Abstract 5767: Landscape of concomitant driver mutations in EGFR-mutated NSCLCs
Authors: Wang Xiaonan , Zhang Junli , Liang Chuqiao , Yin Jiani C. , Shao Yang 
Published: June 2022

Abstract
Background While most oncogenic driver mutations are mutually exclusive, next-generation sequencing (NGS) has led to the identification of concomitant driver alterations in non-small cell lung cancer (NSCLC). However, the landscape of concomitant drivers and the clinical relevance remain to be explored.
Methods: We profiled concomitant driver alterations, including EGFR, KRAS, ALK, RET, ROS1, MET, BRAF and ERBB2 from baseline tumor tissues of 22,610 NSCLC patients by using targeted NGS. The associated genomic and clinical features were analyzed and validated in a TCGA dataset of 136 EGFR+ NSCLC patients.
Results: The overall frequency of concomitant driver mutations in EGFR+ patients was 3.09% (334/10,801). EGFR activating mutations most commonly co-occurred with KRAS mutations (2.42%), followed by ERBB2 (1.09%), MET (0.75%) and BRAF (0.15%). A total of six EGFR+ patients were identified with co-occurring ALK (n=2), RET (n=1), or ROS1 (n=3) fusions. Patients with dual EGFR/KRAS mutations were more likely to carry the p.G13D (6.1% vs. 2.9%, P&lt;.05), p.G12S (6.1% vs. 2.3%, P&lt;.01), p.A146T (8.3% vs. 0.9%, P&lt;.0001), p.A146V (3.9% vs. 0.5%, P&lt;.001)variants in KRAS, whereas those with single KRAS were enriched with p.G12C (15.0% vs. 33.0%, P&lt;.0001) and p.G12A (3.9% vs. 8.5%, P&lt;.05) variants. Patients with dual EGFR/MET alterations had a higher frequency of MET amplification (71.4% vs. 43.3%) and lower exon 14 skipping mutations (28.6% vs. 56.7%, P=.0001) than MET single drivers. Patients with dual EGFR/ERBB2 alterations had higher ERBB2 amplification (40.7% vs. 16.5%, P&lt;.0001) and p.S310F/Y mutations (44.4% vs. 4.3%, P&lt;.0001), and lower ERBB2 exon 20 insertions (9.9%, vs. 70.6%, P&lt;.0001). In addition, dual drivers had higher frequencies of TP53 (P&lt;.01), RB1 (P&lt;.05), ARID2 (P&lt;.05), NTRK1 (P&lt;.01), TSC2 (P&lt;.001), and BRIP1 (P&lt;.01) alterations than single drivers. At the genomic level, dual drivers had higher mutational load than those with only EGFR mutations (median 4 vs. 2 muts, P&lt;.01). In 75% of dual drivers, EGFR mutant allele frequency (MAF) was higher than that of the other concomitant driver. In patients with sufficient clinical follow-up, dual drivers were associated with unfavorable PFS outcomes compared with single drivers (HR=2.87, P=.04) following first-line first-generation EGFR TKIs, which was mainly attributed to the presence of MET amplification or PIK3CA mutations. In addition, in dual EGFR/KRAS and EGFR/BRAF drivers, a higher MAF of EGFR than that of the respective co-occurring driver was associated with a trend towards prolonged PFS (11.0 vs. 8.1m, HR= 0.21, P=.15), likely suggesting clonal advantage of EGFR sensitizing mutations in response to first-generation TKIs.
Conclusion: In our large cohort study, we present the landscape of EGFR+ dual drivers and their associated clinical and genomic features and survival outcomes, which could aid in therapeutic decisions and facilitate the development of combination therapies.
Citation Format: Xiaonan Wang, Junli Zhang, Chuqiao Liang, Jiani C. Yin, Yang Shao. Landscape of concomitant driver mutations in EGFR-mutated NSCLCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5767.