O-1 Results from a global phase 2 study of tislelizumab, an investigational PD-1 antibody, in patients with unresectable hepatocellular carcinoma

Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding of FcyR on macrophages to help abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Two early phase studies (NCT02407990, CTR20160872) demonstrated that single-agent tislelizumab (200 mg) administered intravenously (IV) every 3 weeks (Q3W) was generally well tolerated and showed preliminary antitumor activity in patients with advanced solid tumors, including hepatocellular carcinoma (HCC). This global Phase 2 study (NCT03419897) examined single-agent tislelizumab (200 mg IV Q3W) in patients with unresectable HCC with Child-Pugh A and Barcelona Clinic Liver Cancer (BCLC) stage B/C who had received at least one prior line of systemic therapy. The primary endpoint was overall response rate by independent review committee (IRC) (ORR IRC) per RECIST v1.1. Secondary endpoints included progression-free survival by IRC (PFS IRC), ORR per investigator (ORR INV), duration of response (DoR), overall survival (OS), and the safety/tolerability profile of tislelizumab. As of Aug 2019, 249 patients (median age 62 years) were enrolled. At study entry, 225 (90%) patients had BCLC stage C and 200 (80%) had extrahepatic spread; 111 (45%) patients had received ≥2 prior systemic therapies and 233 (94%) had received prior sorafenib. Across the study population, confirmed ORR IRC was 12.4% (95% CI: 8.6, 17.2) with 2 complete responses (CR) and 29 partial responses (PR); ORR INV was 14.1% (95% CI: 10, 19.0) with 1 CR and 34 PRs. With a median study follow-up of 9.1 months, DoR IRC was not reached (NR). Median OS and PFS IRC were 12.4 months (95% CI: 10.8, NR) and 2.7 months (95% CI: 1.5, 2.8), respectively; the 1-year OS rate was 51.9% (95% CI: 44, 59). Number of prior lines of therapy did not impact response (1 prior line, ORR IRC = 13.0% [95% CI: 7.9, 19.8]; ≥2 prior lines, ORR IRC =11.7% [95% CI: 6.4, 19.2]) or survival estimates (1 prior line, median OS=13.0 months [95% CI: 10.5, NR], median PFS=2.6 months [95% CI: 1.4, 2.8]; ≥2 prior lines, median OS=11.8 months [95% CI: 10.6, NR], median PFS=2.7 months [95% CI: 1.4, 2.8]). The most common treatment-related adverse events (TRAEs) were increased AST (n=30; 12%) and ALT (n=2; 9%); increased AST (n=6; 2%) was the only grade 3–4 TRAE occurring in ≥2% of patients. Two patients had fatal AEs (infectious pneumonia, hepatic encephalopathy; n=1 each); neither was attributed to treatment by investigator. Tislelizumab demonstrated durable responses and was well tolerated in patients with previously systemically treated unresectable HCC, a patient population with a continued high unmet medical need. A large, global, randomized Phase 3 study comparing tislelizumab with reference standard of care sorafenib as a first-line treatment in adult patients with unresectable HCC (NCT03412773) is currently ongoing.