Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06)
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 l...
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BMJ Publishing Group
2024-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/3/e008638.full |
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| author | Jae Ho Byun Jeeyun Lee Kyong Hwa Park Eun Joo Kang Sang Joon Shin In Gyu Hwang Ju Won Kim Hyo Jin Lee Ji Yoon Lee Jason K Sa Sook Ryun Park Jung Sun Kim Yu Jung Kim Woo Kyun Bae Won Jin Chang Eun-Ok Kim |
| author_facet | Jae Ho Byun Jeeyun Lee Kyong Hwa Park Eun Joo Kang Sang Joon Shin In Gyu Hwang Ju Won Kim Hyo Jin Lee Ji Yoon Lee Jason K Sa Sook Ryun Park Jung Sun Kim Yu Jung Kim Woo Kyun Bae Won Jin Chang Eun-Ok Kim |
| author_sort | Jae Ho Byun |
| collection | DOAJ |
| description | 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.Trial registration number NCT04761744. |
| format | Article |
| id | doaj-art-3b976b2bbe094530abf0fc108109580d |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-03-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-3b976b2bbe094530abf0fc108109580d2025-08-20T01:58:12ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-03-0112310.1136/jitc-2023-008638Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06)Jae Ho Byun0Jeeyun Lee1Kyong Hwa Park2Eun Joo Kang3Sang Joon Shin4In Gyu Hwang5Ju Won Kim6Hyo Jin Lee7Ji Yoon Lee8Jason K Sa9Sook Ryun Park10Jung Sun Kim11Yu Jung Kim12Woo Kyun Bae13Won Jin Chang14Eun-Ok Kim15Division of Oncology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaDivision of Hemato-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, Republic of KoreaDivision of Hemato-Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Anam Hospital, Seoul, Republic of KoreaDivision of Hemato-Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul, Republic of KoreaDivision of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seodaemun-gu, Republic of KoreaDepartment of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine and Graduate School of Medicine, Dongjak-gu, Republic of KoreaDivision of Hemato-Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Anam Hospital, Seoul, Republic of KoreaDivision of Hemato-Oncology, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of KoreaDepartment of Biomedical Informatics and Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of KoreaDepartment of Biomedical Informatics and Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of KoreaDepartment of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of KoreaDivision of Hemato-Oncology, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of KoreaDivision of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of KoreaDivision of Hemato-Oncology, Department of Internal Medicine, Chonnam National University Medical School & Hwasun Hospital, Hwasun, Republic of KoreaDivision of Hemato-Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Anam Hospital, Seoul, Republic of KoreaMedical Science Research Center, College of Medicine, Korea University, Seongbuk-gu, Republic of KoreaBackground 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.Trial registration number NCT04761744.https://jitc.bmj.com/content/12/3/e008638.full |
| spellingShingle | Jae Ho Byun Jeeyun Lee Kyong Hwa Park Eun Joo Kang Sang Joon Shin In Gyu Hwang Ju Won Kim Hyo Jin Lee Ji Yoon Lee Jason K Sa Sook Ryun Park Jung Sun Kim Yu Jung Kim Woo Kyun Bae Won Jin Chang Eun-Ok Kim Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06) Journal for ImmunoTherapy of Cancer |
| title | Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06) |
| title_full | Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06) |
| title_fullStr | Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06) |
| title_full_unstemmed | Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06) |
| title_short | Phase II study of nivolumab in patients with genetic alterations in DNA damage repair and response who progressed after standard treatment for metastatic solid cancers (KM-06) |
| title_sort | phase ii study of nivolumab in patients with genetic alterations in dna damage repair and response who progressed after standard treatment for metastatic solid cancers km 06 |
| url | https://jitc.bmj.com/content/12/3/e008638.full |
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