LBA36 - Final analysis of RATIONALE-301: Randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma

Background

Tislelizumab (TIS), an anti-PD-1 monoclonal antibody, has demonstrated durable responses and was well tolerated as monotherapy in 2L+ treatment in patients (pts) previously treated systemically for unresectable HCC (Ducreux et al, 2021). TIS has been further evaluated against sorafenib (SOR) in a global randomized Phase 3 study (RATIONALE-301; NCT03412773) as 1L treatment in adult pts with unresectable HCC.

Methods

Systemic therapy-naïve adults with histologically confirmed HCC BCLC Stage B/C who were not amenable to or progressed after loco-regional therapy, Child-Pugh A, with ≥1 measurable lesion per RECIST v1.1, and an ECOG PS ≤1 were eligible. Pts were randomized 1:1 to receive TIS (200 mg IV Q3W) or SOR (400 mg PO BID) until disease progression, intolerable toxicity, withdrawal, or no longer benefiting from therapy. The primary endpoint was OS; secondary endpoints included ORR, PFS, and DOR by blinded independent review committee, and safety. Non-inferiority of OS between TIS and SOR was tested against the non-inferiority margin of 1.08.

Results

A total of 674 pts were randomized (n=342, TIS; n=332, SOR); at data cutoff (11 Jul 2022) minimum study follow up was 33 months (mo). In this final analysis, RATIONALE-301 met its primary endpoint of OS non-inferiority (mOS: 15.9 mo [TIS] vs 14.1 mo [SOR]; stratified HR: 0.85 [95.003% CI: 0.712, 1.019]). TIS was associated with higher ORR (14.3% vs 5.4%) and more durable responses (mDoR: 36.1 mo vs 11.0 mo) compared with SOR. Median PFS with TIS was 2.2 mo and 3.6 mo with SOR (HR: 1.1 [95% CI: 0.92, 1.33]). Median treatment duration was longer with TIS vs SOR (4.1 mo vs 2.7 mo). The safety profiles for both treatments were consistent with prior reports. Incidence rates of grade ≥3 AEs (48.2% vs 65.4%) and AEs leading to discontinuation (10.9% vs 18.5%) were lower with TIS compared with SOR; AEs leading to death were low across both treatments (4.4%, TIS; 5.2%, SOR). Immune-mediated AEs occurring in ≥5% TIS-treated pts were hepatitis (5.3%) and hypothyroidism (5.3%).

Conclusions

Single-agent TIS demonstrated clinically meaningful OS benefit that was non-inferior to SOR with a favorable safety profile as a 1L treatment option for pts with unresectable HCC.

Clinical trial identification

NCT03412773.

Editorial acknowledgement

This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Arezou Seyed Hossein, MPharm, of Ashfield MedComms, an Ashfield Health company, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

M. Kudo: Financial Interests, Invited Speaker: Eli Lilly, Bayer, Eisai, Chugai, Takeda; Financial Interests, Research Grant: Gilead Sciences, Taiho, Sumitomo Dainippon Pharma, Takeda, Otsuka, EA Pharma, AbbVie, Eisai. T. Meyer: Financial Interests, Advisory Board: MSD, Ipsen, AstraZeneca, Eisai, Roche, Adaptimmune; Financial Interests, Institutional, Funding, Grant to institution: MSD, BTG. R.S. Finn: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, CStone, Bayer, BMS, Exelixis, Eli Lilly, Eisai,Hengrui, Merck, Pfizer, Roche/ Genenentech; Financial Interests, Institutional, Research Grant: Adaptimmune, Bayer, BMS, Eli Lilly, Eisai,Merck, Pfizer, Roche/ Genentech; Non-Financial Interests, Principal Investigator: Eisai, Merck, Roche/Genentech, BMS, Pfizer. A. Vogel: Financial Interests, Invited Speaker: Roche, Bayer, BMS, Lilly, EISAI, AstraZeneca, Ipsen, MSD, Sirtex, BTG, Servier, Terumo, Imaging Equipment Ltd (AAA); Financial Interests, Advisory Board: Roche, Bayer, BMS, Lilly, EISAI, AstraZeneca, Ipsen, MSD, Sirtex, BTG, Servier, Terumo, Imaging Equipment Ltd (AAA). A. Hiraoka: Non-Financial Interests, Speaker’s Bureau: Chugai Pharma., Lilly, Beyer. D. Marino: Financial Interests, Advisory Board: Roche, MSD; Financial Interests, Sponsor/Funding, Travel and meeting expenses: Pierre-Fabre. E. Assenat: Financial Interests, Advisory Board: Roche, Astra Zeneca, Servier,Ipsen. M. Calvo Campos: Financial Interests, Advisory Role: Roche/Eisai/Bayer/MSD. K. Hsing-Tao: Financial Interests, Principal Investigator: BeiGene Ltd. F. Boisserie: Financial Interests, Full or part-time Employment: BeiGene; Financial Interests, Stocks/Shares: BeiGene. S. Li: Financial Interests, Full or part-time Employment: BeiGene, Ltd. Y. Chen: Financial Interests, Full or part-time Employment: BeiGene, Ltd. A.X. Zhu: Financial Interests, Advisory Role, Consulting fee: Merck, Roche, Sanofi, Eisai, Exelixis, Bayer, Lilly. All other authors have declared no conflicts of interest.