Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA.

  • Ghassan K. Abou-Alfa
    Department of Medicine, Memorial Sloan Kettering Cancer Center & Weill Medical College at Cornell University, New York, NY;
  • Stephen Lam Chan
    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, China;
  • Masatoshi Kudo
    Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan;
  • George Lau
    Humanity and Health Clinical Trial Center, Humanity and Health Medical Group, Hong Kong, China;
  • Robin Kate Kelley
    University of California, San Francisco, San Francisco, CA;
  • Junji Furuse
    Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan;
  • Wattana Sukeepaisarnjaroen
    Department of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand;
  • Yoon-Koo Kang
    Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea;
  • Tu V. Dao
    National Cancer Hospital and Hanoi Medical University, Hanoi, Viet Nam;
  • Enrico N. De Toni
    Department of Medicine II, University Hospital, LMU Munich, Munich, Germany;
  • Lorenza Rimassa
    Department of Biomedical Sciences, Humanitas University, Pieve Emanuele & Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy;
  • Valeriy Vladimirovich Breder
    Chemotherapy Department №17, N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation;
  • Alexander Vasilyev
    Railway Clinical Hospital, Moscow, Russian Federation;
  • Alexandra Heurgue
    Service d'Hépato-Gastro-entérologie, Hôpital Robert-Debré, Reims, France;
  • Vincent Tam
    Tom Baker Cancer Centre, Department of Oncology, University of Calgary, Calgary, AB, Canada;
  • Kabir Mody
    Division of Hematology/Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL;
  • Satheesh Chiradoni Thungappa
    Sri Venkateshwara Hospital, Bangalore, India;
  • Philip He
    AstraZeneca, Gaithersburg, MD;
  • Alejandra Negro
    AstraZeneca, Gaithersburg, MD;
  • Bruno Sangro
    Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain;

抄録

<jats:p> 379 </jats:p><jats:p> Background: A single priming dose of T (anti-CTLA-4) added to D (anti-PD-L1) in the STRIDE (Single T Regular Interval D) regimen, formerly T300+D, showed encouraging clinical activity and limited toxicity in a phase 2 uHCC study (Study 22, NCT02519348), suggesting single exposure to T is sufficient to improve upon D activity. HIMALAYA (NCT03298451) evaluated the efficacy and safety of STRIDE or D vs sorafenib (S) in uHCC. Methods: HIMALAYA is an open-label, multicenter, phase 3 study, in which pts with uHCC and no prior systemic therapy were initially randomized to STRIDE (T 300 mg plus D 1500 mg [one dose] plus D 1500 mg every 4 weeks [Q4W]), D (1500 mg Q4W), S (400 mg twice daily), or T 75 mg Q4W (4 doses) plus D 1500 mg Q4W (T75+D). Recruitment to T75+D ceased after a planned analysis of Study 22 showed T75+D did not meaningfully differ from D. The primary objective was overall survival (OS) for STRIDE vs S. The secondary objective was OS noninferiority (NI) of D to S (NI margin: 1.08). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR; RECIST v.1.1), duration of response (DoR), and safety. Results: In total, 1171 pts were randomized to STRIDE (N=393), D (N=389), or S (N=389). At data cutoff (DCO), the primary objective was met: OS was significantly improved for STRIDE vs S (hazard ratio [HR], 0.78; 96% confidence interval [CI], 0.65–0.92; p=0.0035; Table). D met the objective of OS NI to S (HR, 0.86; 96% CI, 0.73–1.03). ORRs were higher for STRIDE (20.1%) and D (17.0%) than for S (5.1%). No new safety signals were identified. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 25.8% (STRIDE), 12.9% (D), and 36.9% (S) of pts. Grade 3/4 hepatic TRAEs occurred in 5.9% (STRIDE), 5.2% (D), and 4.5% (S) of pts. No TRAE of esophageal varices hemorrhage occurred. Rates of TRAEs leading to discontinuation were 8.2% (STRIDE), 4.1% (D), and 11.0% (S). Conclusions: HIMALAYA was the first large phase 3 trial with a diverse, representative uHCC population and extensive long-term follow-up to assess both mono- and combination immunotherapy. D was noninferior to S with favorable safety. The combination of a single priming dose of T plus D in STRIDE displayed superior efficacy and a favorable benefit-risk profile vs S. STRIDE is a proposed, novel, first-line standard of care systemic therapy for uHCC. Clinical trial information: NCT03298451. [Table: see text] </jats:p>

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