Ceralasertib plus durvalumab in Ras mutant and Ras wild type advanced non-small cell lung cancer: Two cohorts of the phase II platform National Lung Matrix Trial

Purpose: Pre-clinical data suggests that ceralasertib, a potent ATR inhibitor, might reverse resistance to anti-PD-(L)1 in KRAS mutant lung adenocarcinoma (LUAD). Activity of ceralasertib/durvalumab was, therefore, assessed in two prospective, parallel immune checkpoint blockade (ICB)-resistant cohorts, one harbouring KRAS mutations (J1), the other without (NAJ), within the National Lung Matrix Trial. Methods: Oral ceralasertib was administered (240 mg twice daily on days 15-28) with durvalumab (1500 mg IV, on day 1 of every 28-day cycle) until disease progression. Co-primary outcomes were objective response (OR) and 24-week durable clinical benefit (DCB). Biological impacts of ceralasertib were assessed in a human BJ-hTERT KRASV12ER-TAM model. Immunological impact of KRAS mutation was assessed using gene-level processed LUAD TCGA PanCancer data. Results: Between 02-Jul-2020 and 31-Oct-2021, 43 patients were registered; 19 and 18 of whom were evaluable for outcome analysis in cohorts J1 and NAJ, respectively. Cohort target recruitment (30 participants each) was not reached due to trial closure at the pre-planned end of funding. Bayesian estimates of DCB rates (95% credible intervals) were 37.7% (19.1-59.2) for J1 and 29.3% (12.6-51.2) for NAJ. Two participants demonstrated OR, both KRAS mutant, one of whom had KEAP1/STK11 co-mutation. KRAS mutation significantly increased the proportion of cells harbouring ceralasertib-induced micronuclei. Ceralasertib blunted KRAS-mediated STAT1 downregulation. Conclusion: Whilst outcome measures on ceralasertib/durvalumab in anti-PD-(L)1 resistant LUAD patients are modestly higher in KRAS mutant participants, these differences are not significant, a result likely related to the modest impact of KRAS mutation alone on the immunobiology of LUAD.