Phase 1 study of ceralasertib, an ATR kinase inhibitor, in combination with durvalumab in patients with recurrent or metastatic NSCLC or HNSCC

Background: This multicentre, modular, Phase 1 study evaluated escalating doses of ATR (ataxia telangiectasia and Rad3-related kinase) inhibitor ceralasertib plus PD-L1 inhibitor durvalumab in patients with previously treated advanced/metastatic non-small-cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (HNSCC). Methods: Patients received ceralasertib 80/160/240 mg twice-daily (BID) or 320 mg once-daily (QD) for 7 (Days 22–28) or 14 (Days 15–28) days, plus durvalumab 1500 mg (Day 1), per 28-day cycle. The primary objective was to investigate the safety/tolerability of the combination. Results: Sixty patients were treated. Two patients had dose-limiting toxicities of: Grade 3 thrombocytopenia with Grade 3 anaemia (ceralasertib 320 mg QD for 14 days); and Grade 4 thrombocytopenia with Grade 3 neutropenia accompanied by systemic chest infection (ceralasertib 240 mg BID for 14 days). Overall, 59 (98.3%) patients had treatment-emergent adverse events; 31 (51.7%) had grade ≥3 events. The recommended Phase 2 dose was durvalumab 1500 mg (Day 1) plus ceralasertib 240 mg BID (Days 15–28). Five (8.3%) patients had objective responses; 31 (51.7%) had stable disease. Pharmacodynamic activity (pRAD50 increase) was observed in 10/14 paired biopsies. Conclusion: Ceralasertib plus durvalumab was tolerated and associated with antitumour activity in advanced/metastatic NSCLC and HNSCC.