TACE combined with lenvatinib-pembrolizumab shows improved PFS in intermediate stage liver cancer

Prof Josep Llovet - Hospital Clinic Barcelona, Barcelona, Spain

Thank you very much, I’m going to summarise the background and results of the LEAP-012 study that is a randomised double-blind placebo-controlled trial comparing lenvatinib plus pembrolizumab plus TACE versus dual placebo plus TACE in patients with intermediate HCC.

Intermediate HCC patients are those that have a tumour confined to the liver without vascular invasion or extrahepatic spread. For the last 20 years the primary treatment of these patients has been transarterial chemoembolization. Around 15 randomised controlled trials have been conducting combining transarterial chemoembolization with systemic therapies and, unfortunately, all of them have been negative.

So we are presenting here the LEAP-012 study that combines lenvatinib, pembrolizumab plus TACE, up to two years, versus dual placebo plus TACE also up to two years. We randomised 480 patients to be allocated to either lenvatinib/pembrolizumab/TACE or dual placebo/TACE. 100 of the patients allocated to the lenvatinib/pembrolizumab/TACE arm discontinued the treatment due to progressive disease and 215 in the treatment arm. The median follow-up of the study was 25 months.

The primary endpoint of the study was progression free survival. At the first interim analysis after 286 events the primary endpoint was hit. The median progression free survival for the combo arm was 14.5 months and for the dual placebo arm was 10 months with a hazard ratio of 0.66, a p-value of 0.0002. So this profound effect was observed throughout the subgroup analysis, confirming the impact of these therapies in all the aetiologies and all the stages of the disease.

The second endpoint was overall survival. The first interim analysis, that was this one, was a bit immature in terms of number of events – 151. Nonetheless, we already see a non-significant trend with a hazard ratio of 0.8 and a p-value of 0.086.

Another endpoint was objective response rate and the difference between the groups was remarkable because the objective response rate in the combo arm achieved 72% of the patients achieved an objective response rate, among which 56% achieved complete response, as opposed to 49% objective response in the dual placebo arm. This difference was statistically significant.

Of course these three elements – substantial and clinically relevant, significant difference in progression free survival, a non-significant trend in OS and a significant difference in objective response rate – provide a rationale to suggest that this therapy should be the new standard of care. But this comes also with adverse events associated with that. Actually for the combo arm, grade 3/4 treatment-related adverse events account for 70% of the patients and in the TACE arm 30%. So this means that the toxicity directly related to TACE leads to 30% grade 3/4 of the events. The most common treatment-related adverse events in the combo arm were proteinuria, hypertension, AST/ALT increase, hyperthyroidism and then post-embolization syndrome that is associated with the TACE treatment.

So therefore after 20 years with a standard of care of TACE and having seen around 15 randomised controlled trials with a combination of TACE and systemic therapies that unfortunately have been negative, we have a strong trial that shows differences in progression free survival, a trend in overall survival and a substantial difference in objective response that provides a rationale to support this approach as the primary treatment for patients with intermediate HCC that represent 30% of the patients that actually suffer this disease.