Key Clinical Summary

• CTNNB1 co-mutations were associated with 100% complete response to osimertinib in EGFR-mutated NSCLC.
• TP53 co-mutations correlated with all cases of disease progression and higher PD-L1 expression.
• Findings underscore the prognostic value of co-mutation profiling in guiding EGFR-TKI therapy.

A retrospective study presented at the Association for Molecular Pathology (AMP) 2025 Annual Meeting & Expo reports that co-mutations in CTNNB1 may enhance response to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). The research adds to growing evidence that molecular co-mutations play a key role in predicting response to targeted therapies such as osimertinib.

The study analyzed 129 cases of EGFR-mutated NSCLC treated with osimertinib, stratifying them into 3 groups: EGFR alone (n = 90), EGFR + TP53 (n = 31), and EGFR + CTNNB1 (n = 8). Clinical responses were evaluated according to RECIST 1.1 criteria.

Results revealed a significant association between co-mutation status and therapeutic response (P <.001). Notably, all cases of progressive disease occurred in the EGFR + TP53 group, while 100% (n = 6) of patients harboring EGFR + CTNNB1 co-mutations achieved complete responses. In contrast, two-thirds of patients in the EGFR-only group demonstrated complete or partial responses, with the remainder showing stable disease.

Smoking history emerged as an important modifier. Current or former smokers—particularly those with TP53 co-mutations—showed higher rates of treatment failure. However, in the CTNNB1 group, half were smokers, yet none exhibited disease progression.

PD-L1 expression also varied by subgroup (P <.001). Elevated PD-L1 levels (tumor proportion score ≥1%) were most prevalent among EGFR + TP53 patients (87.1%), compared with 33.4% in EGFR-only and 37.5% in EGFR + CTNNB1 cases. Age, gender, and disease stage were not correlated with PD-L1 expression.

These findings suggest that CTNNB1 co-mutations may confer a unique sensitivity to EGFR-TKI therapy, potentially offsetting other negative predictors such as smoking. Conversely, TP53 co-mutations appear linked to poorer outcomes and heightened PD-L1 expression—factors that may signal intrinsic resistance to TKIs.

Clinicians may consider molecular co-mutation profiling to refine prognosis and guide therapy selection. The distinct PD-L1/TP53 relationship could also have implications for immunotherapy sequencing in EGFR-mutated NSCLC. As precision oncology evolves, integrating multi-gene mutation data may enhance individualized treatment planning.

Although limited by small subgroup sizes, this study highlights the prognostic and therapeutic relevance of co-mutation profiling in EGFR-mutated NSCLC. Further prospective research is warranted to validate CTNNB1’s predictive potential and to refine molecularly informed treatment strategies.

Source:

Htoo A, Liu X, Bello S, et al. Not All Co-Mutations Are Created Equal: CTNNB1 May Predict Favorable EGFR TKI Response. Presented at the 2025 AMP Annual Meeting. November 11-15, 2025; Boston, Massachusetts. ST126