Tislelizumab Yields QOL Benefit Over Sorafenib in First-Line Hepatocellular Carcinoma


Patients with unresectable hepatocellular carcinoma experienced an improvement in several health-related quality of life measures following treatment with first-line tislelizumab compared with sorafenib.

Treatment with first line tislelizumab resulted in an improvement in health-related quality of life (QOL) compared with sorafenib (Nexavar) in a population diagnosed with unresectable hepatocellular carcinoma (HCC), according to findings from the phase 3 RATIONALE-301 trial presented at the 2023 Gastrointestinal Cancers Symposium.1

In the RATIONALE-301 trial (NCT03412773), tislelizumab demonstrated improved EORLC GHS/QoL (European Organisation for Research and Treatment of Cancer Global Health Score/Quality of Life) scores, physical functioning, fatigue, and HCC symptom index versus sorafenib. However, it did not significantly reduce pain compared with sorafenib. QOL was maintained from cycle 4 to 6 in the tislelizumab arm whereas patients who received sorafenib deteriorated more significantly over the treatment period.

“Liver cancer represents a global health burden and while there have been advances of recent in the management of the disease, still new treatments are required,” Richard S. Finn, MD, a professor at UCLA’s Geffen School of Medicine, stated in his presentation.

The global phase 3 RATIONALE-301 trial randomly assigned 674 patients to receive tislelizumab, an IgG4 anti–PD-1 monoclonal antibody, or sorafenib, a tyrosine kinase inhibitor (TKI). The efficacy results of the study previously demonstrated noninferiority of tislelizumab versus sorafenib for overall survival and objective response rate (ORR), as well as showing improvements in tolerability.2

The participants in this study had treatment-naive HCC, Child-Pugh class A, ECOG performance status of 0 or 1, and no tumor thrombus involving main the trunk of portal vein, inferior vena cava, or clinical evidence of portal hypertension with bleeding varices at screening.

Health-related QOL was a key secondary end point in the study, and investigators employed 3 patient-reported outcome (PRO) surveys: the EORTC QLQ-C30 questionnaire for physical functioning and fatigue, the HCC-specific QLQ-HCC18 index, fatigue, and pain scores, and the EQ-5D-5L for descriptive purposes. Over 95% completed surveys at baseline, and the adjusted completion rates for both arms at cycle 4 and 6 were greater than 92%.

When looking at the QLQ-C30 survey’s GHS/QoL scores, patients maintained QOL with tislelizumab and QOL declined with sorafenib. The least square mean difference in scores between the arms was 4.3 favoring tislelizumab (95% CI, 1.4 to 7.3; nominal P ≤ .01). Tislelizumab’s mean score change from baseline to cycle 4 was -0.7 (95% CI, -3.0 to 1.6) versus -5.1 (95% CI, -7.6 to -2.6; P = .0037) for sorafenib. At cycle 6, the mean difference increased to 5.0 favoring tislelizumab (95% CI, 1.8 to 8.2; nominal P ≤ .01) and the mean score change from baseline to cycle 6 was -0.9 with tislelizumab (95% CI, -3.4 to 1.6) and -5.9 with sorafenib (95% CI, -8.6 to -3.2; P = .0022). The hazard ratio (HR) was 0.68 favoring tislelizumab (95% CI, 0.49 to 0.94).

The QLQ-C30 estimated mean physical functioning score showed a difference of 6.4 favoring tislelizumab (95% CI, 4.2 to 8.6; nominal P ≤ .01) after 4 cycles of treatment. After 6 cycles, the difference was 6.2 (95% CI, 3.7 to 8.6; nominal P ≤ .01) favoring tislelizumab. The HR for reduced physical functioning was 0.46 (95% CI, 0.33-0.64)

When evaluating reported fatigue based on the QLQ-C30 results, the mean difference in reported fatigue score was -7.6 (95% CI, -10.6 to -4.7; nominal P ≤ .01) at 4 cycles and -7.6 (95% CI, -10.8 to -4.3;nominal P ≤ .01) at 6 cycles. The HR favoring tislelizumab was 0.48 (95% CI, 0.37 to 0.63).

For the EORTC QLQ-HCC18 index score, the HR favoring tislelizumab was 0.53 (95% CI, 0.34 to 0.81; nominal P ≤ .01). At cycle 4, the mean difference was -2.3 (95% CI, -3.8 to -0.8; nominal P ≤ .01) and at cycle 6 the mean difference was -2.7 (95% CI, -4.7 to -0.7; nominal P ≤ .01).

When looking at patient-reported fatigue based on the QLQ-HCC18 questionnaire, the mean treatment difference in fatigue at 4 cycles was -6.2 (95% CI, -9.0 to -3.4; nominal P ≤ .01) and at 6 cycles was -6.0 (95% CI, -9.4 to -2.5; nominal P ≤ .01), both favoring tislelizumab. The HR for fatigue favoring tislelizumab was 0.60 (95% CI, 0.46 to 0.80).

The QLQ-HCC18 results for patient-reported pain impacting their QOL showed the mean difference in reported pain score was -0.6 (95% CI, -3.3 to 2.1) at 4 cycles and -0.4 (95% CI, -3.6 to 2.9) at 6 cycles. The HR favoring tislelizumab was 0.78 (95% CI, 0.56 to 1.09), not showing a significant difference in reported pain between the 2 study arms.

In the EQ-5D-5L VAS (visual analogue scale) for general health status, patients who received sorafenib appeared to decline further from baseline between cycles 4 and 6. There was a mean change from baseline of -4.3 (standard deviation [SD], 12.92) at cycle 4 and a mean change of -5.4 (SD, 13.09) at cycle 6 with sorafenib, whereas those who received tislelizumab had a mean change of -0.4 (SD, 14.52) at cycle 4 and -0.2 (SD, 17.03) at cycle 6.

These results, along with the improvements in survival, response, and safety shown in the original presentation of the study findings, suggest that overall health-related QOL will be improved with the single-agent immunotherapy versus the TKI.1,2

“In conclusion, RATIONALE-301 met its primary end point of demonstrating noninferiority to sorafenib in the frontline setting. It also met key clinical end points of including increasing ORR, as well as a favorable safety profile consistent with the class of the PD-1 inhibitor,” said Finn. “As we see here in this noninferiority study, QOL readouts favored tislelizumab versus sorafenib. And together these data support the potential of tislelizumab as a frontline option for patients who may not be a candidate for PD-1 doublet therapy.”


  1. Finn RS, Qin S, Kudo M, et al. Tislelizumab versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: Impact on health-related quality of life in RATIONALE-301 population. J Clin Oncol. 2023;41(suppl 4):495. doi:10.1200/JCO.2023.41.3_suppl.495
  2. 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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