FDA Grants Breakthrough Therapy Designation to BNT323/DB-1303 in Endometrial Cancer

The FDA has granted breakthrough therapy designation to the HER2-targeted antibody-drug conjugate (ADC) BNT323/DB-1303 for use as a potential therapeutic option in patients with advanced endometrial cancer who have progressed on or after treatment with immune checkpoint inhibitors.¹

This decision was supported by topline data from a phase 1/2 trial (NCT05150691), in which BNT323/DB-1303 elicited an unconfirmed overall response rate (ORR) of 58.8% and an unconfirmed disease control rate (DCR) of 94.1% in 17 evaluable patients who received the ADC at doses of 7.0 mg/kg or 8.0 mg/kg.²

BNT323/DB-1303 is a third-generation topoisomerase-1 inhibitor–based ADC built from the DualityBio Duality Immune Toxin Antibody Conjugates platform.¹ This ADC has been associated with antitumor activity in HER2-positive and HER2-low tumor models, as well as in patients with advanced solid tumors including breast, gastric, biliary tract, and endometrial cancers.

“The breakthrough therapy designation for BNT323/DB-1303 shows the potential of our ADC candidate to address current treatment challenges for patients with advanced HER2-expressing endometrial cancer who progressed under several lines of systemic therapy,” professor Özlem Türeci, MD, chief medical officer and cofounder of BioNTech, stated in a news release. “For these patients, the survival rates are still low, and the medical need for new and more effective treatments remains high. With the designation and support by the FDA, we seek to expedite further development of BNT323/DB-1303.”

The phase 1/2 global, first-in-human trial is evaluating the ADC in patients with advanced or metastatic HER2-expressing solid tumors who have progressed on previous systemic therapies.³ Patients must have an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy of at least 3 months. Phase 1 follows a 3+3 design to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Phase 2 is a dose-expansion phase to confirm the tolerability and safety of the agent and explore its efficacy at the MTD or RP2D.

In phase 1, patients receive intravenous BNT323/DB-1303 monotherapy once every 3 weeks at 1 of 5 experimental dose levels or 13 dose-expansion dose levels.

The primary end points of the phase 1 portion of the trial include the percentages of dose-limiting toxicities, treatment-emergent adverse effects (TEAEs), and serious AEs, as well as the determination of the MTD and the RP2D. The primary end points of the phase 2 portion include the percentages of TEAEs and serious AEs, as well as ORR. Secondary end points in both phases include pharmacokinetics, pharmacodynamics, DCR, duration of response, time to response, time on therapy, percent change in target lesion, progression-free survival, and overall survival.

At a data cutoff date of May 8, 2023, 32 patients in the endometrial cancer cohort had received the agent at 7.0 mg/kg or 8.0 mg/kg.² Histological subtypes included uterine serous papillary carcinoma (34.4%), adenocarcinoma (25.0%), and uterine carcinosarcoma (18.8%). The median duration of treatment was 2.6 months (range, 0.7-10.4), and 90.6% of patients remained on treatment at the data cutoff. Patients had received a median of 2 prior lines of therapy (range, 1-10), including 59.4% of patients who had received prior immunotherapy.

When stratified by histology, 87.5%, 50.0%, 50.0%, and 33.3% of patients with uterine serous papillary carcinoma, uterine carcinosarcoma, mixed adenocarcinoma, and adenocarcinoma experienced responses, respectively.

The ORRs in patients who received the 7.0 mg/kg and 8.0 mg/kg doses were 50.0% and 61.5%, respectively.

Overall, 93.8% of patients experienced any-grade TEAEs, the most common being nausea (50.0%), fatigue (31.2%), and vomiting (28.1%). Grade 3 or higher TEAEs occurred in 31.2% of patients, the most common being hypokalemia (12.5%), anemia (6.2%), and syncope (6.2%). No cases of interstitial lung disease were reported, and no TEAEs led to treatment discontinuation or death.

“The FDA’s decision is an important milestone in the development of our novel differentiated ADC candidate directed at HER2,” Vivian Gu, MD, chief medical officer of DualityBio, added in the news release.1 “The HER2 protein overexpression and/or gene amplification is present in approximately 17% to 38% of patients with endometrial cancer, and more than 50% of patients in late disease stage exhibit HER2 overexpression. We believe BNT323/DB-1303 has the potential to serve as a new therapeutic option for patients with HER2-expressing advanced endometrial carcinoma, including both patients with high and low expression levels of HER2. We are committed to advancing BNT323/DB-1303 with the aim to improve outcomes for patients in late disease stages.”

In addition to the phase 1/2 trial in solid tumors, a phase 3 trial (NCT06018337) is ongoing investigating BNT323/DB-1303 in patients with hormone receptor–positive, HER2-low metastatic breast cancer who have progressed on hormone therapy and/or CDK4/6 inhibitors.

References

1. BioNTech and DualityBio receive FDA breakthrough therapy designation for antibody-drug conjugate candidate BNT323/DB-1303 in endometrial cancer. News Release. BioNTech. December 21, 2023. Accessed December 21, 2023. https://www.globenewswire.com/news-release/2023/12/21/2799939/0/en/BioNTech-and-DualityBio-Receive-FDA-Breakthrough-Therapy-Designation-for-Antibody-Drug-Conjugate-Candidate-BNT323-DB-1303-in-Endometrial-Cancer.html
2. Moore K, Makker V, Yeku O, et al. DB-1303, a HER2-targeting ADC, for patients with advanced/metastatic endometrial cancer: preliminary clinical results from an ongoing phase 1/2a trial (NCT05150691). Int J Gynecol Cancer. 2023;33(suppl 3):A9-A10. doi:10.1136/ijgc-2023-ESGO.14
3. A study of DB-1303 in advanced/metastatic solid tumors. ClinicalTrials.gov. Updated October 19, 2023. Accessed December 21, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05150691