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Correlations of switch/sucrose nonfermentable complex mutations with clinical outcomes in advanced non-small cell
Geyun Chang1, Weihua Li2, Hua Bai1
1State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Background:
The switch/sucrose nonfermentable complex mutations (SWI/SNF-mut) are common in non-small cell lung cancer (NSCLC). However, the association of SWI/SNF-mut with the clinical outcomes of immune checkpoint inhibitors (ICIs), particularly of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has not been established.
Methods:
We retrospectively collected data of patients at Cancer Hospital Chinese Academy of Medical Sciences. Patients with advanced NSCLC who received programmed cell death protein-1 or programmed cell death ligand 1 (PD-[L]1) inhibitors were included in cohort 1 and those with EGFR mutations (EGFR-mutant) received EGFR-TKIs monotherapy were included in cohort 2. Two reported Memorial Sloan-Kettering Cancer Center (MSKCC) cohorts received immunotherapy alone used as the validation for cohort 1. We analyzed the relationship between SWI/SNF alterations and clinical outcomes in each cohort.
Results:
In total, 1162 patients were included, of which 230 patients (19.8%) were identified as SWI/SNF-mut with the most common genetic alterations being ARID1A (33.4%) and SMARCA4 (28.3%). In cohort 1 (n = 146), patients with co-mutations of SWI/SNF and Kirsten rat sarcoma oncogene (KRAS) (SWI/SNFmutKRASmut, n = 18) had significantly prolonged progression-free survival (PFS) (8.6 m vs. 1.9 m; hazard ratio [HR], 0.31; 95% confidence intervals [CI], 0.11-0.83; p = 0.032) to PD-(L)1 inhibitors monotherapy, which was consistent with the MSKCC cohorts (not reach [NR] vs. 6.3 m; HR, 0.36, 95% CI, 0.15-0.82; p = 0.016). In cohort 2 (n = 205), ARID1A-mut (n = 16) was associated with improved PFS after EGFR-TKIs (20.6 m vs. 11.2 m; HR, 0.47, 95% CI, 0.27-0.94; p = 0.023).
Conclusions:
In advanced NSCLC, patients with SWI/SNFmutKRASmut seem to benefit more from ICIs. Furthermore, ARID1A-mut may provide a protective effect to EGFR-TKIs in EGFR-mutant patients. However, this is a retrospective single-institution analysis that requires further validation by large prospective studies.
Insights
SWI/SNF mutations in non-small cell lung cancer (NSCLC) impact treatment outcomes. Patients with SWI/SNF and KRAS co-mutations may benefit more from immune checkpoint inhibitors (ICIs), while ARID1A mutations show promise with EGFR-TKIs.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Switch/sucrose nonfermentable (SWI/SNF) complex mutations are prevalent in non-small cell lung cancer (NSCLC).
- The clinical impact of SWI/SNF mutations on outcomes with immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains unclear.
Purpose of the Study:
- To investigate the association between SWI/SNF alterations and clinical outcomes in advanced NSCLC patients treated with ICIs or EGFR-TKIs.
- To determine if specific SWI/SNF mutations predict response to different targeted therapies.
Main Methods:
- Retrospective analysis of 1162 advanced NSCLC patients across two cohorts: cohort 1 (n=146) treated with PD-(L)1 inhibitors and cohort 2 (n=205) treated with EGFR-TKIs.
- Utilized Memorial Sloan-Kettering Cancer Center (MSKCC) cohorts for validation of immunotherapy outcomes.
- Analyzed SWI/SNF alterations, including ARID1A and SMARCA4, and their correlation with progression-free survival (PFS).
Main Results:
- SWI/SNF mutations were identified in 19.8% of patients, with ARID1A and SMARCA4 being the most common.
- Patients with SWI/SNF and KRAS co-mutations (SWI/SNFmutKRASmut) showed significantly prolonged PFS with PD-(L)1 inhibitors (8.6 months vs. 1.9 months), validated in MSKCC cohorts.
- ARID1A mutations were associated with improved PFS in EGFR-mutant patients receiving EGFR-TKIs (20.6 months vs. 11.2 months).
Conclusions:
- SWI/SNF-mutated NSCLC patients with KRAS co-mutations may derive greater benefit from ICIs.
- ARID1A mutations could indicate a favorable response to EGFR-TKIs in EGFR-mutant NSCLC.
- Further validation in large prospective studies is warranted to confirm these findings.
