Diffuse and Strong TTF-1 Expression Predicts Response to Pemetrexed-Based Immunochemotherapy in Advanced Lung Adenocarcinoma

Thyroid transcription factor-1 (TTF-1) is a good prognostic factor for non-small cell lung carcinoma (NSCLC). It is unclear how much TTF-1 staining is sufficient to predict therapeutic response in immunochemotherapy. We evaluated the cut-off of TTF-1 considering the percentage of positive cells and staining intensity as a predictive factor. We conducted a retrospective multicenter study of patients with advanced lung adenocarcinoma or NSCLC favor adenocarcinoma treated with immunochemotherapy. One pathologist centrally examined the immunohistochemical staining of TTF-1 using 8G7G3/1 and provided scores of 0-5 based on the staining intensity and ratio. We analyzed 95 patients. As TTF-1 has previously been shown to be a predictive factor for pemetrexed, there were significant differences in PFS of patients treated with pemetrexed-based immunochemotherapy between TTF-1 scores of 5 (diffuse and strong staining) and ≤4, but not between 0 (no staining) and 2-4 (partial or weak staining). We defined a TTF-1 score of ≥5 as positive for the predictive factor and the positivity ratio was 61.1%. Patients who tested negative for TTF-1 had a significantly higher proportion of programmed death ligand 1 (PD-L1) tumor proportion score (TPS) <1%. Excluding mutation-positive patients, PFS in TTF-1 positivity was significantly longer than in negativity (8.0 and 5.9, hazard ratio (HR): 0.58 (0.34-0.98), p = 0.04), while TTF-1 negativity was not inferior to positivity in PFS with taxane-based immunochemotherapy. Patients treated with pemetrexed-based immunochemotherapy who tested positive for TTF-1 had significantly longer PFS than those who tested negative (HR: 0.51 (0.27-0.99), p = 0.045) in the multivariate analysis incorporating age, PD-L1, PS, and TTF-1. Diffuse and strong TTF-1 positivity may be useful for the predictive factor for pemetrexed-based immunochemotherapy. TTF-1 staining may be desirable to develop a more optimal immunochemotherapy for lung adenocarcinoma.