Predictive value of TTF-1 expression for stratifying outcomes between dual ICI and chemoimmunotherapy in patients with PD-L1-negative NSCLC

Background: Thyroid transcription factor-1 (TTF-1) has emerged as a novel predictive biomarker associated with the prognosis and treatment response of non-squamous non-small-cell lung cancer (NSCLC) to cytotoxic chemotherapy. This study evaluated the clinical significance of TTF-1 expression in advanced NSCLC with programmed death-ligand 1 (PD-L1) < 1%, with a specific focus on its utility in stratifying treatment outcomes between dual immune checkpoint inhibitor (IO–IO) therapy and chemoimmunotherapy. Methods: We conducted a multicenter retrospective study across 22 Japanese institutions, evaluating 194 patients with advanced or recurrent non-squamous NSCLC and PD-L1 < 1% treated with IO–IO therapy or chemoimmunotherapy between 2019 and 2022. Survival outcomes were analyzed using multivariable Cox regression. Results: TTF-1-positive patients had significantly longer progression-free survival (PFS) and overall survival (OS) than TTF-1-negative patients [adjusted hazard ratio (HR) for PFS: 0.65, p = 0.009; adjusted HR for OS: 0.69, p = 0.04]. Among TTF-1-positive patients, no significant difference in survival was observed between IO–IO therapy and chemoimmunotherapy. By contrast, TTF-1-negative patients experienced significantly improved outcomes with chemoimmunotherapy than with IO–IO therapy (adjusted HR for PFS: 0.37, p = 0.01; adjusted HR for OS: 0.39, p = 0.02). Conclusion: TTF-1 expression may serve as a prognostic and potentially predictive biomarker in PD-L1-negative NSCLC patients. TTF-1-negative patients appeared to derive greater benefit from the addition of chemotherapy. These findings suggest that TTF-1 expression may have potential utility in guiding treatment selection and warrant prospective validation.