Clinical impact of genomic co-mutation profiles including TP53 in resected early-stage <i>EGFR</i> -mutated NSCLC: LC-SCRUM-Advantage.

Abstract

8035 Background: Adjuvant osimertinib is the standard of care for resected stage IB–IIIA EGFR-mutated non-small cell lung cancer (NSCLC), and its benefit in stage IA2–IA3 disease is being evaluated in ADAURA2. However, the prognostic impact of genomic co-alterations, particularly TP53, in early-stage EGFR-mutated NSCLC remains unclear. This study characterized genomic co-alterations and their association with clinicopathologic features in resected early-stage EGFR-mutated NSCLC. Methods: LC-SCRUM-Advantage is a prospective genomic screening program for resected NSCLC. Postoperative tumor specimens were analyzed using the Oncomine Precision Assay to identify co-alterations, including TP53 and other recurrent genes, across major EGFR mutation subtypes. PD-L1 expression was assessed by immunohistochemistry. Clinico-genomic characteristics and survival outcomes were evaluated. Results: Among 1052 enrolled patients, 327 had EGFR-mutated adenocarcinoma (19del 42%, L858R 47%, others 11%). Among tumors with common EGFR mutations, single EGFR alterations accounted for 59%, while co-alterations were detected in 41%. Frequent co-alterations included TP53 (19%), CTNNB1 (4%), PIK3CA (4%), additional EGFR mutations (5%), and EGFR amplification (12%). Co-alteration prevalence increased with pathological stage (IA1 25%, IA2–IA3 41%, IB 53%, II 47%, III 46%), with TP53 showing a similar pattern (IA1 8%, IA2–IA3 18%, IB 19%, II 28%, III 27%). PD-L1 positivity also increased progressively with disease stage (I 37%, II 52%, III 73%; p = 0.0002). TP53-mutated tumors showed a significantly higher PD-L1 positivity rate than TP53 wild-type tumors (60% vs. 39%; p = 0.007). Co-alteration frequencies were comparable across EGFR subtypes. With limited follow-up, five recurrences were observed (IB 1, IIA 1, IIIA 2, IVA 1); three involved co-alterations (TP53, EGFR amplification, EGFR E709V). Conclusions: Genomic co-alterations, including TP53, were common and increased with pathological stage in early-stage EGFR-mutated NSCLC. Co-altered tumors exhibited features associated with aggressive biology, including higher PD-L1 expression. Early recurrences were frequently observed in patients with co-alterations, underscoring their potential prognostic relevance. These findings highlight substantial molecular heterogeneity within early-stage EGFR-mutated NSCLC and support incorporating co-alteration status into risk stratification and adjuvant treatment planning. Ongoing follow-up from this study will further clarify the prognostic and predictive significance of co-alterations, particularly regarding their implications for adjuvant targeted therapy.