1187P - A mutation characteristics analysis of SMARCA4defSMARCA2wt in lung cancer

Background

SMARCA2 and SMARCA4 are the key catalytic subunit of SWI/SNF complex. Selective SMARCA2 degrading agents (such as ACBI1, one of PROTAC drugs) can induce the death of SMARCA4-deficient cancer cells. We retrospectively investigated features of medication-related alterations of SMARCA4^defSMARCA2^wt in a Chinese lung cancer cohort.

Methods

We analyzed 330 SMARCA4 mutation cases of 20,656 lung cancer samples which underwent OncoPanscan^TM panel based sequencing (Genetron Health), simultaneously co-mutation analysis was conducted.

Results

Our results showed SMARCA4^defSMARCA2^wt (120 cases) mutation features: 50% of lung adenocarcinoma, 86.67% of male, 70.49% of TMB-high (TMB≥10 mut/Mb) and 8.70% of PD-L1 high-expression (TPS≥50%). In the SMARCA4^defSMARCA2^wt cases, SMARCA4 and drug-sensitive mutations of 7 genes (EGFR, ALK, KRAS, MET, RET, BRAF, ROS1) were mutually exclusive (Table). 82.5% SMARCA4^defSMARCA2^wt cases without current drug target suggested that SMARCA4 is a strong driver gene and may be appropriate for treatment with SMARCA2 degradation agents. 17 SMARCA4^defSMARCA2^wt cases were found with EGFR co-mutations, including 6 cases with current drug target (19Del, L858R), which may benefit from EGFR TKI. TMB-high and PD-L1 highly expressive SMARCA4^defSMARCA2^wt cases may benefit from immunotherapy. SMARCA4^defSMARCA2^wt cases with co-mutation of KRAS accounted for 13.33% (16 cases) in our data, prone to super-advanced immunotherapy potentially. 7 cases of KRAS (G12C / D) may be suitable for KRAS targeted drugs, while the other 9 cases more appropriate for treatment with SMARCA2 degrading agents.

Conclusions

Our analysis indicate the medication-related mutation characteristics of SMARCA4^defSMARCA2^wt in lung cancer, and may contribute to medication guidance. Table: 1187P

SMARCA4^defSMARCA2^wt mutation features

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

J. Chen, X. Zhang, Y. Fang, T. Ma: Financial Interests, Institutional, Full or part-time Employment: Genetron Health (Beijing) Technology Co., Ltd., All other authors have declared no conflicts of interest.