Trastuzumab Pamirtecan Provides Meaningful Survival Benefit in Pretreated HER2-Expressing Endometrial Cancer

Trastuzumab pamirtecan (T-Pam; BNT323/DB-1303) provided meaningful survival benefit in patients with previously treated, HER2-expressing, advanced or recurrent endometrial cancer, according to results from a phase 2 dose-expansion cohort of a phase 1/2 trial (NCT05150691) presented at the 2026 ESMO Gynaecological Cancers Congress.¹

At a data cutoff date of October 17, 2025, and a median follow-up of 13.2 months, the median progression-free survival (PFS) was 8.0 months (95% CI, 5.6-8.3), and the median overall survival (OS) was 15.0 months (95% CI, 12.0-17.8) among all patients treated with the agent (n = 145). The confirmed objective response rate (ORR) by independent review committee (IRC) assessment was 44.1% in the modified full analysis set (n = 143).

"T-Pam shows encouraging, and now we'd say durable, activity and a meaningful signal of survival in this phase 2 dose-expansion cohort," said lead study author Kathleen N. Moore, MD, MS, during the presentation.

Moore is a professor in the Section of Gynecologic Oncology and the deputy director and director of phase 1 oncology trials at the Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, in Omaha.

Why do trastuzumab pamirtecan's survival and subgroup data matter in HER2-expressing endometrial cancer?

In the United States, endometrial cancer is one of the few solid tumors with rising incidence and mortality—a burden that falls disproportionately on Black and African American women—and options remain limited after platinum-based chemotherapy and immune checkpoint inhibition (ICI), Moore noted. HER2 overexpression in EC has been linked to aggressive disease and poor prognosis.

Trastuzumab pamirtecan is an investigational, humanized HER2-directed antibody-drug conjugate (ADC) that pairs a HER2-targeting antibody with a topoisomerase I inhibitor payload at a drug-to-antibody ratio of approximately 8. In December 2023, the FDA granted breakthrough therapy designation to the drug for use as a potential therapeutic option in patients with advanced, recurrent, HER2-expressing endometrial cancer.² The decision was based on top-line data from the trial.

The cohort subsequently met its primary end point at the 2026 SGO Annual Meeting on Women's Cancer, where the agent elicited a confirmed ORR of 49.3% (95% CI, 37.4%-61.3%) by central immunohistochemistry (IHC) testing in patients with prior ICI exposure and HER2 expression (n = 73).³ Notably, responses were observed across all HER2 expression levels, with respective ORRs by central testing of 34.5% (95% CI, 17.9%-54.3%), 44.2% (95% CI, 29.1%-60.1%), and 70.8% (95% CI, 48.9%-87.4%), in those with IHC 1+ (n = 29), IHC 2+ (n = 43), and IHC 3+ (n = 24) status.

In an exclusive interview with OncLive®, Bhavana Pothuri, MD, discussed the significance of the data:⁴ “Having an objective response rate of close to 50% is clearly tremendous, with a duration of response [DOR] of 9.9 months. Seeing these durable responses that last is really important.”

Pothuri is a professor in the Department of Obstetrics and Gynecology at NYU Grossman School of Medicine, a professor in the Department of Medicine at NYU Grossman School of Medicine, director of Gynecologic Oncology Research, medical director of the Clinical Trials Office at Perlmutter Cancer Center, and director of Gynecologic Oncology Clinical Trials at NYU Langone Health, in New York.

The ESMO Gynaecological Cancers Congress analysis extends those data with survival outcomes and subgroup ORR.¹

How was the phase 2 dose-expansion cohort of trastuzumab pamirtecan designed?

Cohort 2b of the open-label, dose-escalation/expansion study enrolled patients with advanced, unresectable, recurrent, or metastatic endometrial cancer and locally documented HER2 expression (IHC 1+, 2+, or 3+, or in situ hybridization positivity) who had progressed on or following at least 1 line of systemic therapy with or without an ICI. Patients had received platinum-based therapy with up to 3 prior lines for advanced disease, and had an ECOG performance status no higher than 1. Patients could not have prior exposure to a HER2-directed ADC except ado-trastuzumab emtansine (Kadcyla).

Patients on the trial were given trastuzumab pamirtecan at a dose of 8 mg/kg every 3 weeks.

The primary end points of the overall study were safety and ORR by IRC assessment in those with HER2-expressing disease by central testing who had prior exposure to ICI.³ Key secondary end points included ORR, DOR, disease control rate, and PFS in those with HER2-expressing disease per local testing.

The median patient age was 66.0 years, and 69.7% of patients were enrolled in the United States; 16.6% were Black or African American.¹ “[One thing to note is that] at least in the United States, endometrial cancer is one of the few solid tumors increasing in incidence and mortality, largely at the expense of Black and African American women,” Moore said. “We were very intentional in site selection and activities for this study, which was largely completed in the United States, to make sure we had a diverse population. We're very pleased to have 17% of this study represented by Black or African American women.”

Most patients (76.6%) had received 2 or fewer prior lines of therapy, and 75.9% had prior ICI treatment.

What were the confirmed response rates with trastuzumab pamirtecan across endometrial cancer subgroups?

In the modified full analysis set (n = 143), confirmed ORR was generally consistent across prespecified subgroups. By race, confirmed ORR was 41.9% in White patients (n = 62), 38.0% in Asian patients (n = 50), and 56.5% in Black or African American patients (n = 23). Response rates were similar by prior lines of therapy (44.0% for 2 or fewer lines [n = 109]; 44.1% for 3 lines [n = 34]) and by prior ICI exposure (45.9% in treated patients [n = 109]; 38.2% in ICI-naive patients [n = 34]). By local HER2 IHC score, confirmed ORR was 33.9% in IHC 1+ disease (n = 59), 40.4% in IHC 2+ disease (n = 57), and 73.1% in IHC 3+ disease (n = 26).

"In many settings, Black and African American women actually have worse outcomes with therapeutics. Here, we see it's at least as good, if not better, which is a very promising signal," Moore said.

What did the safety analysis of trastuzumab pamirtecan show?

Treatment-related adverse effects (TRAEs) occurred in 95.9% of patients (n = 145), with grade 3 or higher TRAEs occurring in 46.9%. Serious TRAEs were experienced by 18.6% of patients. Moreover, TRAEs led to dose reduction in 22.8% of patients, drug interruption in 26.9%, and discontinuation in 29.0%. TRAEs led to death in 3 patients (2.1%), comprising 2 cases of pneumonitis and 1 case of acute respiratory failure.

Treatment-related adverse effects of special interest (AESIs) were identified in 41 patients (28.3%), of which 38 were pneumonitis; grade 3 or higher AESIs occurred in 8 patients (5.5%), including 7 cases of pneumonitis.

“[The safety was] very consistent with this class of medications, with common but low-grade gastrointestinal toxicities, and some hematologic toxicities,” Moore said. The most common TRAEs occurring in at least 15% of patients were nausea (62.8%) and anemia (49.0%); any-grade pneumonitis occurred in 21.4% of patients, and gastrointestinal effects were largely low grade and responsive to antiemetics.

"Pneumonitis and interstitial lung disease remains an AE that requires careful attention,” Moore noted. “The management and mitigation strategies that were implemented about midway through this protocol resulted in a dramatic decrease in grade 3 or higher events, and this will continue.”

What are the next steps for trastuzumab pamirtecan in recurrent endometrial cancer?

The findings supported the launch of Fern-EC-01 (NCT06340568), a phase 3, randomized, open-label trial evaluating trastuzumab pamirtecan vs investigator's choice of chemotherapy (ICC) in patients with previously treated, HER2-expressing, recurrent endometrial carcinoma following previous anti–PD-(L)1 therapy.⁵

In cohort 1 (HER2 IHC 1+/2+), patients are randomly assigned 2:1 to trastuzumab pamirtecan or ICC with doxorubicin or paclitaxel. PFS by blinded independent central review (BICR) serves as the primary end point, and OS as a key secondary end point. Cohort 2 (HER2 IHC 3+) is a single-arm group with ORR by BICR serving as the primary end point.

The trial is enrolling globally.

Disclosures: Moore reported acting in a consulting or advisory role for Aadi Bioscience, AbbVie, AstraZeneca, BioNTech, Caris Life Sciences, Corcept, Daiichi Sankyo, DualityBio, Eli Lilly, Genmab, Gilead, GSK/Tesaro (institutional), ImmunoGen, Iovance Biotherapeutics, Janssen, Merck, Mersana Therapeutics (institutional), Novartis, Pfizer, Regeneron, Takeda, Tubulis, Verastem Oncology, and Zymeworks; and receiving institutional research funding from Agenus, Amgen, Artios Pharma, AstraZeneca, Bolt Biotherapeutics, Bristol Myers Squibb, Clovis Oncology, Cyteir, Daiichi Sankyo/Lilly, Genentech, Immunocore, ImmunoGen, Lilly, Lilly Foundation, Merck, Novartis Pharmaceuticals UK Ltd, Novogen, PTC Therapeutics, Regeneron Pharmaceuticals, Takeda Pharmaceutical, Tesaro, and Verastem Oncology.

References

1. Moore KN, Wu X, Makker V, et al. Trastuzumab pamirtecan (T-Pam/DB-1303/BNT323) in patients with previously treated, HER2-expressing, advanced endometrial cancer: overall survival and efficacy in patient subgroups of a phase 2 dose-expansion cohort. Presented at: 2026 ESMO Gynaecological Cancers Congress; June 17-19, 2026; Copenhagen, Denmark. Abstract 83RO.
2. BioNTech and DualityBio receive FDA breakthrough therapy designation for BNT323/DB-1303 for the treatment of advanced endometrial cancer. News release. BioNTech SE. December 21, 2023. Accessed June 17, 2026. https://investors.biontech.de/news-releases/show-release-details/biontech-and-dualitybio-receive-fda-breakthrough-therapy
3. Pothuri B, Richardson DL, Makker V, et al. Trastuzumab pamirtecan (DB-1303/BNT323) in patients with previously treated, HER2-expressing, advanced/metastatic endometrial cancer: first global clinical phase 2 data. Presented at: 2026 SGO Annual Meeting on Women's Cancer; April 10-13, 2026; San Juan, Puerto Rico.
4. Pothuri B. Dr Pothuri on preliminary data with trastuzumab pamirtecan in HER2-expressing endometrial cancer. OncLive.com. April 12, 2026. Accessed June 17, 2026. https://www.onclive.com/view/dr-pothuri-on-preliminary-data-with-trastuzumab-pamirtecan-in-her2-expressing-endometrial-cancer
5. A clinical study of anti-cancer effects of an investigational therapy or chemotherapy in patients with recurring uterine cancer (Fern-EC-01). ClinicalTrials.gov. Updated May 20, 2026. Accessed June 17, 2026. https://clinicaltrials.gov/study/NCT06340568