After a surprise failure in advanced liver cancer, Merck & Co. and Eisai are hoping new data can make their Keytruda-Lenvima combination a standard of care in intermediate-stage disease.
The positive readout from the phase 3 LEAP-012 study was unveiled Saturday for the first time at the European Society of Medical Oncology (ESMO) 2024 annual meeting. The addition of Keytruda and Lenvima to standard transarterial chemoembolization (TACE) reduced the risk of disease progression or death by 34% versus TACE alone, the trial found.
Patients who took the experimental combo lived a median 14.6 months without disease progression versus 10 months for those in the control arm.
The results were presented during a presidential symposium session designated for “practice-changing trials” at the ESMO meeting. However, a couple questions remain for the proposed regimen.
First, Keytruda and Lenvima’s combination with TACE has not yet proven it can prolong patients’ lives. The relative risk of death so far showed an early trend in favor of the triplet by 20%, although the number has not met the statistical significance bar. So far, 47.5% deaths required for a final overall survival analysis had occurred, and investigators were still following the patients. Overall survival is a dual primary endpoint of the study.
The overall survival data are important, because the triplet added significant toxicity versus TACE alone. The rate of treatment-related adverse events at grade 3 or above was 71.3% for the combo group versus 31.5% for the control arm. Discontinuations caused by treatment-related side effects were also markedly higher for the combo.
Questions could also be raised about the contribution of each treatment component in the triplet, especially Keytruda.
The LEAP-012 readout comes two years after the Keytruda-Lenvima cocktail failed to beat Lenvima alone in newly diagnosed advanced liver cancer in the LEAP-002 trial. At that time, investigators said the trial’s findings continued to support Lenvima monotherapy as a standard-of-care first-line therapy for advanced liver cancer.
That was not the first time Keytruda had come up short in liver cancer. The KEYNOTE-240 trial narrowly missed statistical significance in advanced liver cancer patients following first-line treatment with Bayer’s Nexavar, as Keytruda failed to beat placebo on the measure of overall survival. At that time, an FDA advisory panel voted to keep Keytruda’s accelerated approval in second-line liver cancer in place partly because of a pending readout from a sister trial conducted in Asia.
The phase 3 KEYNOTE-394 study later found that Keytruda cut the risk of death by a statistically significant 21% versus placebo in Asian patients with previously treated liver cancer.
In January of this year, the FDA converted Keytruda’s second-line accelerated approval to a full nod but only in patients with liver cancer secondary to hepatitis B who have received a non-PD-1/L1 regimen.
Meanwhile, Lenvima as a single agent has shown some activity in intermediate-stage liver cancer, although not in patients with the exact same characteristics as in the current LEAP-012 trial. A single-arm phase 2 study conducted by Japanese researchers linked the Lenvima-TACE regimen to median progression-free survival of 28 months and a response rate of 88.7%. The team concluded that the results support the efficacy and favorable safety profile of the combo in patients who’re ineligible for locoregional therapy.
About 30% of liver cancer patients are diagnosed with intermediate-stage disease. The disease represents a heterogenous population, and LEAP-012 enrolled those not amenable to curative treatment and who belong to the Child-Pugh class A, a group with relatively normal liver function. An approval in the indication could support Keytruda’s revenue growth before its loss of exclusivity in 2028, Leerink Partners analysts said in a recent note.