO induction strategies. IO Sequencing Strategy Median PFS (mo) HR for PFS (95% CI) Median OS (mo) HR for OS (95% CI) IO induction 31.71 0.65 (0.55–0.78) 44.95 0.79 (0.65–0.96) CRT-IO 15.38 0.99 (0.88–1.12) 44.43 0.82 (0.71–0.95) ICRT 14.68 Ref 37.88 Ref