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: Preclinical data suggest 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 2 prospective, parallel immune checkpoint blockade–resistant cohorts, 1 harboring KRAS mutations (J1) and the other without (NAJ), within the National Lung Matrix Trial.

Patients and Methods: Oral ceralasertib was administered (240 mg twice daily on days 15–28) with durvalumab (1,500 mg i.v., on day 1 of every 28-day cycle) until disease progression. Coprimary 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. Immunologic impact of KRAS mutation was assessed using gene-level processed LUAD The Cancer Genome Atlas PanCancer data.

Results: Between July 2, 2020, and October 31, 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 preplanned 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, 1 of whom had KEAP1/STK11 co-mutation. KRAS mutation significantly increased the proportion of cells harboring ceralasertib-induced micronuclei. Ceralasertib blunted KRAS-mediated STAT1 downregulation.

Conclusions: Although outcome measures on ceralasertib/durvalumab in anti–PD-(L)1–resistant patients with LUAD 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.