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613 A 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)
  1. Ju Won Kim1,
  2. Hyo Jin Lee2,
  3. Ji Yoon Lee3,
  4. Jason K Sa3,
  5. Sook Ryun Park4,
  6. Yu Kim5,
  7. In Gyu Hwang6,
  8. Woo Kyun Bae7,
  9. Jae Ho Byun8,
  10. Jung Sun Kim9,
  11. Eun Joo Kang10,
  12. Jeeyun Lee11,
  13. Sang Shin12 and
  14. Kyong Hwa Park1
  1. 1Korea University Anam Hospital, Seoul, Republic of Korea
  2. 2Chungnam National University Hospital, Daejeon, Republic of Korea
  3. 3Korea University College of Medicine, Seoul, Republic of Korea
  4. 4Asan Medical Center, Seoul, Republic of Korea
  5. 5Seoul National University Bundang Hospital, Seongnam, Korea, Republic of Korea
  6. 6Chung-Ang University Hospital, Seoul, Korea, Republic of Korea
  7. 7Chonnam National Univertisy Medical School and Hwasun Hospital, Hwasun, Republic of Korea
  8. 8The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon, Republic of Korea
  9. 9Korea University Ansan Hospital, Ansan, Republic of Korea
  10. 10Korea University Guro Hospital, Seoul, Republic of Korea
  11. 11Samsung Medical Center, Seoul, Republic of Korea
  12. 12Yonsei Cancer Center, Seoul, Republic of Korea


Background Immune-modulating antibodies targeting PD-1/PD-L1 have demonstrated promising anti-tumor efficacy in various types of cancers, especially in 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, a limited number of studies have validated the aberration of DDR genes as a predictive biomarker for response to immune-modulating antibodies.

Methods KM-06 was an open-label, multicenter, single-arm, phase II trial to evaluate the safety and efficacy of nivolumab in refractory solid cancers with DDR gene mutations. DDR gene mutations were assessed by clinical targeted sequencing. Patients with a history of any prior treatment with PD-1 or PD-L1 inhibitors were excluded. Nivolumab was administered every 2 weeks at a dose of 3mg/kg until disease progression, unacceptable toxicity, or 24 months of treatment. The primary endpoint was the objective response rate (ORR) as per RECIST v1.1 criteria.

Results A total of 48 patients were enrolled in the study, with a median age of 61 years and 58.3% being male. The most common cancer type was colorectal cancer (41.7%), followed by prostate and biliary tract cancer (8.3%, each). Among the participants, 45 patients were eligible for assessing tumor response. 8 patients achieved partial response as their best overall response, resulting in an ORR of 17.8%. The disease control rate (DCR) was 60.0%. Median progression-free survival (mPFS) was 2.9 months. Treatment-related adverse events of any grade and grade ≥ 3 occurred in 44 (91.7%) and 3 (6.3%) patients.

Both TMB and microsatellite instability (MSI) were inferred by clinical targeted sequencing data. Using a TMB cutoff of 12mut/Mb, there were significant differences in PFS (p=0.0061) and BOR (p=0.05). Also, patients with high MSI scores (>2.5) demonstrated an increased response to nivolumab. In the RNA sequencing analysis, nivolumab responders showed activation of the interleukin signaling pathway. Patients who experienced early progression presented high activation of the epithelial-mesenchymal transition signaling pathway. No significant difference was found in PD-1+ CD8 T cells between nivolumab responders and non-responders. However, responders exhibited a marked increase in PD-1-/Ki67+ CD8 T cells at the early stage of treatment (C3D1) compared to 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 (>12mut/Mb) and MSI score (>2.5) determined through clinical target sequencing presented significant discriminatory power for nivolumab response.

Trial Registration Identifier: NCT04761744

Ethics Approval This clinical trial was reviewed and approved by IRB of Korea University Anam Hospital (IRB No. 2018AN0419)

Consent Written informed consent was obtained from the patient for publication of this abstract.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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