Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer.

person Minsuk Kwon Department of Hematology-Oncology, Ajou University, Suwon, South Korea info_outline Minsuk Kwon, Seung Tae Kim, Jung Yong Hong, Gahyun Kim, Simon Smith, Peter G. Mortimer, Bienvenu LoembE, Emma Dean, Won Ki Kang, Jeeyun Lee

Authors person Minsuk Kwon Department of Hematology-Oncology, Ajou University, Suwon, South Korea info_outline Minsuk Kwon, Seung Tae Kim, Jung Yong Hong, Gahyun Kim, Simon Smith, Peter G. Mortimer, Bienvenu LoembE, Emma Dean, Won Ki Kang, Jeeyun Lee Organizations Department of Hematology-Oncology, Ajou University, Suwon, South Korea, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Seoul, South Korea, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, South Korea, Early Oncology Clinical Science, R&D Oncology, AstraZeneca, Cambridge, United Kingdom, AstraZeneca, Oss, Netherlands, University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom Abstract Disclosures Research Funding Other Foundation Pharmaceutical/Biotech Company Background: Alterations in DNA damage response (DDR) and repair are associated with genomic instability and increased somatic tumor mutational burden, and modulating DNA repair using specific inhibitors is a promising strategy to boost the efficacy of cancer immunotherapy. Ceralasertib is an oral inhibitor of the serine/threonine protein kinase Ataxia Telangiectasia and Rad3 Related (ATR), which is crucial to the cell’s response to replication stress. Methods: This phase 2 trial was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with advanced gastric cancer (AGC). The study drug regimen was ceralasertib 240 mg BD days 15 to 28 in a 28-day cycle in combination with durvalumab at 1500 mg day 1 every 4 weeks. The primary end point was overall response rate (ORR) by RECIST (v1.1). Exploratory biomarker analysis was performed using fresh tumor biopsies in all enrolled patients. Results: 31 patients (median no. of prior lines, 2; range, 2-5) were enrolled between Jul 2019 and Mar 2020. All enrolled patients had confirmed microsatellite stable tumors, 5 patients were EBV positive, and 24 patients were PD-L1 positive (CPS≥1). Two patients had received prior anti-PD-1 treatment. At the time of data cut-off (Dec 2020), 30 patients were evaluable for response: 7 partial responses (one patient with prior anti-PD-1 treatment), 11 stable disease, and 12 disease progression were observed. The ORR was 22.6%, DCR 58.1 %, median PFS 3.0 months (95% confidence interval (CI), 2.1-3.9), median duration of response 5.7 months (95% CI, 4.9-6.5), and median OS was 6.7 months (95% CI, 3.8-9.6). A subgroup of patients (n = 11) who with loss of ATM expression and/or high proportion of mutational signature attributable to homologous repair deficiency (sig. HRD) demonstrated significantly longer PFS than those (n = 12) who had intact ATM and low sig. HRD (5.60 vs 1.65 months, hazard ratio 0.13, 95% CI 0.045-0.39, long-rank P < 0.001). The most common adverse events of any grade were fatigue (n = 22, 71.0%), nausea (n = 20, 64.5%) and anorexia (n = 19, 61.3%), and the most common adverse events of grade 3 or more were anemia and thrombocytopenia (n = 11, 35.5% each). Conclusions: Ceralasertib in combination with durvalumab demonstrated promising anti-tumor activity with durable responses in refractory AGC. Clinical trial information: NCT03780608.