Fern-EC-01 (BNT323-01): A phase 3 trial of trastuzumab pamirtecan (HER2 ADC) versus investigator’s choice of chemotherapy in patients with previously treated, HER2-expressing, recurrent endometrial cancer (EC).

TPS5645 Background: Despite advancements in frontline therapies for EC, treatment options for recurrent/refractory disease remain limited. HER2 overexpression in EC is associated with rapid disease progression, tumor invasiveness, a high risk of recurrence, and poor prognosis. Trastuzumab pamirtecan (T-Pam; BNT323/DB-1303) is an investigational HER2-targeting antibody-drug conjugate (ADC) with a DNA topoisomerase I inhibitor payload and a drug-to-antibody ratio of ~8. In a phase 1/2a trial (NCT05150691), T-Pam demonstrated encouraging clinical benefit in patients with HER2-expressing EC, efficacy was observed across all HER2 expression levels and patient subgroups with a manageable safety profile. Methods: Following a protocol amendment, this open-label, randomized, multi-site, phase 3 trial (Fern-EC-01; BNT323-01) is enrolling patients with recurrent, HER2 expressing EC (assessed by central laboratory testing using IHC) who have measurable disease defined by RECIST v1.1, an ECOG PS of 0-2, and have received ≥1 prior line of platinum-based therapy (in any setting) and prior immune-checkpoint inhibitor treatment. Up to three lines of prior therapy are permitted. Prior hormonal therapy and radiation are allowed but do not count as prior lines of therapy. Prior exatecan-containing treatment is not allowed. All patients will receive treatment until RECIST v1.1 defined progressive disease, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met. The trial is enrolling two cohorts. In Cohort 1, ≈420 patients with HER2-expressing (IHC 1+ or 2+) EC will be randomized 2:1 to evaluate the efficacy and safety of T-Pam vs investigator’s choice of chemotherapy (doxorubicin, paclitaxel, or docetaxel in case of contraindication to paclitaxel and availability at the site). Stratification is based on HER2 expression (IHC 1+; 2+) and prior lines of therapy (1; 2+). The primary endpoint for Cohort 1 is progression-free survival (PFS) by blinded independent central review (BICR); overall survival is a key secondary endpoint. In Cohort 2, ≈60 patients with HER2 IHC 3+ EC will receive T-Pam; the primary endpoint for this cohort is objective response rate by BICR. Enrollment is ongoing globally. Clinical trial information: NCT06340568 .