한빛사논문
- 조회544
Minsuk Kwon,1,2 Gahyun Kim,3,4 Ryul Kim,1 Kyu-Tae Kim,5 Seung Tae Kim,1 Simon Smith,6 Peter G S Mortimer,6 Jung Yong Hong,1 Arsene-Bienvenu Loembé,6 Itziar Irurzun-Arana,6 Loumpiana Koulai,6 Kyoung-Mee Kim,7 Won Ki Kang,1 Emma Dean,6 Woong-Yang Park,8 Jeeyun Lee1,9
1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 2Department of Hematology-Oncology, Ajou University, Suwon, Republic of Korea 3Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea 4Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea 5Department of Physiology, Ajou University, Suwon, Republic of Korea 6Oncology R&D, AstraZeneca, Cambridge, UK 7Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 8Samsung Genome Institute, Samsung Medical Center, Gangnam-gu, Republic of Korea 9Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, Republic of Korea
MK and GK contributed equally.
Correspondence to Jeeyun Lee
Abstract
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.
논문정보
- Research article
- 2022년 07월 (BRIC 등록일 2022-07-12)
- 국내(교신)+국외 연구진
- 의약학 > 종양의학
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