# TTF-1 Negativity Predicts Poor Outcomes in Advanced Non-Squamous NSCLC Also in the Immunotherapy Era: A Multicenter Cohort Study and Meta-Analysis

## TL;DR

TTF-1 negativity is linked to worse outcomes in lung cancer patients receiving immunotherapy, even when PD-L1 levels are high, suggesting it could help guide treatment decisions.

## Contribution

This study shows TTF-1 is an independent predictor of poor prognosis in immunotherapy-treated non-squamous NSCLC, beyond PD-L1 status.

## Key findings

- TTF-1-negative patients had significantly worse progression-free and overall survival compared to TTF-1-positive patients.
- Meta-analysis confirmed TTF-1 negativity predicts poor outcomes across multiple immunotherapy regimens.
- PD-L1 expression had limited predictive value in TTF-1-negative tumors.

## Abstract

Lung cancer treatment has greatly improved thanks to immunotherapy, but not all patients respond equally. Currently, oncologists mainly use PD-L1 to decide who might benefit most from these treatments, but this is not always accurate. Our study examines another protein called Thyroid Transcription Factor-1 (TTF-1) to see if it could help predict outcomes in lung cancer patients treated with immunotherapy. We analyzed patient data from multiple hospitals and reviewed the existing scientific literature. We found that patients whose tumors did not produce TTF-1 had significantly worse outcomes, even if their PD-L1 levels were high. These results suggest that TTF-1 testing might be very useful to better select patients who need different or more aggressive treatment strategies. Including TTF-1 status in clinical practice could improve personalized treatment for lung cancer patients, but further studies are needed to confirm these findings.

Background/Objectives: Despite advances in immunotherapy, reliable biomarkers beyond PD-L1 expression are urgently needed to optimize treatment decisions in advanced non-squamous NSCLC. Thyroid Transcription Factor-1 (TTF-1), a biomarker associated with favorable prognosis in chemotherapy-treated patients, has unclear prognostic implications in the immunotherapy era. Methods: We conducted a multicenter retrospective study involving 163 advanced non-squamous NSCLC patients treated with first-line immunotherapy or chemo-immunotherapy and an additional historical chemotherapy-only cohort (n = 37). We evaluated the prognostic significance of TTF-1 expression for progression-free survival (PFS) and overall survival (OS). A systematic review and meta-analysis, performed following PRISMA guidelines, integrated our findings with existing evidence. Hazard ratios (HRs) were calculated using Cox proportional hazards models. Results: TTF-1 negativity was associated with significantly worse median PFS (6.7 vs. 16 months; HR 2.22, 95% CI 1.59–3.13; p < 0.001) and OS (11.5 vs. 26.4 months; HR 2.33, 95% CI 1.64–3.45; p < 0.001) compared to TTF-1 positivity. The prognostic value of TTF-1 was independent of PD-L1 status, with limited predictive relevance of PD-L1 expression observed within TTF-1-negative tumors. Meta-analysis (9 studies, 14 cohorts, n = 2019 patients) confirmed significantly inferior outcomes for TTF-1-negative patients across multiple immunotherapy-based regimens (pooled HR for PFS: 1.75, 95% CI 1.50–2.04; OS: 1.76, 95% CI 1.45–2.14). Conclusions: TTF-1 negativity independently predicts poor prognosis in advanced non-squamous NSCLC treated with immunotherapy-based regimens, identifying patients with limited benefit despite high PD-L1 expression. Integrating TTF-1 status into clinical practice may guide personalized treatment strategies, highlighting the need for prospective validation.