TTF-1 negativity as a biomarker of outcomes to immunotherapy, chemoimmunotherapy, and KRAS G12C inhibitors in lung adenocarcinoma.
Authors: Alessandro Di Federico, Lingzhi Hong, Arielle Elkrief, Rohit Thummalapalli, Alissa Jamie Cooper, Narek Shaverdian, Biagio Ricciuti, Joao Victor Machado Alessi, Andrea De Giglio, Federica Pecci, Giuseppe Lamberti, Malini Marion Gandhi, Lynette M. Sholl, Mizuki Nishino, Andrea Ardizzoni, Rebecca Suk Heist, Kathryn C. Arbour, Adam Jacob Schoenfeld, Natalie I Vokes, Mark M. Awad
Journal: Journal of Clinical Oncology (2024)

8608 Background: Thyroid transcription factor 1 (TTF-1) expression is routinely assessed in lung adenocarcinomas (LUAD) and is negative (TTF-1 Neg ) in 15-20% of cases. Whether these tumors differ from LUAD expressing TTF-1 (TTF-1 Pos ) in terms of biologic features and outcomes is unclear. Methods: Patients (pts) with LUAD and available TTF-1 expression by IHC at five institutions were included. Clinicopathologic, genomic, and outcomes data were compared according to TTF-1 expression. Results: Among 3,315 pts with LUAD, TTF-1 was negative in 15% (N=499). Compared to TTF-1 Pos (N=2,816), pts with TTF-1 Neg LUAD were more likely male (44% vs 38%, P=0.01), smokers (82% vs 74%, P&lt;0.001), with stage IV disease at diagnosis (76% vs 71%, P&lt;0.001), and lower median PD-L1 tumor proportion score (TPS, 1% vs 10%, P&lt;0.001). At stage IV diagnosis, TTF-1 Neg cases less commonly had brain metastasis than TTF-1 Pos cases (35% vs 44%, P=0.04), but more frequently had bone metastasis (53% vs 45%, P=0.03). TTF-1 Neg LUAD was enriched for KRAS, STK11, KEAP1, SMARCA4, and CDKN2A mutations (q&lt;0.05), while TTF-1 Pos LUAD was enriched for EGFR and MET mutations (q&lt;0.05). Compared to TTF-1 Pos LUAD, TTF-1 Neg LUAD had higher prevalence of KRAS G12D (12% vs 4%, P&lt;0.001) and G12V mutations (11% vs 7%, P=0.001), but similar frequency of G12C mutations (14% vs 15%, P=0.82). The association between TTF-1 and treatment outcomes was next investigated. Pts with stage III unresectable TTF-1 Neg LUAD who received durvalumab after chemo-radiation (N=20), compared to TTF-1 Pos cases (N=174), had shorter median progression-free survival (mPFS, 7.6 vs 24.7 months, P=0.01) and overall survival (mOS, 22.7 months vs not reached, P=0.01). Among pts with stage IV LUAD, TTF-1 Neg cases treated with immune checkpoint inhibitors (N=237), compared to TTF-1 Pos (N=1,161), had worse objective response rate (ORR, 17% vs 28%, P&lt;0.001), mPFS (2.5 vs 4.7 months, P&lt;0.001) and mOS (9.8 vs 20.9 months, P&lt;0.001). Similarly, pts with TTF-1 Neg LUAD (N=297) treated with chemoimmunotherapy, compared to TTF-1 Pos cases (N=920), had worse ORR (27% vs 42%, P&lt;0.001), mPFS (4.6 vs 8.1 months, P&lt;0.001) and mOS (11.2 vs 23.4 months, P&lt;0.001). TTF-1 negativity retained its association with worse outcomes after adjusting for treatment line, ECOG performance status, smoking status, PD-L1 TPS, STK11/ KEAP1 mutation status in multivariable cox regression models. Lastly, pts with KRAS G12C mutated TTF-1 Neg LUAD treated with KRAS inhibitors (N=25), compared to TTF-1 Pos (N=138), had worse ORR (12% vs 35%, P=0.03), mPFS (2.7 vs 5.9 months, P&lt;0.001), and mOS (4.4 vs 12.1 months, P&lt;0.001). After excluding mucinous LUAD cases, which are more commonly TTF-1 Neg , similar results were observed. Conclusions: TTF-1 negativity identifies a unique clinicopathologic and genomic subset of LUAD with worse outcomes to diverse systemic therapies.