Merck & Co. and Eisai previously had high hopes for their Keytruda-Lenvima combination in a liver cancer subtype based on positive progression-free survival data, but now the combo’s promise has once again been dented by a miss on another endpoint.

PD-1 inhibitor Keytruda and tyrosine kinase inhibitor (TKI) Lenvima, when added to standard transarterial chemoembolization (TACE), couldn’t help patients with unresectable, non-metastatic hepatocellular carcinoma (HCC) live longer compared to TACE alone, Merck and Eisai’s phase 3 LEAP-012 study has found.

The overall survival miss was determined at a pre-specified interim analysis, Merck said in an Oct. 29 press release, as the likelihood of meeting the threshold for statistical significance in the endpoint at a future analysis was deemed “low” by the companies.

With that, the partners are shutting the study down, although further analysis of the data is ongoing.

“Although the progression-free survival results from this study are encouraging, unfortunately, the addition of Keytruda plus Lenvima to TACE did not show the overall survival benefit we hoped,” Merck’s VP of global clinical development, Gregory Lubiniecki, M.D., concluded in the release.

Eisai’s head of oncology clinical development, Corina Dutcus, M.D., adds that the findings provide “important insights” for treating the cancer, as many patients on standard-of-care TACE experience disease progression.

The outcome is the latest twist in a rocky development pathway for Keytruda and Lenvima in liver cancer. In a prior study in 2022, the pairing wasn’t able to extend the lives of patients with newly diagnosed metastatic liver cancer compared to Lenvima alone.

But Merck and Eisai gained renewed confidence when LEAP-012 hit its progression-free survival endpoint as the combo, plus TACE, cut the risk of disease progression or death by 34% versus TACE on its own. The companies presented the results at a “practice-changing trials” symposium session at the 2024 European Society of Medical Oncology (ESMO) meeting, although questions surrounding the other primary endpoint of overall survival remained.

At the time, the relative risk of death showed an early trend in favor of the treatment, but meeting the overall survival bar was especially important considering the added toxicity of triplet compared to TACE alone. At the last readout, 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, and discontinuation caused by treatment-related side effects were higher for the combo.

As of the recent interim analysis, the safety profile of the Keytruda plus Lenvima-based regimen was “consistent with that observed in previously reported studies evaluating the combination” and in earlier analyses of LEAP-012, Merck and Eisai said in the release.

The benefits of the Keytruda and Lenvima combo have been a bit of a mixed bag thus far. The pairing missed the overall survival mark in a gastroesophageal adenocarcinoma subtype earlier this year and in bladder cancer in 2022. However, the duo has won approvals in renal cell carcinoma and other types of advanced endometrial carcinoma.

Despite the overall survival flop, Merck and Eisai’s dreams of their combo plus TACE in unresectable, non-metastatic HCC may live on in China, where it was approved earlier this year.

Meanwhile, Merck is busy planning for its post-Keytruda patent cliff future with its rising successor Welireg. On Tuesday, Welireg plus Lenvima proved that it can help certain patients with advanced renal cell carcinoma live longer without their disease getting worse, although overall survival results had not yet reached statistical significance.