Merck and Eisai's Lenvima-Keytruda combo flunks first-line melanoma trial

The tag team of Merck & Co.’s PD-1 wunderkind Keytruda plus Eisai’s tyrosine kinase inhibitor Lenvima has conquered oncology frontiers in the past, notably triggering best-in-class evaluations in previously untreated kidney cancer. But a recent losing streak has cast a pall over the combo.

At the behest of an independent data monitoring committee, Merck and Eisai have called it quits on their phase 3 study of Keytruda plus Lenvima as an initial treatment in unresectable or metastatic melanoma. At an interim analysis, the combination failed to help stave off death better than Keytruda alone—one of two primary endpoints in the trial LEAP-003—the partners said in a Friday press release.

The flop follows an earlier analysis in which Keytruda plus Lenvima charted statistically significant improvements on survival time without disease worsening. That result formed the other main endpoint in the now-defunct study.

Adding to the clinical misfortune, Keytruda and Lenvima also missed the mark on overall survival in another phase 3 trial, LEAP-017, which is pitting the combination against unresectable and metastatic colorectal cancer. Specifically, Eisai and Merck are studying their drug pairing in patients whose disease is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H) and who’ve failed on a prior line of therapy. The trial is testing the pair against the chemotherapy Stivarga (regorafenib) or TAS-102, also known as Lonsurf.

The colorectal cancer results weren’t all bad, with the Keytruda-Lenvima cocktail trending toward improvement across overall survival, progression-free survival, objective response rate and response duration, Eisai and Merck explained in a press release. 

Merck and Eisai appear to be pressing on with LEAP-017. The partners made no mention of a trial discontinuation in the press release.

Safety proved a silver lining in the pair of studies, with the combo’s profile matching up to previously reported data, Merck and Eisai said.

The partners continue to invest in Keytruda and Lenvima’s future in more than 10 other LEAP trials tackling a range of tumor types, including endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, head and neck cancer and esophageal cancer.

“While these results are different from our initial expectation, insights from both studies will help contribute to our understanding of Keytruda plus Lenvima," Corina Dutcus, M.D., Eisai’s senior vice president of oncology clinical development, said in a statement. 

So far, the Keytruda-Lenvima duo has ginned up two approved indications. The pair first clinched an accelerated approval in endometrial cancer in 2019 and converted that nod into a full green light in the summer of 2021. A few weeks after that, the combo scored its second thumbs-up from the FDA in newly diagnosed patients with advanced kidney cancer.

That approval was based on data from the KEYNOTE-581 trial, which showed the combo slashed the risk of disease progression or death by a whopping 61% over Pfizer’s aging standard-of-care Sutent. In addition, the combo also cut the risk of death by 34% over Sutent.

Still, the past year and change has brought multiple misses from the cancer duo.

In December 2021, the combination failed to extend patients’ lives over Keytruda monotherapy in newly diagnosed non-small cell lung cancer with PD-L1 expression covering at least 1% of tumor cells.

Three months later, Keytruda plus Lenvima fell short in bladder cancer, failing once again to extend patients’ lives over Keytruda alone.

And in September, the combo failed to top Lenvima solo at extending the lives of patients with newly diagnosed liver cancer. The drug cocktail curbed the risk of death by 16% over Eisai’s therapy alone, which fell short of the statistical significance threshold.