Neoadjuvant retlirafusp alfa (anti-PD-L1/TGF-β bifunctional fusion protein) with or without chemotherapy in unresectable stage III non-small cell lung cancer: updated results from the phase 2 TRAILBLAZER trial

TRAILBLAZER is a proof-of-concept phase 2 study (ClinicalTrials.gov, NCT04580498) of neoadjuvant retlirafusp alfa (an anti-PD-L1/TGF-β bifunctional agent) in unresectable stage III non-small cell lung cancer (NSCLC) not harboring EGFR or ALK alterations. During induction, retlirafusp alfa was administered either with chemotherapy or as monotherapy, followed by surgery or radiotherapy as assessed by a local multidisciplinary team and consolidation retlirafusp alfa. Patients without high PD-L1 expression were allocated to retlirafusp alfa plus chemotherapy (arm A; n = 88); patients with high PD-L1 expression were randomly allocated at a 1:1 ratio to retlirafusp alfa combination (arm B; n = 9) or monotherapy (arm C; n = 10). In this updated analysis (data cutoff, March 24, 2025), the median follow-up was 39.4 months. The event-free survival (EFS) rate at 3 years was 50.5% (95% CI 39.0–61.0) in arm A + B and 77.1% (34.5–93.9) in arm C; the corresponding overall survival (OS) rates at 3 years were 68.3% (95% CI 57.5–77.0) and 87.5% (38.7–98.1), respectively. Among 27 patients who underwent surgery, the 3-year EFS and OS rates were 69.5% (95% CI 48.1–83.5) and 84.9% (64.5–94.0), respectively, versus 50.8% (36.5–63.4) and 70.4% (56.7–80.5), respectively, in radiotherapy-treated patients. The safety data were consistent with those in a previous report. With extended follow-up, the study regimen showed sustained survival benefits with no new safety signals. Patients who underwent surgery after induction treatment achieved clinically meaningful survival gains. Our findings support the use of neoadjuvant immunotherapy with a response-adapted surgical strategy as a promising approach for unresectable stage III NSCLC.