Hepatocellular carcinoma is the most common primary liver cancer and one of the deadliest tumours. It usually develops in people who have suffered from chronic liver diseases such as viral hepatitis or fatty liver. One quarter (25%) of patients are diagnosed in an intermediate stage, with an unresectable tumour, meaning one that cannot be operated on, but that has not yet metastasised. For 20 years, the standard treatment for these patients has been chemoembolisation, which restricts or blocks the blood supply to the tumour, leading to necrosis, or cell death, in the tumour tissue. This treatment was established at IDIBAPS-Hospital Clínic Barcelona in 2002 and adopted by European and American clinical guidelines. Although chemoembolisation ensures an average survival period of between 20 and 30 months, attempts to boost it with new treatments have been unsuccessful.
Now, an article published in The Lancet presents the results of a phase 3 clinical trial led by Josep M Llovet, the head of the IDIBAPS research group Translational research in hepatic oncology, a professor of Medicine at the University of Barcelona, an ICREA professor and a professor of Medicine at the Icahn School of Medicine at Mount Sinai, New York. The article shows that in addition to chemoembolisation, the administration of the drugs lenvatinib and pembrolizumab significantly prolongs the progression-free survival of patients with intermediate-stage hepatocellular carcinoma. Specifically, such patients enjoy a progression-free survival period of 14.6 months, compared to 10 months with chemoembolisation alone. Furthermore, the antitumour response is 72% vs 50%, respectively.
‘This study marks a paradigm shift in managing patients with intermediate stages of hepatocellular carcinoma. It moves from treatment with chemoembolisation alone to incorporating systemic treatment, with a multikinase inhibitor and immunotherapy. This approach improves patients’ prognosis by lowering the risk of disease progression by 34%’, says Josep M. Llovet, the lead researcher of the international clinical trial, which involves 137 centres from around the world.
The study included 480 patients divided into two groups. All participants underwent chemoembolisation, but only one group was administered lenvatinib orally and pembrolizumab intravenously. The other group was given a placebo. In the follow-up, which lasted over two years, some improvement in the patients’ overall survival was observed, in addition to the antitumour response and progression-free survival, though the data are not yet sufficiently mature.
‘To state with certainty that the combination of lenvatinib and pembrolizumab increases patient survival, we need to conduct a more extensive follow-up to get more data that will indicate whether there is statistical significance’, Josep M. Llovet says. ‘In any case, the data we have so far are quite encouraging’.
Lenvatinib and pembrolizumab: the combination of kinase inhibitors and immunotherapy
Lenvatinib belongs to the kinase inhibitor family and blocks cell signalling that induces division and halts the spread of cancer. It is a drug already approved for treating patients with advanced hepatocellular carcinoma who cannot benefit from chemoembolisation or whose chemoembolisation treatment has failed. Pembrolizumab is an antibody that helps the immune system to attack tumour cells and has already been approved for use in the United States.
‘We chose these two drugs because we believed that combining immunotherapy with a multikinase inhibitor could prevent the immunosuppression present in these tumours, thereby increasing antitumour activity. We also thought it could also prevent the formation of new blood vessels in the tumour, which would increase the effect of chemoembolisation’, Llovet explains.
The presentation of the results of this trial was the main item on the agenda of the plenary session of the ESMO congress, which was held in Barcelona in the autumn and brought together over 30,000 professionals. This clinical trial was carried out with funding from Eisai and Merck.
Original paper
Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab versus dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study. Kudo, Masatoshi et al. The Lancet, Volume 0, Issue 0.
