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.

Abstract

379 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]

Frontline therapy for advanced hepatocellular carcinoma: an update

“…The results of this study were recently reported at ASCO Gastrointestinal Cancers Syposium. 42 The combination therapy improved survival compared with sorafenib (16.4 months versus 13.8 months, HR = 0.78, 95% CI 0.65–0.92, p = 0.0035). Single-agent durvalumab was found to be noninferior to sorafenib (HR = 0.86; 95% CI 0.73–1.03).…”

Systemic Therapy for Hepatocellular Carcinoma: Current Updates and Outlook

“… 219 The latest findings of the multicenter, phase III HIMALAYA study based on this revealed the superiority of the higher tremelimumab dose regimen over sorafenib on survival benefits (OS, 16.4 vs 13.8 months, P = 0.0035), thus strongly supporting the use of the Single Tremelimumab Regular Interval Durvalumab regimen (tremelimumab 300 mg+durvalumab 1500 mg followed by durvalumab every 4 weeks) as first-line therapy for aHCC. 220 Moreover, numerous ICI combination regimes ( Table 1 ), like IBI310 (anti-CTLA-4 antibody) plus sintilimab, are undergoing to explore a highly efficacious systemic therapy with a favorable safety profile.…”

Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology

“…Additionally, single agent durvalumab was noninferior to sorafenib, with a median OS of 16.6 versus 13.8 months (HR 0.86, noninferiority margin 1.08) and ORR of 17%. Based on these results, dual ICI combination and single agent durvalumab may become potential first-line systemic therapy options for advanced HCC in the near future ( 61 , 77 ). Other potential targets of checkpoint blockade include TIM-3 and LAG-3, which are both expressed along with PD-1 on CD8+ T cells and contribute to T cell dysfunction and suppression ( 78 ).…”