Frontline Tislelizumab Vs Sorafenib Yields Survival Benefit in Unresectable HCC


Results from the phase 3 RATIONALE-301 trial showed improved overall survival for patients who were given frontline tislelizumab for unresectable hepatocellular carcinoma.

At the 2022 European Society for Medical Oncology Congress (ESMO), a meaningful overall survival (OS) benefit and higher objective response rate (ORR) was observed when frontline tislelizumab was given compared with sorafenib (Nexavar) for patients with unresectable hepatocellular carcinoma.

Data looking at the humanized IgG4 anti–PD-1 monoclonal antibody as a monotherapy in these patients came from the final analysis of the randomized phase 3 RATIONALE-301 (NCT03412773) study that looked at a total of 674 patients randomized to either tislelizumab (n = 342) or sorafenib (n = 332).

Researchers found a non-inferior median OS of 15.9 months (95% CI, 13.2-19.7, months) in the tislelizumab arm compared with 14.1 months (95% CI, 12.6-17.4, months) in the sorafenib arm (HR 0.85; 95.003% CI, 0.712-1.019, P = .0398). However, OS superiority for tislelizumab compared with sorafenib was not met, but the study still reached its primary end point of OS non-inferiority in the monotherapy vs sorafenib.

This OS benefit was also observed across all subgroups, according to Masatoshi Kudo, MD, PhD, a lead investigator of the study who presented the final analysis results at the 2022 ESMO Congress in Paris, France, this year.

Key subgroups where OS favored tislelizumab included patients 65 years or older (HR 0.76; 95% CI, 0.57-1.02), patients in which microvascular invasion and/or extrahepatic spread was absent (HR 0.78; 95% CI, 0.56-1.07), patients with hepatitis C infection (HR 0.64; 95% CI, 0.38-1.08), and female patients (HR 0.62; 95% CI, 0.39-0.99).

“There are currently no single agent checkpoint inhibitors approved in this setting,” explained Kudo, professor and chairman in the Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, in his presentation when explaining the background of this study. “Tislelizumab is a monoclonal antibody, which has a hybrid binding affinity for [PD-1] and was specifically engineered to minimize FCy gamma receptor binding on macrophages. Tislelizumab monotherapy has progressively demonstrated durable responses and was generally well tolerated in patients with previously treated advanced HCC.”

This study randomized patients 1:1 to either 200 mg of intravenous tislelizumab given every 3 weeks or 400 mg of oral sorafenib given twice a day. Eligible patients had to have histologically confirmed HCC, were naïve to systemic therapy, Child-Pugh class A, an ECOG performance score of 1, and no tumor thrombus involving the main trunk of the portal vein or inferior vena cava. Patients remained on treatment until disease progression or intolerable toxicity.

According to Kudo, the study consisted ofmostly Asian patients (excluding Japan) at 62.9% (n = 215) in the tislelizumab arm and 63.3% (n = 210) in the sorafenib arm. Patients from Japan on either the study drug or control drug made up 11.1% and 11.7% of patients, respectively, followed by 26.0% and 25.0% from the rest of the world. The median age of patients in each arm was comparable at 62 years of age (range, 25.0-86.0) in the tislelizumab arm and 60 years old (range, 23.0-86.0) in the sorafenib arm. Moreover, over 80% of patients in both arms were male, over 75% were Barcelona-Clinic Liver Cancer stage C at the time of enrollment, and over 70% of patients in both arms had a Child Pugh score of 5. Most patients also had hepatitis B across both arms at 59.4% in the tislelizumab arm and 62.0% in the control arm.

When assessing these patients for the continuation of durable responses tislelizumab was associated with a higher ORR of 14.3% (95% CI, 10.8%-18.5%) vs 5.4% (95% CI, 3.2%-8.4%) in the sorafenib arm. Moreover, there were 10 complete responses in the tislelizumab arm compared with 1 patient in the sorafenib arm. However, 139 patients in the sorafenib arm had stable disease compared with 94 in the study arm, whereas 169 patients in the study arm had progressive disease vs 121 in the sorafenib arm.

Median duration of response was also longer in the study arm responders (n = 49) at 36.1 months compared with 11 months in the sorafenib responders (n = 18). Of these patients 71.4% have an ongoing response with tislelizumab compared with 40.0% with sorafenib. Yet, when looking at the median progression-free survival between both groups sorafenib was longer at 3.6 months (95% CI, 2.2-4.1) compared with 2.2 months in the study arm (95% CI, 2.1-3.5) with a hazard ratio of 1.11 (95% CI, 0.92-1.33).

Treatment-emergent adverse events (TEAEs) and treatment related AEs at grade 3 or higher were less frequent with the study drug at 48.2% and 22.2%, respectively, compared to 65.4% and 53.4% in the sorafenib arm. This also led to fewer discontinuations and dose modifications in the study drug compared with sorafenib at 10.9% and 31.1% vs 18.5% and 64.8%, respectively. However, TEAEs leading to death were comparable at 4.4% in the tislelizumab arm and 5.2% in the sorafenib arm.

Grade 3 or greater incidences of increased aspartate aminotransferase and/or alanine transaminase, increased blood bilirubin, decreased platelet counts, and diarrhea were lower in the tislelizumab group, below 50%, compared with higher rates in the sorafenib arm. According to Kudo this was especially so in the hypertension group and only patients on sorafenib experienced grade 3 or greater palmar-plantar erythrodysesthesia.

“To conclude, single agent tislelizumab demonstrated a clinically meaningful anti-tumor benefit vs sorafenib with a favorable and manageable safety profile in this patient setting,” Kudo said. “We hope to provide further insights on these data at future medical meetings.”


Kudo M, Qin S, Meyer T, et al. Final analysis of RATIONALE-301: Randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089.

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