Titin mutation in circulatory tumor DNA is associated with efficacy to immune checkpoint blockade in advanced non-small cell lung cancer

BACKGROUND: Only a fraction of patients with advanced non-small cell lung cancer (NSCLC) respond well to immune checkpoint blockade (ICB) therapy. Here, we investigated whether Titin (TTN) mutation, which has been demonstrated to be a predictive biomarker in tissue-based analysis, can identify patients with a greater likelihood in response to ICB based on circulatory tumor DNA (ctDNA) sequencing. METHODS: In this retrospective analysis, 92 patients with advanced NSCLC from two independent cohorts who received ICB treatment were included. A probe panel covering all exons of TTN was developed and validated to detect TTN mutation in ctDNA. Baseline plasma samples were collected and subjected to ctDNA sequencing with the TTN probe panel. RESULTS: Of the 92 patients, 28.3% harbored TTN mutation in their baseline ctDNA. Progression-free survival was significantly improved in patients with the mutated TTN (212 days and 334.5 days for cohort 1 and 2) compared to those without the mutation (113 days and 147 days for cohort 1 and 2). Objective response to ICB treatment (40% for TTN(mut) and 15.8% for TTN(wt) in cohort 1; 50% for TTN(mut) and 23.4% for TTN(wt) in cohort 2) was common in patients with mutated TTN. Stratified analysis showed a generally predictive potential of TTN mutation in patients with advanced NSCLC. CONCLUSIONS: The presence of mutated TTN in pre-treatment peripheral blood was associated with favorable objective response and survival with ICB administration. Therefore, circulatory TTN mutation may be applicable for guiding ICB immunotherapy in patients with NSCLC.