Trastuzumab Pamirtecan Elicits Responses in HER2-Expressing Advanced/Metastatic Endometrial Cancer

The antibody-drug conjugate (ADC) trastuzumab pamirtecan (BNT323/DB-1303) showcased activity with a manageable toxicity profile in pretreated patients with advanced, recurrent, or metastatic HER2-expressing endometrial cancer, according to primary results from cohort 2B of a global phase 1/2 trial (NCT05150691) presented during the 2026 Society of Gynecologic Oncology Annual Meeting.¹

The confirmed objective response rate (ORR) in patients with HER2-expressing disease by central immunohistochemistry (IHC) assessment who had prior exposure to immune checkpoint inhibition (ICI; n = 73) was 49.3% (95% CI, 37.4%-61.3%) with the agent, with a median duration of response (DOR) of 9.9 months (95% CI, 7.0-not evaluable [NE]). The disease control rate (DCR) was 79.5% (95% CI, 68.4%-88.0%), and median progression-free survival (PFS; n = 74) was 6.8 months (95% CI, 5.4-11.0). In all patients with HER2-expressing disease by central testing (n = 96), the confirmed ORR was 47.9% (95% CI, 37.6%-58.4%), the median DOR was 11.1 months (95% CI, 9.0-18.3), the DCR was 83.3% (95% CI, 74.4%-90.2%), and the median PFS (n = 97) was 8.1 months (95% CI, 5.5-11.8).

In patients with prior ICI who had HER-expressing disease by local IHC assessment (n = 109), the confirmed ORR was 45.9% (95% CI, 36.3%-55.7%). The median DOR was 9.9 months (95% CI, 7.3-NE), the DCR was 78.9% (95% CI, 70.0%-86.1%), and the median PFS (n = 110) was 8.0 months (95% CI, 5.5-8.3). In all patients with HER2-expressing disease by local testing (n = 143), the confirmed ORR with the ADC was 44.1% (95% CI, 35.8%-52.6%), the median DOR was 10.3 months (95% CI, 7.6-18.3), the DCR was 81.8% (95% CI, 74.5%-87.8%), and the median PFS (n = 145) was 8.0 months (95% CI, 5.6-8.3).

“Trastuzumab pamirtecan demonstrated encouraging antitumor activity in a large cohort of 145 patients with HER2-expressing recurrent endometrial cancer and has received FDA breakthrough [therapy] designation,” Bhavana Pothuri, MD, said in a presentation of the data. “The safety profile was manageable and as expected for this class of drugs. [Gastrointestinal adverse effects] were mostly low-grade and manageable. [Interstitial lung disease]/pneumonitis is a clinically important [adverse effect] for patients, and proactive education, monitoring, and management strategies are critical to ensure patient safety.”

Pothuri is a professor in the Department of Obstetrics and Gynecology and Department of Medicine at the NYU Grossman School of Medicine in New York, New York. She is also the director of Gynecologic Oncology Research and medical director of the Clinical Trials Office at Perlmutter Cancer Center, as well as director of gynecologic oncology clinical trials.

What was the design of the early-phase study examining trastuzumab pamirtecan?

The open-label, dose-escalation, dose-expansion study enrolled patients with pathologically confirmed advanced, unresectable, recurrent, or metastatic endometrial cancer and documented HER2 expression (IHC 1+, 2+, or 3+; or in situ hybridization positive).

Patients must have experienced disease progression on or following at least 1 line of systemic treatment with or without ICI. These patients previously received platinum-based therapy but no more than 3 lines of therapy for advanced/unresectable or metastatic disease. They had an ECOG performance status of 0 or 1 and no prior exposure to a HER2-directed ADC.

Study participants (n = 145) were administered trastuzumab pamirtecan at 8 mg/kg every 3 weeks. The primary end points of the study were safety and ORR by independent review committee in those with HER2-expressing disease by central testing who had prior exposure to ICI. Key secondary end points included ORR, DOR, DCR, and PFS in those with HER2-expressing disease per local testing.

The median follow-up for the data shared during the meeting was 13.2 months, and the data cutoff for the analysis was October 17, 2025.

What were the baseline characteristics and demographics of the population enrolled in the study?

In all patients (n = 145), the median age was 66.0 years (range, 39-88). Almost half of the patients were White (43.4%), 34.5% were Asian, 16.6% were Black or African American, and 5.5% were other. Most patients were from the United States or Australia (71.0%), and 29.0% were from China. Moreover, 46.2% of patients had an ECOG performance status of 0, and 53.8% had a status of 1.

Patients had adenocarcinoma (31.0%), uterine serous papillary carcinoma (22.1%), uterine carcinosarcoma (11.0%), or another histopathological classification (35.9%). They had metastasis in the lung (42.8%), liver (30.3%), bone (7.6%), brain (1.4%), or other (94.5%). Patients had received a median of 2 prior regimens for recurrent or metastatic disease (range, 0-5). All patients had prior exposure to chemotherapy, 75.9% had prior ICI exposure, and 21.4% had previously received anti-HER2 therapy. Patients had a HER2 IHC score of 1+ (40.7%), 2+ (40.7%), or 3+ (17.9%) per local testing; this information was missing for 0.7% of patients. By central testing, 26.2%, 20.0%, 29.7%, and 17.2% of patients had HER2 IHC scores of 0, 1+, 2+, and 3+, respectively; this information was missing for 6.9% of patients.

“To date, this is the largest cohort of patients with HER2-expressing, recurrent endometrial cancer who have received prior treatments that are reflective of contemporary real-world clinical practice,” Pothuri noted in the presentation.

What effect did trastuzumab pamirtecan have in terms of HER2 IHC score?

In the subgroup of patients with HER2 IHC 1+ by local testing (n = 59), the ADC elicited a confirmed ORR of 33.9% (95% CI, 22.1%-47.4%); in those with HER2 IHC 1+ by central testing (n = 29), the confirmed ORR was 34.5% (95% CI, 17.9%-54.3%). In those with HER2 IHC 2+ by local (n = 57) and central (n = 43) testing, the confirmed ORRs with the agent were 40.4% (95% CI, 27.6%-54.2%) and 44.2% (95% CI, 29.1%-60.1%), respectively. Lastly, in those with HER2 IHC 3+ by local (n = 26) and central (n = 24) testing, the confirmed ORRs were 73.1% (95% CI, 52.2%-88.4%) and 70.8% (95% CI, 48.9%-87.4%), respectively.

What was the safety profile of the ADC in patients with HER2-expressing endometrial cancer?

Of the 145 total patients, 95.9% experienced treatment-related adverse effects (TRAEs), and 46.9% of these cases were grade 3 or higher. Serious treatment-related toxicities occurred in 18.6% of patients. TRAEs led to dose reduction, interruption, or treatment discontinuation for 22.8%, 26.9%, and 29.0% of patients, respectively. TRAEs of special interest occurred in 28.3% of patients and were grade 3 or higher for 5.5% of patients. TRAEs proved fatal for 3 patients; 2 of these patients had pneumonitis, and 1 had acute respiratory failure.

The most common TRAEs were nausea (grade 1/2, 62.1%; grade ≥3, 0.7%), anemia (28.3%; 20.7%, respectively), decreased platelet count (22.7%; 15.9%), fatigue (36.5%; 2.1%), vomiting (33.8%; 0%), increased aspartate aminotransferase level (27.6%; 1.4%), decreased appetite (26.9%; 0.7%), hypokalemia (20.7%; 3.4%), decreased neutrophil count (14.5%; 6.9%), pneumonitis (18.6%; 2.8%), increased alanine aminotransferase level (17.9%; 0.7%), decreased white blood cell count (14.5%; 3.4%), decreased weight (15.1%; 2.1%), constipation (16.6%; 0%), diarrhea (15.2%; 0.7%), hyboalbuminemia (13.1%; 0.7%), and hypomagnesemia (11.0%; 0%).

In terms of AEs of special interest, 1 patient experienced any-grade treatment-related infusion-related reaction, and 1 patient experienced grade 3 reduced left ventricular ejection fraction.

Moreover, 38 patients experienced adjudicated ILD/pneumonitis; 6 had a grade 1 event, 25 had a grade 2 event, and 7 had a grade 3 or higher event. “Following a protocol amendment for clinical trial protocol v7.0, an updated monitoring and management plan for ILD/pneumonitis was implemented,” Pothuri noted. Six cases of ILD/pneumonitis occurred before clinical trial protocol v7.0 (n = 118), and 1 case occurred on or after v7.0 (n = 27).

What is next for trastuzumab pamirtecan?

The randomized, open-label, phase 3 Fern-EC-01 study (NCT06340568) is currently enrolling patients with recurrent endometrial cancer and HER2 IHC score of 1+, 2+, or 3+ per central testing.² Patients are required to have prior exposure to an anti–PD-L1 therapy, have disease recurrence under 12 months from completion of platinum-based chemotherapy in the adjuvant setting for stage I to III disease, or disease recurrence following platinum-based chemotherapy in the recurrent or metastatic setting.¹ They must have previously received up to 3 lines of therapy, have measurable disease by RECIST 1.1, and an ECOG performance status of 0, 1, or 2.

Those in cohort 1 (HER2 IHC 1+ or 2+) will be randomly assigned 2:1 to receive trastuzumab pamirtecan (n = 280) or chemotherapy in the form of doxorubicin or paclitaxel (n = 140). The primary end point is PFS by blinded independent central review (BICR); overall survival (OS) will be a key secondary end point. Other secondary end points include PFS by investigator assessment, ORR, DOR, and safety. Those in cohort 2 (HER2 IHC 3+) will receive the ADC (n = 60). ORR by BICR is the primary end point, and secondary end points include investigator-assessed ORR, DOR, PFS, OS, and safety.

Disclosures: Pothuri disclosed serving in a consulting or advisory role for AstraZeneca, BioNTech, Daiichi Sankyo, Gilead Sciences, GOG Foundation, GSK, ImmunoGen, Incyte, Karyopharm Therapeutics, Loxo/Lilly, Merck, Mersana, Onconova Therapeutics, OnCusp Therapeutics, R-Pharm, Regeneron, Seagen, and Signatera. Research funding to the institution has been provided by Acrivon Therapeutics, Agenus, AstraZeneca, Celsion, Daiichi Sankyo, DualityBio, Eisai, GSK, ImmunoGen, Incyte, Karyopharm Therapeutics, Loxo/Lilly, Merck, Mersana, Mural, NRG Oncology, Onconova Therapeutics, Pfizer, Seagen, Sutro Biopharma, Toray Industries, and Xencor. Travel, accommodations, and expenses were provided by BioNTech, GOG Foundation, GSK, and Merck. Pothuri also disclosed affiliation with the Society of Gynecologic Oncology.

References

1. 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; April 10-13, 2025; San Juan, Puerto Rico.
2. A clinical study of the anti-cancer effects of an investigational therapy or chemotherapy in patients with recurring uterine cancer (Fern-EC-01). ClinicalTrials.gov. Updated March 31, 2026. Accessed April 11, 2026. https://clinicaltrials.gov/study/NCT06340568