(1) Four-year Overall Survival from the HIMALAYA Study of Tremelimumab + Durvalumab in Unresectable Hepatocellular Carcinoma

Stephen Chan, MD – Dr, State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir Yue-Kong Pao Center for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, China; Robin Kate Kelley, MD – Dr, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA; George Lau, MD, FRCP – Dr, Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong SAR, China; Masatoshi Kudo, MD, PhD – Prof, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan; Wattana Sukeepaisarnjaroen, MD – Dr, Department of Medicine, Songklanagarind Hospital, Khon Kaen University, Khon Kaen, Thailand; Enrico De Toni, MD, PhD – Prof, Department of Medicine II, University Hospital, LMU Munich, Munich, Germany; Junji Furuse, MD, PhD – Prof, Kanagawa Cancer Center, Yokohama, Japan; Yoo Koo Kang, MD, PhD – Prof, Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; Peter Galle, MD, PhD – Prof, Department of Internal Medicine I, University Medical Center, Mainz, Germany; Lorenza Rimassa, MD – Dr, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy and Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Alexandra Heurgué, MD – Dr, Department of Hepato-Gastroenterology, Robert-Debré Hospital, Reims, France; Vincent Tam, MD – Dr, Tom Baker Cancer Centre, Department of Oncology, University of Calgary, Calgary, AB, Canada; Tu Van Dao, MD, PhD – Prof, Cancer Research and Clinical Trials Center, Department of Optimal Therapy, National Cancer Hospital, Hanoi, Vietnam; Satheesh Chiradoni Thungappa, MD – Dr, Health Care Global Enterprises Ltd, Bangalore, India; Valeriy Breder, MD, PhD – Prof, N. N. Blokhin Russian Cancer Research Center, Chemotherapy Unit, Moscow, Russia; Yuriy Ostapenko, MD – Dr, Department of Minimally Invasive and Endoscopic Surgery, Interventional Radiology, National Cancer Institute, Kyiv, Ukraine; Maria Reig, MD, PhD – Prof, Barcelona Clinic Liver Cancer (BCLC), Liver Unit, Hospital Clinic de Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain; Mallory Makowsky, PharmD – Dr, Oncology R&D, Late-Stage Development, AstraZeneca, Gaithersburg, MD, USA; Charu Gupta, MSc – Dr, Oncology Biometrics, Late Oncology Statistics, AstraZeneca, Wilmington, DE, USA; Alejandra Negro, PhD – Dr, Oncology R&D, Late-Stage Development, AstraZeneca, Gaithersburg, MD, USA; Bruno Sangro, MD, PhD – Prof, Liver Unit and HPB Oncology Area, Clínica Universidad de Navarra and CIBEREHD, Pamplona, Spain

Purpose: In the primary analysis (data cut-off: 27 August 2021) of the phase 3 HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) and demonstrated a durable long-term survival benefit versus sorafenib; durvalumab monotherapy was noninferior to sorafenib (Abou-Alfa et al. NEJM Evid 2022). Here, we report an updated 4-year OS analysis of HIMALAYA.

Material and Methods: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (tremelimumab 300 mg for one dose plus durvalumab 1500 mg every 4 weeks [Q4W]), durvalumab (1500 mg Q4W) or sorafenib (400 mg twice daily). Data cut off was 23 January 2023 (STRIDE OS data maturity, 78%). OS and serious treatment-related adverse events (TRAEs) were assessed. In addition, baseline demographics and disease characteristics were assessed in long-term survivors (LTS; participants surviving ≥36 months beyond randomization).

Results: In total, 1171 participants were randomized to STRIDE (n=393), durvalumab (n=389) or sorafenib (n=389); median (95% CI) duration of follow-up for the OS analysis in all participants was 49.12 (46.95–50.17), 48.46 (46.82–49.81) and 47.31 (45.08–49.15) months, respectively. The OS HR for STRIDE versus sorafenib (0.78; 95% CI, 0.67–0.92) and estimated 36-month OS rates for STRIDE (30.7%) and sorafenib (19.8%) were consistent with the primary analysis. The 48-month OS rate remained higher for STRIDE (25.2%) versus sorafenib (15.1%). Serious TRAEs occurred in 17.5% of participants treated with STRIDE and 9.6% of participants treated with sorafenib, with no new events occurring after the primary analysis for STRIDE (17.5%). Durvalumab OS noninferiority to sorafenib and safety was consistent with the primary analysis. Baseline demographics, clinical characteristics and subsequent therapies, including tremelimumab rechallenge, for LTS in the STRIDE arm were generally consistent with the full analysis set, suggesting that LTS were not from any particular subgroup.

Conclusions: These data reinforce the sustained, long-term OS benefit of STRIDE versus sorafenib in a diverse uHCC population, demonstrating unprecedented 3- and 4-year OS rates and longest follow-up to date in phase 3 uHCC studies. STRIDE maintained a tolerable safety profile, with no new serious safety events. This abstract was originally presented at the 2023 World Congress on Gastrointestinal Cancer.