한빛사논문
- 조회477
고려대학교 안암병원
Ju Won Kim1, Hyo Jin Lee2, Ji Yoon Lee3, Sook Ryun Park4, Yu Jung Kim5, In Gyu Hwang6, Woo Kyun Bae7, Jae Ho Byun8, Jung Sun Kim9, Eun Joo Kang10, Jeeyun Lee11, Sang Joon Shin12, Won Jin Chang1, Eun-Ok Kim13, Jason K Sa3 * and Kyong Hwa Park1 *
1Division of Hemato-Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
2Division of Hemato-Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea
3Department of Biomedical Informatics and Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea
4Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
5Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
6Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine and Graduate School of Medicine, Dongjak-gu, Republic of Korea
7Division of Hemato-Oncology, Department of Internal Medicine, Chonnam National University Medical School & Hwasun Hospital, Hwasun, Republic of Korea
8Division of Oncology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Republic of Korea
9Division of Hemato-Oncology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea
10Division of Hemato-Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
11Division of Hemato-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
12Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seodaemun-gu, Republic of Korea
13Medical Science Research Center, College of Medicine, Korea University, Seongbuk-gu, Republic of Korea
*Corresponding authors: correspondence to Professor Jason K Sa or Dr Kyong Hwa Park
Abstract
Background: Immune-modulating antibodies targeting programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have demonstrated promising antitumor efficacy in various types of cancers, especially highly mutated ones. Genetic alterations in DNA damage response and repair (DDR) genes can lead to genetic instability, often accompanied by a high tumor mutation burden (TMB). However, few studies have validated the aberration of DDR genes as a predictive biomarker for response to immune-modulating antibodies.
Methods: The KM-06 open-label, multicenter, single-arm, phase II trial evaluated the safety and efficacy of nivolumab in refractory solid cancers with DDR gene mutations assessed by clinically targeted sequencing. Nivolumab (3 mg/kg) was administered every 2 weeks until disease progression, unacceptable toxicity, or for 24 months. The primary endpoint was the objective response rate (ORR) as per RECIST V.1.1 criteria.
Results: A total of 48 patients were enrolled in the study (median age 61, 58.3% male). The most common cancer type was colorectal cancer (41.7%), followed by prostate and biliary tract cancer (8.3% each). Eight patients achieved a partial response as their best overall response, resulting in an ORR of 17.8%. The disease control rate was 60.0%. The median progression-free survival was 2.9 months. Treatment-related adverse events of any grade and grade ≥3 occurred in 44 (91.7%) and 4 (8.3%) patients, respectively. Clinically targeted sequencing data inferred both TMB and microsatellite instability (MSI). Using a TMB cut-off of 12 mut/Mb, there were significant differences in overall survival (p=0.00035), progression-free survival (p=0.0061), and the best overall response (p=0.05). In the RNA sequencing analysis, nivolumab responders showed activation of the interleukin signaling pathway. Patients who experienced early progression presented high epithelial-mesenchymal transition signaling pathway activation. The responders exhibited a marked increase in PD-1-/Ki67+CD8 T cells at the early stage of treatment (C3D1) compared with non-responders (p=0.03).
Conclusions: In this phase II trial, nivolumab demonstrated moderate efficacy and manageable toxicity in patients with solid cancer harboring DDR gene mutations. A high TMB (>12 mut/Mb) and MSI score (>2.5) determined through clinically target sequencing presented significant discriminatory power for the nivolumab response.
논문정보
- Research article
- 2024년 03월 (BRIC 등록일 2024-03-22)
- 국내 연구진
- 생명과학 > 노화/암생물학
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