R Kim1, M Kwon2, M An3, S T Kim1, S A Smith4, A B Loembé4, P G S Mortimer4, J Armenia4, N Lukashchuk4, N Shah4, E Dean4, W-Y Park5, J Lee6. 1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 2. Department of Hematology-Oncology, Ajou University School of Medicine, Suwon, Korea. 3. Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea. 4. Oncology R&D, AstraZeneca, Cambridge, UK. 5. Samsung Genome Institute, Samsung Medical Center, Seoul, Korea; Geninus Inc., Seoul, Korea. 6. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Intelligent Precision Healthcare Convergence, Sungkyunkwan University, Suwon, Korea. Electronic address: jyunlee@skku.edu.
Abstract
BACKGROUND: Modulating the DNA damage response and repair (DDR) pathways is a promising strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related protein, which is crucial for DDR. PATIENTS AND METHODS: This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy. RESULTS: Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months). Common adverse events were largely hematologic and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to the study treatment. CONCLUSION: We conclude that ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and constitute a population with unmet needs.
BACKGROUND: Modulating the DNA damage response and repair (DDR) pathways is a promising strategy for boosting cancer immunotherapy. Ceralasertib (AZD6738) is an oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related protein, which is crucial for DDR. PATIENTS AND METHODS: This phase II trial evaluated ceralasertib plus durvalumab for the treatment of patients with metastatic melanoma who had failed anti-programmed cell death protein 1 therapy. RESULTS: Among the 30 patients, we observed an overall response rate of 31.0% and a disease control rate of 63.3%. Responses were evident across patients with acral, mucosal, and cutaneous melanoma. The median duration of response was 8.8 months (range, 3.8-11.7 months). The median progression-free survival was 7.1 months (95% confidence interval, 3.6-10.6 months), and the median overall survival was 14.2 months (95% confidence interval, 9.3-19.1 months). Common adverse events were largely hematologic and manageable with dose interruptions and reductions. Exploratory biomarker analysis suggested that tumors with an immune-enriched microenvironment or alterations in the DDR pathway were more likely to respond to the study treatment. CONCLUSION: We conclude that ceralasertib in combination with durvalumab has promising antitumor activity among patients with metastatic melanoma who have failed anti-programmed cell death protein 1 therapy, and constitute a population with unmet needs.
Authors: Reza Sari Motlagh; Mohammad Abufaraj; Pierre I Karakiewicz; Pawel Rajwa; Keiichiro Mori; Dong-Ho Mun; Shahrokh F Shariat Journal: World J Urol Date: 2021-09-03 Impact factor: 3.661