Tislelizumab OS benefit vs sorafenib as first line treatment for unresectable hepatocellular carcinoma

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Published: 11 Sep 2022
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Prof Richard S Finn - UCLA Health Santa Monica Cancer Care, Santa Monica, USA

Prof Richard S Finn speaks to ecancer about the final analysis of RATIONALE-301, a randomised, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. 

The primary endpoint was OS; secondary endpoints included ORR, PFS, and DOR by blinded independent review committee, and safety.

The results showed single-agent tislelizumab demonstrated clinically meaningful OS benefit that was non-inferior to SOR with a favourable safety profile as a first line treatment option for patients with unresectable hepatocellular carcinoma.

RATIONALE-301 is a phase III study evaluating tislelizumab versus sorafenib also in the frontline
setting of advanced liver cancer. This study was an open label study, a global study, and was
powered for non-inferiority. We have seen that single agent PD-1 inhibitors are active in liver cancer,
however, they have not been able to improve survival versus sorafenib. But this study did meet its
endpoint of non-inferiority with a survival in the treatment arm with tislelizumab of over 15 months and
survival in the sorafenib arm of about 14 months and a hazard ratio of about 0.86. Now, the upper
limit of that confidence interval for the hazard ratio does cross 1.0 but it is under the non-inferiority
threshold of 1.08.

So this is a positive study and, just like a few months back we saw data from the HIMALAYA study of
durvalumab versus sorafenib, the PD-L1 inhibitor, and that also met non-inferiority, it seemed very
similar. The objective response rates with tislelizumab are as expected with a single agent PD-1
inhibitor of about 15% and these drugs are very safe.

So collectively we have three phase III studies of single agent PD-1 inhibitors, initially CheckMate 459
of nivolumab versus sorafenib which was powered for superiority and did not meet superiority but had
it been a non-inferiority study it probably would have met that endpoint. Then from HIMALAYA we
have durvalumab single agent versus sorafenib which met a non-inferiority endpoint and now
tislelizumab which also met its non-inferiority endpoint with a very favourable safety profile.

So how do single agent PD-1 inhibitors fit into our armamentarium? The most active regimen we have
right now in liver cancer in the frontline setting is atezolizumab and bevacizumab, based on the
IMbrave 150 study, but a subset of patients probably won’t be a candidate for that because of
potential risks from bevacizumab such as high-risk bleeding, a recent high-grade bleeding event. So
for those patients who are otherwise candidates for a PD-1 inhibitor, single agent tislelizumab may be
an option. What’s also potentially an option would be durvalumab and tremelimumab, that regimen
from the HIMALAYA study. But what’s also still very provocative is that single agent lenvatinib gave a
survival of 19 months which is longer than what we’ve seen in any other liver cancer study other than
IMbrave 150 in regards to drugs that are approved at this time.

So the liver cancer space is rapidly changing for the better for patients and there are still some data
we’re waiting to see.