140P - Predictive value of DNA damage response and repair gene alterations and neoscore for neoadjuvant immunotherapies in non-small cell lung cancer

Background

Although alterations in DNA damage response and repair (DDR) genes showed the potential to predict immunotherapy benefit in advanced non-small cell lung cancers (NSCLC), their predictive value for neoadjuvant immunotherapies remains to be revealed.

Methods

Sixty-five patients with NSCLC (stage IB-IIIA) who were treated with neoadjuvant immunotherapies at our center between September 2020 and December 2022 were enrolled. Next-generation sequencing was utilized to determine the mutational status across a panel of 36 DDR genes. Subsequently, an eight-DDR-gene score (NeoScore) was developed by employing LASSO Cox regression followed by stepwise regression analysis, which illustrated the association between the mutational status of DDR genes and the pathological complete response (pCR) status after immune checkpoint blockade (ICB) treatment.

Results

Eight DDR genes that displayed a strong correlation with pCR included ATM, ATR, BRIP1, ERCC4, FANCA, PARP1, POLE, and RAD50. A higher NeoScore demonstrated a significant association with an increased pCR rate (46% vs. 21%, p<0.01). This association between a higher NeoScore and improved pCR was observed across different drug classes, such as PD-1 or PD-L1 inhibitors. Moreover, the NeoScore exhibited statistical significance in predicting the benefit of major pathological response (MPR) (61% vs. 34%, p<0.01). Notably, the combination of NeoScore and tumor mutational burden (tTMB), with a cutoff of ≥10 muts/Mb, displayed even better predictive value compared to NeoScore alone.

Conclusions

The NeoScore demonstrated promising and consistent predictive value for neoadjuvant immunotherapies across different drug classes. Furthermore, the combination of NeoScore and tumor mutational burden (TMB) showed improved accuracy in prediction.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.