ESMO: Merck's Keytruda-Lenvima aims to change liver cancer treatment despite past challenges

Merck & Co. and Eisai have unveiled promising new data that could position their Keytruda-Lenvima combination as a standard treatment for intermediate-stage liver cancer. This revelation came following the phase 3 LEAP-012 study, presented at the European Society of Medical Oncology (ESMO) 2024 annual meeting. The study demonstrated that adding Keytruda and Lenvima to the standard transarterial chemoembolization (TACE) treatment significantly reduced the risk of disease progression or death by 34% compared to TACE alone. Patients treated with the combination therapy experienced a median of 14.6 months without disease progression, compared to 10 months for those on TACE alone.

However, despite these promising results, some questions remain unanswered. One major concern is that the combination treatment has not yet conclusively proven it can extend overall survival. While early data show a 20% reduction in the relative risk of death favoring the combination, this figure has not reached statistical significance. To date, 47.5% of the necessary deaths for final overall survival analysis have occurred, and patient monitoring continues. The overall survival rate is a critical endpoint for the study, given the significant increase in treatment-related adverse events with the combination therapy. In the trial, 71.3% of patients in the combination group experienced severe treatment-related side effects, compared to 31.5% in the control group. Additionally, treatment discontinuations due to side effects were notably higher in the combination group.

Another point of discussion is the individual contribution of each component in the combination therapy, especially Keytruda, to the observed outcomes. This scrutiny follows the earlier LEAP-002 trial where the Keytruda-Lenvima combination failed to outperform Lenvima alone in newly diagnosed advanced liver cancer patients. At that time, the results upheld Lenvima monotherapy as the standard first-line treatment for advanced liver cancer.

This isn't the first time Keytruda has struggled in liver cancer trials. The KEYNOTE-240 trial previously missed its statistical significance target in advanced liver cancer patients treated with Bayer’s Nexavar. Despite this, the FDA advisory panel decided to retain Keytruda’s accelerated approval for second-line liver cancer treatment, partly due to pending data from a similar trial in Asia. Later, the phase 3 KEYNOTE-394 study showed that Keytruda significantly reduced the risk of death by 21% compared to placebo in Asian patients with previously treated liver cancer. As a result, the FDA granted full approval for Keytruda in January for second-line treatment in liver cancer patients with hepatitis B who had received a non-PD-1/L1 regimen.

Meanwhile, Lenvima has shown some efficacy as a standalone treatment in intermediate-stage liver cancer in a different patient population. A phase 2 study conducted by Japanese researchers indicated that the Lenvima-TACE combination led to a median progression-free survival of 28 months and a response rate of 88.7%. These findings suggested the regimen could be effective and safe for patients ineligible for locoregional therapy.

Intermediate-stage liver cancer, which accounts for about 30% of liver cancer diagnoses, represents a varied patient population. The LEAP-012 study focused on patients who are not suitable for curative treatment and who have relatively normal liver function (Child-Pugh class A). Approval of the Keytruda-Lenvima combination for this indication could significantly boost Keytruda’s revenue ahead of its 2028 loss of exclusivity, according to analysts from Leerink Partners.