Eisai Explores Novel Dual Mechanism Therapy for Advanced Endometrial Carcinoma

In an interview with Pharmaceutical Executive, Corina Dutcus, SVP, oncology global clinical development lead at Eisai, discussed new long-term data from the LEAP-002 trial and the company’s broader efforts in liver and endometrial cancer. The Phase III LEAP-002 study evaluated lenvatinib alone versus in combination with Keytruda (pembrolizumab) in first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). While the primary endpoint was not met, updated follow-up results presented at nearly five years provide new insights into the therapy’s sustained benefit and reinforce its role in HCC care. Dutcus also shared updates on Eisai’s investigational WNT pathway inhibitor, E7386, and its promising early data in endometrial carcinoma, underscoring the company’s commitment to advancing novel treatment strategies in areas of high unmet need.

Pharmaceutical Executive: Can you discuss the mechanism of action of E7386 and its rationale for combination with lenvatinib in advanced endometrial carcinoma?

Corina Dutcus: E7386 is an oral anti-cancer agent we developed in-house. It functions as a Wnt pathway modulator by inhibiting specific protein-protein interactions—in particular, the interaction between CBP and β-catenin. This inhibition drives its antitumor activity. There may also be a secondary mechanism of action involving inhibition of ATF4, which we are currently investigating further.

The rationale for combining lenvatinib with E7386 is grounded in our existing understanding of lenvatinib’s activity in endometrial carcinoma. At this year’s ASCO, we presented two studies evaluating this combination in the disease. One was a dose-expansion cohort assessing E7386 in combination with lenvatinib in patients who had progressed on prior immunotherapy. This dataset, from 30 patients, was very well received and highlighted as a key presentation in endometrial cancer.

We also presented a trial-in-progress poster outlining the next phase of this program. This study is now advancing into a randomized format, comparing the combination of E7386 and lenvatinib against lenvatinib alone and standard of care in this treatment setting.

Full Interview Summary: The LEAP-002 study was a Phase III trial comparing lenvatinib plus Keytruda) versus lenvatinib monotherapy in patients with unresectable hepatocellular carcinoma (HCC) in the first-line setting. Although the primary endpoint was not met, long-term follow-up at 59 months (nearly five years) reaffirmed the efficacy and safety profile of lenvatinib. Median overall survival for lenvatinib monotherapy remained at 19 months, consistent with earlier findings, and no new safety signals emerged. These results strengthen lenvatinib’s role in monotherapy for appropriately selected HCC patients.

Notably, twice as many patients remained in follow-up in the combination arm, and the long-term survival rate was approximately 20% with the combination versus 10% for lenvatinib alone. Adverse events (Grade 3–5) also remained in line with earlier data. Given the projected 50% increase in HCC incidence over the next two decades, these findings are crucial for guiding current treatment strategies and reinforcing physician confidence.

Looking ahead, Eisai is also investigating earlier-stage HCC through theLEAP-012 trial, evaluating lenvatinib and pembrolizumab with TACE (transarterial chemoembolization). Interim results show a 34% reduction in progression or death, though overall survival data remains immature.

In endometrial carcinoma, Eisai is developing E7386, a WNT pathway modulator that inhibits CBP–β-catenin interaction. Early data from a 30-patient expansion cohort combining E7386 with lenvatinib showed a 30% response rate overall, rising to 44% in lenvatinib-naive patients post-chemotherapy and IO. The median duration of response was eight months.

The company has now advanced to a randomized trial comparing two doses of E7386 plus Lenvatinib, versus lenvatinib aloneand standard of care, in the second-line setting. This approach aims to optimize efficacy while minimizing toxicity, addressing ongoing unmet needs in advanced endometrial carcinoma.