DESTINY-Endometrial01 Will Examine T-DXd Plus Rilvegostomig or Pembrolizumab in HER2+ pMMR Endometrial Cancer

Following robust monotherapy efficacy reported in patients with endometrial cancer in the phase 2 DESTINY-PanTumor02 trial (NCT04482309), there has been an interest in combining fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) with other agents to further improve outcomes for this patient population.1 Thus, the phase 3 DESTINY-Endometrial01/GOG-3098/ENGOT-EN2 study (NCT06989112) is set to evaluate frontline T-DXd in combination with pembrolizumab (Keytruda) or rilvegostomig (AZD2936) in patients with HER2-expressing, mismatch repair–proficient (pMMR), primary advanced or recurrent endometrial cancer, a disease setting in which there are presently no FDA-approved HER2-directed therapies.

“Combining T-DXd and pembrolizumab is a promising approach for treating various malignancies, with positive results [in terms of] objective response rate [ORR] and progression-free survival [PFS] in HER2-expressing or HER2-mutant cancers [such as] non–small cell lung cancer and gastric cancer,” Vicky Makker, MD, a co-investigator of DESTINY-Endometrial01, explained to OncLive®. “Rilvegostomig is a monovalent, bispecific, monoclonal antibody that binds with high affinity to PD-1 and human T-cell immunoreceptor with immunoglobulin and TIGIT receptors, and [it] has shown encouraging preliminary efficacy and tolerability across tumor types. In a preclinical study, T-DXd with a bispecific TIGIT/PD-1 antibody—[a murine surrogate of rilvegostomig]—enhanced tumor growth inhibition compared with T-DXd monotherapy.”

Makker is also the section head of the Endometrial Cancer Program, the director of the Hematology-Medical Oncology Fellowship Training Program, and an attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

What prior data have been reported with T-DXd in endometrial cancer?

In April 2024, the FDA granted accelerated approval to T-DXd for the treatment of patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options.2 The regulatory decision was supported by data from DESTINY-PanTumor02, as well as the phase 2 DESTINY-Lung01 (NCT03505710) and DESTINY-CRC02 (NCT04744831) trials.

DESTINY-PanTumor02 included 7 tumor cohorts, enrolling patients with endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other cancers.3 All patients received T-DXd at 5.4 mg/kg once every 3 weeks. The primary end point was investigator-assessed confirmed ORR; secondary end points included safety, duration of response (DOR), PFS, and overall survival (OS).

Findings from the endometrial cohort (n = 40) of DESTINY-PanTumor02 demonstrated that patients who received T-DXd achieved a confirmed ORR of 57.5% (95% CI, 40.9%-73.0%).3 Patients with a centrally assessed HER2 expression of IHC 3+ (n = 13) experienced an ORR of 84.6% (95% CI, 54.6%-98.1%). Those with a HER2 expression of IHC 2+ (n = 17) had an ORR of 47.1%.

The median OS in the endometrial cohort was 26.0 months (95% CI, 12.8-not reached [NR]). The median OS among patients with a HER2 expression of IHC 3+ and a HER2 expression of IHC 2+ was 26.0 months (95% CI, 18.9-NR) and 16.4 months (95% CI, 8.0-NR), respectively.

The median PFS among all patients with endometrial cancer was 11.1 months (95% CI, 7.1-NR). The median PFS in the HER2 IHC 3+ and 2+ subgroups was NR (95% CI, 7.3-NR) and 8.5 months (95% CI, 4.6-15.1), respectively.

“T-DXd is approved in multiple countries worldwide, including the United States, for adult patients with unresectable or metastatic HER2-positive solid tumors that have progressed after prior systemic treatment, and this approval is partly based on results from DESTINY-PanTumor02 part 1,” Makker said. “The compelling activity in endometrial cancers [in DESTINY-PanTumor02] informed DESTINY-Endometrial01.”

What are the key design characteristics of DESTINY-Endometrial01?

DESTINY-Endometrial01 is an open-label, randomized, multicenter trial that is recruiting adult patients with HER2-expressing (IHC 3+/2+) pMMR endometrial cancer.4 Other key inclusion criteria include being naive to first-line systemic anticancer therapy, having an ECOG performance status of 0 or 1, having a left ventricular ejection fraction of at least 50% within 28 days of random assignment, and having adequate organ and bone marrow function within 14 days of random assignment.1

One prior line of (neo)adjuvant chemotherapy, including trastuzumab (Herceptin), with curative intent is permitted in patients with recurrent disease, if disease recurrence or progression occurred at least 6 months after the last dose of chemotherapy. Patients also need to have FIGO stage III disease with a measurable target lesion at baseline per RECIST 1.1 criteria or primary stage IV or first recurrent disease, regardless of measurable disease status at baseline.

Eligible patients will be randomly assigned 1:1:1 to receive T-DXd plus rilvegostomig (arm A), T-DXd plus pembrolizumab (arm B), or carboplatin/paclitaxel plus pembrolizumab (arm C). In arm A, patients will receive intravenous (IV) T-DXd in combination with IV rilvegostomig every 3 weeks. In arm B, IV T-DXd and pembrolizumab every 3 weeks. Patients in arm C will receive carboplatin, paclitaxel, and pembrolizumab every 3 weeks for 6 cycles, followed by maintenance pembrolizumab every 6 weeks or 14 cycles. Each arm will enroll approximately 200 patients.

The primary end point is PFS per RECIST 1.1 criteria by blinded independent central review (BICR) for arm A vs arm C and arm B vs arm C. OS is the study’s key secondary end point; other secondary end points include investigator-assessed PFS, time to second disease progression or death, investigator- and BICR-assessed ORR and duration of response, BICR-assessed PFS in arm A vs arm B, safety and tolerability, and pharmacokinetic measures.

“The trial is open to accrual in North America, Asia, and other parts of the world, and we look forward to availing this trial to [patients with] HER2-positive advanced/recurrent endometrial cancer,” Makker explained. “I anticipate the study will accrue well, as it targets a biomarker-defined population that [experiences] more modest efficacy with chemotherapy in combination with immune checkpoint inhibitors. [It] offers the opportunity for patients to receive a HER2-targeted antibody-drug conjugate, which has shown compelling activity in more heavily pretreated endometrial cancers. If the experimental arms are positive, this study would inform a new standard of care for pMMR, HER2-positive advanced/recurrent endometrial cancers which are known to be aggressive malignancies, for which a continued unmet therapeutic need persists.”

References

1. Slomovitz BM, Follana P, Geller MA, et al. A randomized phase III study of first-line (1L) trastuzumab deruxtecan (T-DXd) with rilvegostomig or pembrolizumab in patients with HER2-expressing, mismatch repair-proficient (pMMR), primary advanced or recurrent endometrial cancer (EC): DESTINY-Endometrial01/GOG-3098/ENGOT-EN24. Ann Oncol. 2025; 36(suppl 2):S791-S792. doi:10.1016/j.annonc.2025.08.1858
2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed November 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
3. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol. 2023;42(1):47-58. doi:10.1200/JCO.23.02005
4. DESTINY-Endometrial01: a phase III study of trastuzumab deruxtecan plus rilvegostomig or pembrolizumab as first-line treatment of HER2-expressing (IHC 3+/​2+), mismatch repair proficient (pMMR) endometrial cancer (DE-01). ClinicalTrials.gov. Updated November 11, 2025. Accessed November 24, 2025. https://clinicaltrials.gov/study/NCT06989112