Thyroid transcription factor-1 (TTF-1) expression and the efficacy of combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapy in non-squamous non-small cell lung cancer

Hirokazu Iso; Kakeru Hisakane; Erika Mikami; Takahiro Suzuki; Satoru Matsuki; Kenichiro Atsumi; Kohji Nagata; Masahiro Seike; Takashi Hirose

doi:10.21037/tlcr-23-331

Thyroid transcription factor-1 (TTF-1) expression and the efficacy of combination therapy with immune checkpoint inhibitors and cytotoxic chemotherapy in non-squamous non-small cell lung cancer

Transl Lung Cancer Res. 2023 Sep 28;12(9):1850-1861. doi: 10.21037/tlcr-23-331. Epub 2023 Sep 13.

Authors

Hirokazu Iso¹, Kakeru Hisakane¹, Erika Mikami¹, Takahiro Suzuki¹, Satoru Matsuki¹, Kenichiro Atsumi¹, Kohji Nagata², Masahiro Seike³, Takashi Hirose¹

Affiliations

¹ Department of Pulmonary Medicine and Medical Oncology, Nippon Medical School Tamanagayama Hospital, Tokyo, Japan.
² Department of Pathology, Nippon Medical School Tamanagayama Hospital, Tokyo, Japan.
³ Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.

Abstract

Background: Thyroid transcription factor-1 (TTF-1) is expressed in approximately 70% of lung adenocarcinomas and is one of the most reliable makers to distinguish primary lung adenocarcinoma from metastatic disease. TTF-1-negative status is a poor prognostic factor, and TTF-1-negative lung adenocarcinoma is associated with poor efficacy of immune checkpoint inhibitor (ICI) monotherapy. However, the relationship between TTF-1 expression and the efficacy of ICI plus chemotherapy is still unclear.

Methods: We performed a retrospective analysis of 129 consecutive patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC) treated with ICI monotherapy or ICI plus chemotherapy between January 2016 and December 2021. The expression of programmed death ligand-1 (PD-L1) and TTF-1 was also determined in cases for which no previous data were available. We then evaluated the association between TTF-1 expression status and treatment efficacy.

Results: Of the 129 cases, 33 were TTF-1-negative and 96 were positive. In the ICI monotherapy group (N=70), progression-free survival (PFS) was not significantly different between TTF-1-positive and negative patients (median 3.6 vs. 3.8 months, P=0.27); however, in patients with wild-type epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), a trend for worse PFS was observed in TTF-1-negative cases compared with those that were TTF-1-positive (median 3.8 vs. 4.5 months, P=0.088). Moreover, long-term efficacy of ICI monotherapy (>2 years) was not observed in the TTF-1-negative group. TTF-1-negative patients tended to have worse overall survival (OS) than TTF-1-positive patients (median 15.6 vs. 19.5 months, P=0.13). In the ICI plus chemotherapy group (N=59), TTF-1-negative patients tended to have better PFS and similar OS compared with TTF-1-positive patients (median 9.9 vs. 9.6 months, P=0.14; median 32.3 vs. 18.9 months, P=0.78). Long-term efficacy was generally observed in TTF-1-negative patients treated with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) (median PFS 22.5 months, median OS not reached).

Conclusions: ICI monotherapy is generally less efficacious in TTF-1-negative NS-NSCLC patients, and clinicians should consider ICI plus chemotherapy in these cases. Our study suggests that ABCP is an optimal regimen for TTF-1-negative NS-NSCLC.

Keywords: Thyroid transcription factor-1 (TTF-1); atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP); non-squamous non-small cell lung cancer (NS-NSCLC); programmed death ligand-1 (PD-L1).