At the ESMO Congress 2022, Professor Masatoshi Kudo reported the final analysis of the RATIONALE-301 study, which showed that the OS of tirelizumab used in the first-line treatment of unresectable liver cancer was not inferior to sorafenib. We interviewed Professor Kudo and shared the following topics related to the study.
Q1. Can you briefly introduce the final analysis of this RATIONALE-301 study?
Dr Kudo: The RATIONALE-301 study is a phase III randomized clinical trial of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. The primary endpoint was OS (overall survival). The RATIONALE-301 study met its primary endpoint showing OS non-inferiority. This was a non-inferiority study (non-inferiority margin, 1.08) with a 95% CI (confidence interval). Tislelizumab monotherapy demonstrated a clinically meaningful benefit. OS was 15.9 months versus 14.1 months with sorafenib. The OS hazard ratio was 0.85, and the upper boundary of 95% CI was 1.019, so this study met its primary endpoint on non-inferiority to sorafenib. The p-value was also significant - 0.039. The response rate is also significantly higher with tislelizumab - 14.3% versus 5.4% for sorafenib. The most impressive result from this study was the duration of response. The median duration of response was 36.1 months, compared with 11 months on sorafenib. This is very important. Also, the safety profile demonstrated no new safety concerns. Treatment-related adverse events greater than grade 3 were less frequent than with sorafenib, so it has a very manageable safety profile. This study was a positive study. This was a summary of the study.
Q2. RATIONALE-301 is also a non inferiority study design. Do you think PD-1 immunotherapy may be better than targeted therapy? Or maybe each has its own advantages?
Dr Kudo: The result showed non-inferiority, but as I said, the response rate is better for tislelizumab and the duration of response is very long, so once a patient responds to tislelizumab, the patient is expected to live longer. In that sense, compared to TKIs, tislelizumab is a treatment of choice. Clinically, I think it is a meaningful result - a higher response rate and the duration of response is long. In that regard, this is better than TKIs.
Q3. In the RATIONALE-301 study, How dose Asian patients respond and tolerlant to tislelizumab? Is there any difference between the East and the west patients?
Dr Kudo: Tolerability and dose intensity are not being presented at this ESMO meeting. Asian patients (excluding Japan) made up around 63% of enrollments. Japanese patients 11%. Rest of the World 26%. With regard to tolerability, in this presentation there are no data specific to Asian patients, but I think tislelizumab was tolerated very well by that patient population.
Q4. HBV related HCC is common in Asia. How dose these patients respond to tiselizumab? Because some studies show that HBV related HCC is worse on immunotherapy.
Dr Kudo: As far as OS is concerned, the hazard ratio in HBV patients was 0.91, compared to HCV 0.64, and non-viral 0.78. That means the OS benefit is inferior to non-HBV-related HCC, but the number of patients is very small. HBV patients make up around 60%, HCV 13% and non-viral 24% of the study population. For the HBV population, the OS benefit favors tislelizumab, so I think HBV patients can benefit from tislelizumab as well.
Q5. Combination therapy is the current research hotspot. Will there be studies on the combination therapy of tiselizumab in the future?
Dr Kudo: Yes, I believe this pharmaceutical company is planning combination trials.