Oral Wnt-blocking pill plus lenvatinib shows promise in endometrial cancer after immunotherapy fails

An experimental oral cancer drug that disrupts a key molecular switch inside tumour cells, when paired with an established targeted therapy, has produced durable tumour shrinkage in women with advanced endometrial cancer whose disease had already shrugged off both chemotherapy and immunotherapy. The findings, published in EClinicalMedicine, come from the dose-expansion phase of a global phase 1b/2 trial and offer one of the first prospective signals of activity in a patient population where no standard therapy currently exists.

The experimental agent, known as E7386, belongs to a relatively new class of medicines called protein–protein interaction inhibitors. Rather than blocking an enzyme’s active site, it physically prevents the CREB-binding protein (CBP) from docking with β-catenin, a transcriptional co-activator that sits at the heart of the Wnt signalling pathway. When the CBP–β-catenin interaction proceeds unchecked, tumour cells receive a continuous stream of pro-growth and pro-survival instructions. Preclinical work had shown that E7386 suppressed intestinal polyp formation in genetically predisposed mice and shrank tumours in models where the Wnt pathway was overactive, and that combining the drug with lenvatinib — a multi-kinase inhibitor that starves tumours of their blood supply — produced greater antitumour activity than either drug alone in endometrial cancer models, regardless of whether tumours carried mutations in the CTNNB1 gene that encodes β-catenin.

The clinical context is stark. Endometrial cancer incidence is rising worldwide, and while the addition of immunotherapy to first-line chemotherapy has transformed outcomes for many patients, roughly 15 percent of women are diagnosed with advanced-stage disease, for whom five-year survival hovers around 15 to 17 percent. Once a patient’s tumour progresses after platinum-based chemotherapy and an anti-PD-(L)1 immune checkpoint inhibitor, second-line chemotherapy regimens deliver response rates of only about 15 percent. Antibody–drug conjugates have shown encouraging activity in this setting, but they require intravenous infusion and raise concerns about cross-resistance between agents sharing similar payloads, creating a genuine need for orally administered alternatives.

Study 102 enrolled 30 women between January 2023 and May 2024 across 12 sites in Japan, the Republic of Korea, and the United States. All had advanced, unresectable, or recurrent endometrial cancer that had progressed on or after platinum chemotherapy and an anti-PD-(L)1 agent such as pembrolizumab, durvalumab, or dostarlimab. Sixteen of the 30 had already been treated with lenvatinib itself. Participants received E7386 at 120 milligrams twice daily, with the lenvatinib starting dose later reduced from 20 to 14 milligrams once daily after non-clinical data suggested the combination retained its potency even at the lower dose — a change that also widened access for patients previously exposed to the drug.

The efficacy results exceeded what the heavily pretreated population would normally be expected to achieve. Eleven patients had confirmed responses — one complete and ten partial — for an objective response rate of 36.7 percent, roughly double the activity of conventional second-line chemotherapy. Responses proved durable, with a median duration of 9.1 months, and the disease control rate, which counts stable disease as well as shrinkage, reached 70 percent. Median progression-free survival was 5.5 months overall, and median overall survival had not been reached at the data cut-off, with 70 percent of patients alive at both six and twelve months.

The subgroup breakdown was particularly striking. Among the 14 women who had never received lenvatinib, the objective response rate climbed to 57.1 percent, with a median progression-free survival of 10.8 months — figures that compare favourably even with recent antibody–drug conjugate trials in the post-immunotherapy setting. Perhaps more surprising, three of the 16 patients who had already been treated with lenvatinib also responded, including two whose most recent prior therapy had been lenvatinib combined with pembrolizumab. This suggests that E7386 may re-sensitise tumours to lenvatinib’s mechanism, potentiating its antitumour activity rather than simply adding an independent effect.

Safety data supported the combination’s feasibility. Every patient experienced some treatment-emergent adverse event, but the most common — vomiting in 73.3 percent and nausea in 66.7 percent — were predominantly grade 1 or 2 and were largely controlled with standard anti-nausea medications such as 5-HT3 receptor antagonists. No grade 4 or 5 events occurred, and only two patients discontinued treatment because of toxicity. Dose interruptions and reductions were common, particularly for lenvatinib, reflecting the familiar fingerprint of that drug: proteinuria, diarrhoea, and hand–foot skin reactions appeared at rates consistent with its established profile. Because agents targeting the Wnt pathway have previously been linked to bone fragility, the investigators monitored bone density and bone turnover markers throughout; bone events occurred in just three patients, all manageable with supplements or antiresorptive therapy.

Biomarker analyses added a layer of molecular context. Circulating tumour DNA sequencing at baseline identified TP53 mutations as the most frequent alteration, present in 46.7 percent of patients, followed by mutations in KRAS, PIK3CA, PPP2R1A, PTEN, and FBXW7. Notably, a multivariate analysis adjusting for age, mismatch repair status, and prior lenvatinib exposure found no association between TP53 mutation status and any clinical outcome, and responses were seen across mismatch repair proficient and deficient tumours alike. With only 30 participants, however, the study was not powered to detect subtle predictive signatures, and the authors caution that the molecular findings are exploratory.

The trial’s limitations are real but typical of early-phase oncology research: a single-arm design without a control group, a small sample concentrated at Asian sites, and a population skewed toward patients with good performance status. Even so, the enrolled cohort closely mirrors the real-world post-immunotherapy population, with more than 80 percent having received at least two prior lines of systemic therapy. Against benchmarks such as the roughly 15 percent response rate of second-line chemotherapy, the 21 percent of lenvatinib monotherapy, and the 22 percent of sacituzumab govitecan in a mixed immunotherapy-exposed population, the 36.7 percent response rate — and 57.1 percent in lenvatinib-naïve patients — stands out.

The programme is already moving forward. A randomised dose-optimisation phase is now enrolling a more geographically balanced population of lenvatinib-naïve patients with advanced endometrial carcinoma, comparing two doses of E7386 plus lenvatinib against lenvatinib monotherapy or physician’s choice chemotherapy with doxorubicin or paclitaxel. If those results confirm the signals seen here, an all-oral regimen targeting the Wnt pathway and tumour vasculature could become a genuinely new option for women who currently have none — and a demonstration that drugging protein–protein interactions, long considered near-impossible, is becoming practical medicine.

Subject of Research: E7386 plus lenvatinib for advanced endometrial cancer after platinum chemotherapy and anti-PD-(L)1 immunotherapy

Article Title: E7386 plus lenvatinib in patients with advanced endometrial cancer that progressed on platinum-based chemotherapy and an anti-PD-(L)1 immunotherapy: a single-arm, open-label, global phase 1b/2 dose-expansion cohort

Article References: Lee, J.-Y., Hasegawa, K., Kim, B.-G., Berman, B., Suzuki, S., Corr, B., Yunokawa, M., Orr, D., Yamamoto, N., Soliman, P. T., Miller, D. S., Potdar, A. A., Sahara, T., Kimura, T., Dutta, L., Wu, J., McKenzie, J., & Kyi, C. (2026). E7386 plus lenvatinib in patients with advanced endometrial cancer that progressed on platinum-based chemotherapy and an anti-PD-(L)1 immunotherapy: a single-arm, open-label, global phase 1b/2 dose-expansion cohort. eClinicalMedicine, 100, Article 104206. https://doi.org/10.1016/j.eclinm.2026.104206

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104206

Keywords: endometrial cancer, E7386, lenvatinib, CBP–β-catenin inhibitor, Wnt signalling, immunotherapy resistance, phase 1b/2 trial, anti-PD-(L)1, targeted therapy, protein–protein interaction inhibitor, progression-free survival, gynecologic oncology