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울산대학교 의과대학, 서울아산병원 종양내과

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Nat. Med., Feb 19 2024, | https://doi.org/10.1038/s41591-024-02824-y Regorafenib plus nivolumab in unresectable hepatocellular carcinoma: the phase 2 RENOBATE trial

Hyung-Don Kim ^1,11, Seyoung Jung ^2,3,11, Ho Yeong Lim ⁴, Baek-Yeol Ryoo ¹, Min-Hee Ryu ¹, Samuel Chuah ⁵, Hong Jae Chon ⁶, Beodeul Kang ⁶, Jung Yong Hong ⁴, Han Chu Lee ⁷, Deok-Bog Moon ⁸, Ki-Hun Kim ⁸, Tae Won Kim ¹, David Tai ⁹, Valerie Chew ⁵, Jeong Seok Lee ^2,3, Richard S. Finn ¹⁰, June-Young Koh ² & Changhoon Yoo ¹

¹Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

²Genome Insight, Inc., San Diego, La Jolla, CA, USA.

³Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

⁴Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

⁵Translational Immunology Institute, SingHealth-Duke-NUS Academic Medical Centre, Duke-NUS Medical School, Singapore, Singapore.

⁶Department of Medical Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.

⁷Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

⁸Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

⁹Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.

¹⁰Division of Hematology-Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

¹¹These authors contributed equally: Hyung-Don Kim, Seyoung Jung.

Corresponding authors : Correspondence to June-Young Koh or Changhoon Yoo.

Abstract

Regorafenib has anti-tumor activity in patients with unresectable hepatocellular carcinoma (uHCC) with potential immunomodulatory effects, suggesting that its combination with immune checkpoint inhibitor may have clinically meaningful benefits in patients with uHCC. The multicenter, single-arm, phase 2 RENOBATE trial tested regorafenib-nivolumab as front-line treatment for uHCC. Forty-two patients received nivolumab 480 mg every 4 weeks and regorafenib 80 mg daily (3-weeks-on/1-week-off schedule). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). ORR per RECIST version 1.1 was 31.0%, meeting the primary endpoint. The most common adverse events were palmar-plantar erythrodysesthesia syndrome (38.1%), alopecia (26.2%) and skin rash (23.8%). Median PFS was 7.38 months. The 1-year OS rate was 80.5%, and the median OS was not reached. Exploratory single-cell RNA sequencing analyses of peripheral blood mononuclear cells showed that long-term responders exhibited T cell receptor repertoire diversification, enrichment of genes representing immunotherapy responsiveness in MKI67 ⁺ proliferating CD8 ⁺ T cells and a higher probability of M1-directed monocyte polarization. Our data support further clinical development of the regorafenib-nivolumab combination as front-line treatment for uHCC and provide preliminary insights on immune biomarkers of response. ClinicalTrials.gov identifier: NCT04310709 .

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-21)
연구진국내(교신)+국외 연구진
분야 의약학 > 응용의학

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