Endometrial cancer has become one of the most active areas in gynecological oncology research — incidence has been rising with obesity rates, and the discovery that MSI-H/dMMR and TMB-high endometrial cancers respond strongly to pembrolizumab has added an immunotherapy pathway to a tumor type that historically had limited systemic options after first-line platinum-based chemotherapy. Lenvatinib-pembrolizumab combination is now an approved second-line option, and 2026 trials are testing whether immunotherapy can move to the front line, which patients benefit from ADC therapy, and how to improve outcomes in serous and clear-cell histologies that don't respond well to standard approaches.
This article is for informational purposes only and does not constitute medical advice. Clinical trial eligibility and availability vary. Always consult a qualified healthcare professional before making any medical decisions or considering participation in a clinical trial.
Quick Summary
Endometrial cancer trials in 2026 are stratified by molecular subtype: POLE-mutant (best prognosis, immunotherapy trials), dMMR/MSI-H (~30%, pembrolizumab/dostarlimab now standard), p53-mutant (worst prognosis, ADC trials), and NSMP/pMMR. Key approved combinations: dostarlimab+carboplatin/paclitaxel (RUBY), pembrolizumab+chemotherapy (NRG-GY018), lenvatinib+pembrolizumab (second-line). New 2026 trials: HER2-directed ADCs, FRα-targeting mirvetuximab, and PARP inhibitors for BRCA-mutant uterine cancer.
The Molecular Classification That Drives Trial Eligibility
The 2020 WHO classification divides endometrial cancer into four molecular subtypes — each with distinct biology, prognosis, and treatment implications. Understanding your molecular subtype is now essential before searching for trials:
| Subtype | Frequency | Key Treatments/Trials |
|---|---|---|
| POLE-mutant | ~7–10% | Immunotherapy alone (PORTEC-4a), excellent prognosis |
| dMMR/MSI-H | ~25–30% | Pembrolizumab, dostarlimab (approved 1L); neoantigen vaccine trials |
| p53-mutant | ~20–25% | T-DXd (HER2+), ADC trials, PARP inhibitors (BRCA co-mutation) |
| NSMP (no specific molecular profile) | ~40% | Lenvatinib+pembrolizumab (2L); hormone therapy (ER+); FRα trials |
First-Line Advanced Endometrial Cancer: What's Now Standard
The landmark trials of 2022–2023 have already changed first-line treatment for advanced/recurrent endometrial cancer:
RUBY trial (dostarlimab + carboplatin/paclitaxel)
In dMMR/MSI-H patients, 3-year PFS was 61.4% vs. 15.7% placebo. In all-comers, 2-year OS was 71.3% vs. 56.0%. Dostarlimab (Jemperli) + chemotherapy is now FDA/EMA approved for first-line advanced endometrial cancer regardless of MMR status (though the benefit is most dramatic in dMMR).
NRG-GY018 (pembrolizumab + carboplatin/paclitaxel)
Similar results. In dMMR/MSI-H patients, pembrolizumab+chemo reduced progression risk by 70%. In pMMR patients, 12-month PFS was 54% vs. 38%. Both combinations are now standard of care — the choice between them depends on availability and guidelines.
Key Trials Recruiting in 2026
Trastuzumab Deruxtecan (T-DXd) for HER2-Positive Endometrial Cancer
HER2 amplification occurs in ~30% of serous endometrial cancers (p53-mutant subtype). DESTINY-PanTumor02 showed T-DXd overall response rate of 57.5% in HER2-positive endometrial cancer (IHC 3+ or 2+/ISH+). DESTINY-Endometrial01 and related trials are now studying T-DXd in earlier settings and in combination with pembrolizumab. Key eligibility: HER2 IHC 3+ or 2+ by central testing, prior platinum-containing therapy, no prior HER2-directed therapy.
Mirvetuximab Soravtansine for FRα-Expressing Endometrial Cancer
Following its approval in ovarian cancer (FORWARD-I), mirvetuximab is being studied in FRα-positive endometrial cancer. FRANOVA-endo is enrolling patients with high FRα expression (≥75% of cells, 2+ or 3+ staining) who have progressed on at least one prior line. This is a significant opportunity for patients whose tumors have high FRα — testing is required upfront.
PORTEC-4a: De-escalation for POLE-Mutant Disease
PORTEC-4a is testing whether patients with POLE-mutant early-stage endometrial cancer can safely omit adjuvant chemotherapy or radiotherapy in favour of observation alone or single-agent immunotherapy. This is a de-escalation trial — designed to spare patients from overtreatment. Eligibility: POLE exonuclease domain mutation confirmed by NGS, FIGO stage I–II at surgery, no residual disease.
Uterine Sarcoma Trials: Leiomyosarcoma and Carcinosarcoma
Uterine leiomyosarcoma is biologically distinct from endometrial carcinoma and has a very different trial landscape. Active 2026 trials include: eribulin vs. paclitaxel for uterine LMS (Phase 3); trabectedin maintenance; tazemetostat for EZH2-mutant uterine sarcoma; and olaratumab combinations. Carcinosarcoma (malignant mixed Müllerian tumor) — often grouped with endometrial cancer clinically — has specific pembrolizumab combination trials given its MMR-deficient profile in ~20% of cases.
Getting Molecular Testing Before Searching for Trials
Molecular profiling at diagnosis or recurrence is now the gateway to most endometrial cancer trials. What to request:
- MMR/MSI testing: IHC for MLH1, MSH2, MSH6, PMS2 and/or PCR/NGS-based MSI testing. Required for checkpoint inhibitor eligibility.
- POLE sequencing: NGS panel including POLE exonuclease domain mutations (hotspot codons 286, 411, 413, 444, 456, 459). Not all standard oncology panels include POLE — confirm coverage.
- HER2 IHC/ISH: Especially important for serous histology. Required for T-DXd trials.
- TP53 sequencing: Identifies p53-mutant subtype, guides prognosis and trial selection.
- BRCA1/2 germline/somatic testing: A minority of endometrial cancers carry BRCA mutations — these patients may be eligible for PARP inhibitor trials.
Find Uterine Cancer Trials
Search recruiting endometrial and uterine cancer trials by molecular subtype, phase, treatment type, and location.