Tislelizumab non-inferior to sorafenib in the first-line treatment of unresectable hepatocellular carcinoma

At ESMO 2022, the final results of the RATIONALE-301 study, which compared the efficacy and safety of tislelizumab with sorafenib as a single-agent in the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC), were presented. In this analysis, tislelizumab demonstrated a clinically meaningful overall survival benefit that was non-inferior to sorafenib, with a favourable safety profile as a first-line treatment option in this patient population.

In the first-line treatment of hepatocellular carcinoma (HCC), atezolizumab plus bevacizumab is currently the standard of care. No single-agent checkpoint inhibitor has been approved in this setting. Tislelizumab, a monoclonal antibody with high binding affinity for PD-1 was specifically engineered to minimise Fcγ receptor binding on macrophages. In the phase II RATIONALE-208 study, tislelizumab monotherapy demonstrated durable responses and was generally well tolerated in patients with previously-treated advanced HCC. At ESMO 2022, final results of the RATIONALE-301, which compared the efficacy and safety of tislelizumab with sorafenib as a single-agent, in the first-line treatment of patients with unresectable HCC were presented.

Study design

RATIONALE-301 is a randomised, open-label, multicentre, multiregional phase III study. Systemic therapy-naïve adults with histologically confirmed HCC BCLC Stage B/C who were not amenable to or progressed after locoregional therapy, Child-Pugh A, with ≥1 measurable lesion per RECIST v1.1, and an ECOG performance status ≤1 were eligible. Patients were randomised 1:1 to receive tislelizumab (200 mg IV Q3W) or sorafenib (400 mg PO BID) until disease progression, intolerable toxicity, withdrawal, or no longer benefiting from therapy. The primary endpoint was overall survival (OS); secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR) by blinded independent review committee, and safety. Non-inferiority of OS between tislelizumab and sorafenib was tested against the non-inferiority margin of 1.08.

Results

In total, 674 patients were randomised to tislelizumab (N= 342) or sorafenib (N= 332). Minimum study follow-up time was 33.0 months in both treatment arms. The patient baseline characteristics were well-balanced between treatment arms. Median age was 62 years in the tislelizumab arm and 60 years in the sorafenib arm. Approximately 85% of patients were male across the two cohorts. Most patients were from Asia, with about 25% of patients from Europe or the United States. Almost 80% of patients had BCLC stage C at study entry.

In this final analysis, RATIONALE-301 met its primary endpoint of OS non-inferiority (mOS: 15.9 months [tislelizumab] vs. 14.1 months [sorafenib]; stratified HR[95%CI]: 0.85[0.712- 1.019], p= 0.0398). The OS results in the overall population were consistently observed across all subgroups. Tislelizumab was also associated with higher ORR (14.3% vs. 5.4%) and more durable responses (mDoR: 36.1 vs. 11.0 months) compared with sorafenib. The median PFS with tislelizumab was 2.1 months, as compared to 3.4 months with sorafenib (HR[95%CI]: 1.11[0.92- 1.33]). Median treatment duration was longer with tislelizumab vs. sorafenib (4.1 vs. 2.7 months). The safety profiles for both treatments were consistent with prior reports. Incidence rates of grade ≥3 treatment-emergent adverse events (TEAEs, 48.2% vs. 65.4%) and TEAEs leading to discontinuation (10.9% vs. 18.5%) were lower with tislelizumab compared with sorafenib. TEAEs leading to death were low across both treatments (4.4% vs. 5.2% for tislelizumab and sorafenib, respectively). Immune-mediated AEs occurring in ≥5% tislelizumab-treated patients were hepatitis (5.3%) and hypothyroidism (5.3%).

Conclusion

RATIONALE-301 met its primary endpoint of OS non-inferiority with tislelizumab versus sorafenib in first-line HCC. In addition, tislelizumab was associated with a higher ORR and more durable responses vs. sorafenib. Fewer patients experienced TEAEs, grade ≥3 TEAEs, and TEAES leading to discontinuation or dose modification with tislelizumab as compared to sorafenib.

Reference

Kudo M, et al. Final Analysis of RATIONALE-301: Randomized, Phase 3 study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Presented at ESMO 2022; Abstract LBA36.