Researchers from The University of Texas MD Anderson Cancer Center have identified TTF-1 as a predictive biomarker for survival outcomes in patients with advanced KRAS G12C-mutated non-small cell lung cancer (NSCLC) treated with the targeted therapy sotorasib. The findings, published in Nature Medicine, demonstrate significant differences in treatment response based on TTF-1 expression levels.
Dramatic Survival Differences Based on TTF-1 Expression
The study revealed striking disparities in patient outcomes depending on TTF-1 levels. Patients with lung tumors expressing low TTF-1 levels responded poorly to sotorasib, achieving a median progression-free survival (PFS) of 2.8 months and median overall survival (OS) of 4.5 months. In contrast, patients with tumors expressing high TTF-1 levels demonstrated substantially better outcomes with a median PFS of 8.1 months and median OS of 16 months.
"Since TTF-1 testing is routinely performed in lung cancer diagnosis, it gives physicians an immediate tool to help identify those patients who may benefit from sotorasib and those who may need an alternative or intensified treatment approach," said lead author Ferdinandos Skoulidis, M.D., Ph.D., associate professor of Thoracic/Head and Neck Medical Oncology.
Clinical Trial Analysis and Patient Population
The research analyzed 317 biomarker-evaluable patients with previously treated advanced KRAS G12C-mutated NSCLC from the CodeBreaK 200 clinical trial and 112 biomarker-evaluable patients from the CodeBreaK 100 clinical trial. KRAS represents the most common oncogenic driver in non-squamous NSCLC, found to be mutated in 25% to 30% of patients. Sotorasib specifically targets the KRAS G12C mutant protein, which occurs in roughly 13% of lung adenocarcinomas.
Sotorasib received FDA approval in 2021 based on results from the CodeBreaK 100 trial, marking the first direct KRAS inhibitor to achieve regulatory approval.
Tumor Microenvironment and Immunotherapy Insights
The study uncovered important findings regarding the tumor microenvironment's role in sotorasib efficacy. Researchers identified a subgroup of patients with "immune cold" tumors lacking expression of the immune checkpoint protein PD-L1, who responded better to sotorasib than to chemotherapy. These tumors typically show poor response to immunotherapy.
"This finding is encouraging because it suggests that even patients who don't respond to immunotherapy might still benefit from sotorasib," Skoulidis explained. "It also opens the door to exploring combination treatments, like pairing sotorasib with chemotherapy to improve outcomes for even more patients."
Circulating Tumor DNA as Early Response Indicator
The research demonstrated that rapid clearance of circulating tumor DNA (ctDNA) following sotorasib initiation correlated with superior outcomes. Patients with detectable KRAS G12C ctDNA during treatment showed increased risk of progression compared to those achieving ctDNA clearance. Notably, ctDNA levels dropped as early as eight days into treatment in some patients, suggesting that blood tests could quickly identify treatment responders.
Precision Medicine Implications
The findings advance precision medicine approaches for KRAS-mutant NSCLC patients. "Our findings support the use of biomarkers to personalize care and could guide precise application of combination strategies with KRAS inhibitors," Skoulidis noted.
Future research will focus on refining response prediction for patients with TTF-1-expressing tumors and identifying optimal combination strategies for patients with poor prognosis who lack TTF-1 expression. Study limitations included incomplete biomarker data for some patients, potential timing issues in data analysis, and ctDNA panel size constraints.
