Immune checkpoint inhibitors (ICIs), either alone or in combination with conventional chemotherapy, have dramatically expanded the therapeutic landscape of non-small-cell lung cancer (NSCLC). However, only a subset of patients (pts) derives clinical benefit. It is thus critical to reveal the determinants driving response effects. Recently, there is emerging evidence that chromatin remodeling is involved in sensitivity and resistance to ICIs by neoantigen overexpression. Here we explored the relationship between mutations in SWI/SNF subunits (ARID1A, ARID1B) and the efficacy, and then validated the predictive biomarkers of immunotherapy.
Three hundred and fifty NSCLC pts with next-generation sequencing (NGS) and immunotherapy data obtained from MSK-IMPACT clinical cohort (MSKCC) were used to explore the association with ARID1A and/or ARID1B mutation, TMB and efficacy of ICIs. TMB was defined as the total number of somatic nonsynonymous mutations in the coding region. NGS data of 890 NSCLC pts who also detected PD-L1 expression from the Chinese clinical dataset were also analyzed to explore the association with mutation and PD-L1.
In total, 8.57% (30/350) and 3.14% (11/350) NSCLC pts in MSKCC harbored ARID1A and ARID1B mutations, respectively. In the Chinese cohort, the ARID1A mutation ratio (5.17%, 46/890) was lower than MSKCC, while the ARID1B mutation ratio (3.15%, 28/890) was similar to MSKCC. TMB analysis was performed on patients in both MSKCC and Chinese NSCLC cohorts. The TMB level of mutation group (any mutation on ARID1A and ARID1B) was significantly higher than wild-type group (P<0.001). The survival probability of mutation group was significantly longer than wild-type group (P=0.038). In addition, PD-L1 positive expression (≥1%) of mutation group and wild-type was 53.2% (25/47) and 54.6% (273/500).
The results indicated that ARID1A and ARID1B mutations were associated with a higher TMB level in both MSKCC and Chinese NSCLC patients, and patients with these gene mutations may benefit more from ICIs.
Clinical trial identification
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All authors have declared no conflicts of interest.