RT Journal Article
SR Electronic
T1 Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced gastric cancer
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e005041
DO 10.1136/jitc-2022-005041
VO 10
IS 7
A1 Minsuk Kwon
A1 Gahyun Kim
A1 Ryul Kim
A1 Kyu-Tae Kim
A1 Seung Tae Kim
A1 Simon Smith
A1 Peter G S Mortimer
A1 Jung Yong Hong
A1 Arsene-Bienvenu Loembé
A1 Itziar Irurzun-Arana
A1 Loumpiana Koulai
A1 Kyoung-Mee Kim
A1 Won Ki Kang
A1 Emma Dean
A1 Woong-Yang Park
A1 Jeeyun Lee
YR 2022
UL http://jitc.bmj.com/content/10/7/e005041.abstract
AB Background Targeting the DNA damage repair (DDR) pathways is an attractive strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral kinase inhibitor of ataxia telangiectasia and Rad3 related protein, which is a master regulator of DDR. We conducted a phase II trial of ceralasertib plus durvalumab in patients with previously treated advanced gastric cancer (AGC) to demonstrate the safety, tolerability, and clinical activity of the combination.Methods This phase II, open-label, single-center, non-randomized study was designed to evaluate the efficacy and safety of ceralasertib in combination with durvalumab in patients with AGC. The study drug regimen was ceralasertib (240 mg two times a day) days 15–28 in a 28-day cycle in combination with durvalumab (1500 mg) at day 1 every 4 weeks. The primary end point was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (V.1.1). Exploratory biomarker analysis was performed using fresh tumor biopsies in all enrolled patients.Results Among 31 patients, the ORR, disease control rate, median progression-free survival (PFS), and overall survival were 22.6% (95% CI 9.6% to 41.1%), 58.1% (95% CI 39.1% to 75.5%), 3.0 (95% CI 2.1 to 3.9) months, and 6.7 (95% CI 3.8 to 9.6) months, respectively. Common adverse events were manageable with dose modification. A subgroup of patients with a loss of ataxia telangiectasia mutated (ATM) expression and/or high proportion of mutational signature attributable to homologous repair deficiency (sig. HRD) demonstrated a significantly longer PFS than those with intact ATM and low sig. HRD (5.60 vs 1.65 months; HR 0.13, 95% CI 0.045 to 0.39; long-rank p<0.001). During the study treatment, upregulation of the innate immune response by cytosolic DNA, activation of intratumoral lymphocytes, and expansion of circulating tumor-reactive CD8 +T cell clones were identified in responders. Enrichment of the tumor vasculature signature was associated with treatment resistance.Conclusions Ceralasertib plus durvalumab has promising antitumor activity, with durable responses in patients with refractory AGC. Thus, a biomarker-driven trial is required.Trial registration NCT03780608.Data are available on reasonable request. All raw sequencing data were deposited in the European Nucleotide Archive (ENA) (accession number: PRJEB43396).