Josep M. Llovet, MD, PhD, on Intermediate-Stage Hepatocellular Carcinoma: Addition of Lenvatinib Plus Pembrolizumab to TACE

Dr Josep Llovet: Hi. I am going to summarize the study, Phase III LEAP-012, that was aimed to compare lenva, pembrolizumab, and TACE, versus TACE, or transarterial chemoembolization, in intermediate-stage HCC. So the rationale for the study, is that the standard of care for patients with intermediate HCC, defined as those with tumors confined to the liver without extrahepatic spread or vascular invasion, is transarterial chemoembolization for the last 20 years. Despite around 15 randomized controlled trials, all these studies unfortunately have been negative, but have established the median progression-free survival in seven to eight months, and the overall survival in 26 to 30 months. So the purpose of the study was to demonstrate that the combination with immune-based regimes, in this case, pembrolizumab plus lenvatinib, both drugs accepted as a management for advanced HCC, therefore active in HCC, combined with TACE, would be superior as a primary endpoint in terms of progression-free survival, and in terms of overall survival to the standard of care that is transarterial chemoembolization. We randomized for 180 patients, and the primary endpoint was hit. Progression-free survival was significantly superior favoring lenvatinib/pembrolizumab/TACE arm, with a median of 14.5 month, compared to 10 months for the dual placebo TACE with a hazard rate of 0.66 and a P-value of 0.0002. This profound effect in progression-free survival was also confirmed in the pre-specified subgroup analysis according to age, etiology, tumor stage, and so on and so forth. The secondary endpoint was also overall survival that we have a first watch. So it's the first interim analysis of a series of interim analysis, and then we have a final analysis, and therefore, is immature at this point. And nonetheless, we already show a trend favoring lenvatinib/pembrolizumab/TACE versus the TACE, versus the control arm, with hazard ratio of 0.8 and a P-value of 0.086. Again, in the subgroup analysis, we confirm that this effect is stable across the pre-specified subgroups. We also measure objective response rate by modified RECIST. That is the tool recommended by American and European guidelines. And objective response rate in the lenvatinib/pembrolizumab/TACE arm was 72%, among which 56% of the patients achieved complete response, which is remarkable figure, compared with an overall objective response rate of 49% in the TACE arm. And there was a nominal P-value of 0.0005. Of course, these three endpoints, the significant progression-free survival, that was the primary endpoint. Other primary, it was overall survival. There is a trend still the data is immature, and the objective response rate that is very positive, are also balanced by the fact that, as you can imagine with these drugs, there were treatment-related adverse events in the active arm. This accounted for grade 3/4 in 70% of the cases. I mean, the control arm with TACE, 31% of the patients had grade 3/4 treatment-related adverse events related to TACE alone. Overall, the treatment-related adverse events that were more common were hypertension, proteinuria, increased STLT, hypothyroidism, and also the postembolization syndrome associated with the TACE. The treatment-related adverse events leading to discontinuation to both drugs, lenvatinib and pembrolizumab, accounted for 8.2% of the cases, and were associated to grade five toxicity in 1.7% of the cases. So overall, we can conclude that lenvatinib plus pembrolizumab plus TACE is superior to the standard of care, transarterial embolization, in terms of progression-free survival with the hazard ratio of 0.666, meaning that we're able to decrease the progression of the disease 34%. That there is a clear trend in overall survival with hazard ratio of 0.8. And also that induces objective responses in 72% of the patients, 56 of which achieved complete response. This comes with a manageable profile in terms of adverse events that were known, and we did not identify a new treatment-related adverse event. And therefore, the conclusions of the study is that this combination of systemic therapies with lenvatinib plus pembrolizumab plus the local regional therapy, TACE can become the newest standard of care for the management of patients with intermediate HCC. So I would say, that from now on we have this potent combination. It's the first time that we have been able to improve significantly the benefit in patients that otherwise are treated with TACE, or in the US, Y-90, as well with systemic therapies. And therefore, this can be considered the newest standard of care. And this is the proposal from us according to the results. I think that this will change the management of the disease that has not changed for the last 20 years, and may be a tipping point in the management of this difficult disease. Just to frame finally, the impact of this result is that around 30% of the patients in the West are currently diagnosed at intermediate stage, and therefore, they might eventually benefit from these therapies. Thank you very much for your attention.