Uterine and Endometrial Cancer Clinical Trials 2026: Immunotherapy, ADCs, and New Treatments

The RUBY and NRG-GY018 trials are the headline story: both established checkpoint inhibitor plus chemotherapy combinations as the new first-line standard for advanced endometrial cancer in 2022–2023, with the benefit most dramatic in dMMR/MSI-H tumors — where 3-year PFS nearly quadrupled in some analyses. But the field can't stop there. MSI-H tumors represent about 30% of endometrial cancers. The remaining 70% — particularly p53-mutant serous histology and NSMP tumors — still have limited options after platinum-based chemotherapy. The 2026 trial agenda is squarely focused on those populations: HER2-directed ADCs, FRα-targeting mirvetuximab, and POLE de-escalation approaches that could spare some patients from chemotherapy entirely.

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. Knowing your molecular subtype is now the starting point for any conversation about advanced therapy or clinical trial eligibility:

The RUBY and NRG-GY018 Results: What They Changed

These two trials transformed first-line treatment for advanced endometrial cancer within the same 18-month window, and their results are worth understanding in quantitative terms rather than summary language.

RUBY trial (dostarlimab + carboplatin/paclitaxel)

In the dMMR/MSI-H population — approximately 30% of enrolled patients — 3-year progression-free survival was 61.4% in the dostarlimab arm versus 15.7% for placebo plus chemotherapy. Not a modest improvement; a near-fourfold difference in the proportion of patients progression-free at three years. In the overall enrolled population (regardless of MMR status), 2-year overall survival was 71.3% versus 56.0%. Dostarlimab (Jemperli, GSK) plus chemotherapy received FDA and EMA approval as first-line advanced endometrial cancer treatment in 2023–2024.

NRG-GY018 (pembrolizumab + carboplatin/paclitaxel)

Parallel results from the NRG Oncology cooperative group. In dMMR/MSI-H patients, pembrolizumab plus chemotherapy reduced the hazard of progression or death by 70% (HR 0.30) versus placebo plus chemotherapy. In pMMR patients — the majority — 12-month PFS was 54% versus 38%, a more modest but real benefit that supports pembrolizumab use across all MMR strata. Both regimens are now considered standard of care; the choice between them depends on institution preference, cost, and guideline recommendations in a given country.

Key Trials Recruiting in 2026

Trastuzumab Deruxtecan (T-DXd) for HER2-Positive Endometrial Cancer

HER2 amplification or overexpression occurs in approximately 30% of uterine serous carcinomas — the p53-mutant, high-grade histology with the worst prognosis in endometrial cancer and limited benefit from checkpoint inhibitors. Trastuzumab deruxtecan (T-DXd, Enhertu, AstraZeneca/Daiichi Sankyo) is an antibody-drug conjugate — trastuzumab linked to a potent topoisomerase I inhibitor payload, with high membrane permeability that also kills bystander tumor cells without HER2 expression. Its activity across HER2-positive solid tumors has been transformative.

DESTINY-PanTumor02 reported an overall response rate of 57.5% in HER2-positive endometrial cancer (IHC 3+ or IHC 2+/ISH+). DESTINY-Endometrial01 and related trials are now studying T-DXd in earlier settings and in combination with pembrolizumab for HER2-positive disease. Eligibility typically requires: HER2 IHC 3+ or 2+ confirmed by central testing, prior platinum-containing therapy, no prior HER2-directed therapy. HER2 testing should be performed with guidelines-concordant methodology — a non-trivial consideration given that endometrial cancer HER2 scoring uses gynecologic oncology-specific criteria distinct from breast cancer HER2 testing criteria.

Mirvetuximab Soravtansine for FRα-Expressing Endometrial Cancer

Mirvetuximab soravtansine (ELAHERE, ImmunoGen) targets folate receptor alpha (FRα) — a surface protein expressed in many gynecologic malignancies. Following its accelerated approval in ovarian cancer based on FORWARD-I trial data, mirvetuximab is being evaluated in FRα-positive endometrial cancer in the FRANOVA-endo trial. The trial is enrolling patients with high FRα expression (at least 75% of cells staining 2+ or 3+ by immunohistochemistry) who have progressed on at least one prior systemic therapy. FRα expression testing is required upfront and needs to be performed using the VENTANA FOLR1 assay in a certified laboratory — not all pathology departments have this test available, and patients may need to send tissue to a reference lab.

PORTEC-4a: De-escalation in POLE-Mutant Disease

PORTEC-4a (NCT03469674) is a de-escalation trial — one of the most important design concepts in cancer research, and all too rare. POLE-mutant endometrial cancers have an ultramutated genome that generates thousands of neoantigens, making them exquisitely immunogenic. Despite their high mutational burden, they carry the best prognosis of any endometrial cancer molecular subtype, and the question being asked here is whether adjuvant chemotherapy and radiotherapy — which these patients currently receive per standard guidelines — are doing more harm than good. PORTEC-4a randomizes POLE-mutant stage I–II patients post-surgery to adjuvant radiotherapy, observation, or single-agent immunotherapy. POLE mutation confirmation by NGS is required, and critically, not all NGS panels cover the relevant exonuclease domain hotspot codons — patients should verify their panel covers positions 286, 411, 413, 444, 456, and 459.

Uterine Sarcoma: A Distinct Landscape

Uterine leiomyosarcoma is biologically and clinically distinct from endometrial carcinoma and is excluded from most endometrial carcinoma trials. The uterine LMS trial landscape in 2026 includes: eribulin versus paclitaxel (Phase 3) for second-line uterine LMS, trabectedin maintenance for disease stabilized on first-line therapy, and tazemetostat for EZH2-mutant uterine sarcoma (an emerging subgroup defined by EZH2 loss-of-function mutations). Carcinosarcoma (malignant mixed Müllerian tumor) — historically grouped with sarcoma but increasingly understood as metaplastic carcinoma — has specific pembrolizumab combination trials given its ~20% MMR-deficient rate and high microsatellite instability frequency.

Getting Molecular Testing Right Before Searching for Trials

Molecular profiling is now the prerequisite, not the optional add-on, for endometrial cancer trial access. What to request specifically:

• MMR/MSI testing: IHC for MLH1, MSH2, MSH6, PMS2 — loss of any protein defines dMMR. PCR or NGS-based MSI testing is confirmatory. Required for checkpoint inhibitor eligibility and determines the magnitude of benefit.
• POLE sequencing: NGS panel including POLE exonuclease domain mutations at hotspot codons 286, 411, 413, 444, 456, 459. Standard oncology panels may not cover all of these — confirm with the testing laboratory before assuming a negative result is definitive.
• HER2 IHC/ISH: Essential for serous histology (p53-mutant subtype). Gynecologic oncology scoring criteria differ from breast cancer criteria. Required for T-DXd and related HER2-directed ADC trials.
• TP53 sequencing: Identifies the p53-mutant subtype — the highest-risk group with greatest need for novel therapies.
• FRα IHC: Required for mirvetuximab trials. Must use VENTANA FOLR1 assay with the high-expression scoring criterion (≥75% cells 2+ or 3+).
• BRCA1/2 germline and somatic testing: A minority of endometrial cancers carry BRCA mutations; these patients may be eligible for PARP inhibitor trials. Germline testing also has family implications.

Frequently Asked Questions