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Exploring the Promise of E7386 and Lenvatinib Combination Therapy in Endometrial Carcinoma

Corina Dutcus, SVP, oncology global clinical development lead at Eisai, discusses the potential of the E7386 and lenvatinib combination to address unmet needs in second-line treatment for endometrial carcinoma patients.

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: From a clinical development perspective, what challenges have you encountered with the combination therapy of E7386 and lenvatinib?

Corina Dutcus: It’s really exciting to work on this combination. The treatment landscape for endometrial carcinoma has changed significantly with immuno-oncology (IO) moving to first-line treatment in combination with chemotherapy. This shift has created an unmet medical need to explore new options in the second-line setting or after chemotherapy and IO, particularly in patients who are lenvatinib-naive.

As I mentioned earlier, we presented dose expansion data for E7386 combined with lenvatinib in 30 patients. In this population, the overall response rate was 30%. However, in the lenvatinib-naive patients—those treated post-chemotherapy and post-IO—the response rate was 44%, which is very encouraging. Although this is a single-arm, small dataset, seeing such a response rate along with a duration of response around eight months is reassuring.

This data motivated us to further explore the combination in a randomized, dose-optimization phase. Here, we are comparing two doses of E7386—60 mg versus 120 mg—to see if the lower dose can achieve similar efficacy with less toxicity, both combined with lenvatinib at 14 mg. Additionally, there are single-arm cohorts for lenvatinib alone and for standard-of-care treatment.

This approach presents both an opportunity and a challenge. It demonstrates our commitment to patients with endometrial carcinoma and our desire to bring new treatment options to this population.

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.

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