Chan, Stephen L.

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]

259 Background: Belinostat is a novel histone deactylase inhibitor which demonstrates preclinical activity in HCC. We report the results of a phase I/II study on belinostat in patients (pts) with unresectable HCC. Methods: Major eligibility criteria included histologically confirmed HCC not amenable to curative treatment; PS ≤ 2; adequate organ function; prior systemic therapy was allowed. In the phase I portion, belinostat was given i.v. on D1-5 every 3 weeks with dose levels of 600, 900, 1200 and 1400 mg/m2/day. In the phase II portion, belinostat was tested at the MTD. Primary endpoint was PFS and secondary endpoints were RR according to RECIST and OS. CT assessment was done every 8 weeks. Results: Phase I portion: a total of 18 pts were accrued; no DLTs were observed at 1400mg/m2/day for 5 days, and this dose was selected for phase II development. Phase II portion: 42 pts were accrued; Median age = 57.5 years; 41 had Child’s A function, and 24 pt had ECOG 0. Sixteen (38%) had previous systemic therapy, and 21 (50%) had previous transarterial therapy. Median follow-up was 20.0 months. The PR and SD rate was 2.4% (1/42) and 45.2% (19/42). Median PFS was 2.64 months (95%C.I. 1.55-3.17) and OS was 6.60 months (95%C.I. 4.53-11.60). Grade 3 or higher toxicities (>5% rate) were abdominal pain (9.5%), (9.5%) hyperbilirubinemia (9.5%), raised ALT (9.5%); anemia (7.1%) and vomiting (7.1%). Conclusions: Belinostat demonstrates disease stabilization in a predominantly pretreated population of pts with unresectable HCC with an acceptable safety profile. Further randomized studies are warranted.Supported in part by N01-CM-62205.