The FDA has granted fast track designation to BNT325/DB-1305, a next-generation TROP2-directed antibody-drug conjugate (ADC), for treating patients with platinum-resistant ovarian epithelial, fallopian tube, or primary peritoneal cancer who have received 1 to 3 prior lines of systemic therapy. The designation recognizes the potential of this investigational therapy to address a critical unmet medical need in gynecologic oncology.
Clinical Trial Results Drive FDA Decision
The fast track designation is based on preliminary data from an ongoing phase 1/2 trial (NCT05438329) presented at the 2023 ESMO Congress. In 23 patients with TROP2-expressing advanced solid tumors who had received a median of 3 prior lines of therapy (range, 1-6), BNT325/DB-1305 demonstrated an objective response rate (ORR) of 30.4% and an unconfirmed disease control rate (DCR) of 87.0%. Notably, the one patient with fallopian tube cancer experienced an unconfirmed partial response at the 5-mg/kg dose.
"The FDA's decision is an important recognition of the potential of our TROP2-targeting ADC candidate. Platinum-based chemotherapy is the backbone of treatment for ovarian epithelial cancer and related subtypes that form in the epithelial tissue," stated Professor Özlem Türeci, MD, chief medical officer and co-founder at BioNTech. "Patients with platinum resistance who relapse within under 6 months have a poor prognosis, and effective and well-tolerated treatment options remain a substantial unmet medical need."
Novel ADC Design and Mechanism
DB-1305 is a novel ADC composed of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a DNA topoisomerase I inhibitor (P1021) via a cleavable linker. While TROP2 is an integral element of tumor progression, current TROP2-directed therapies are limited in indication to patients with triple-negative breast cancer (TNBC), hormone receptor (HR)–positive breast cancer, HER2-negative breast cancer, and urothelial carcinoma.
Phase 1/2 Trial Design and Safety Profile
The global, open-label, first-in-human phase 1/2 study is evaluating BNT325 in patients with advanced or metastatic solid tumors who progressed on standard treatment or for whom no standard therapy is available. In phase 1, investigators evaluated 5 escalating doses: 2 mg/kg (n = 1), 4 mg/kg (n = 3 to 6), 6 mg/kg (n = 3 to 6), 8 mg/kg (n = 3 to 6), and 10 mg/kg (n = 3 to 6).
At the time of data cutoff, 44 patients had received study treatment, with 25 remaining on therapy. The median duration of treatment was 1.5 months (range, 0.7-6.1). The median age was 59.0 years (range, 40.0-78.0) and the majority were female (59.1%). Most patients had received prior platinum therapy (88.6%) and had an ECOG performance status of 1 (84.1%). Only 2 patients had ovarian cancer in this early analysis.
Dose-limiting toxicities occurred in 3 patients who received the 6-mg/kg dose, establishing 5 mg/kg as the maximum tolerated dose (MTD). Treatment-related adverse effects occurring in at least 20% of patients included stomatitis (all grade, 75.0%; grade ≥3, 22.7%), nausea (29.5%; 2.3%), decreased lymphocyte count (22.7%; 13.6%), infusion-related reaction (20.5%; 0%), decreased appetite (20.5%; 0%), mucosal inflammation (0%; 2.3%), and interstitial lung disease (2.3%; 0%).
Expansion Phase and Future Development
The phase 2 expansion portion evaluates the agent across several cohorts including small cell lung cancer, HR-positive and HER2-negative breast cancer, oncogene driven–negative non–small cell lung cancer, sacituzumab govitecan-naive and -exposed TNBC, NSCLC with actionable genomic alterations, and other solid tumors, with preference for patients with epithelial ovarian and endometrial cancer.
"BNT325/DB-1305 is the second investigational asset in our strategic collaboration which has received FDA fast track designation highlighting the potential of the candidate to fill an unmet medical need," said Vivian Gu, MD, chief medical officer at DualityBio. "Data from the phase 1/2 clinical trial with BNT325/DB-1305 have demonstrated encouraging anti-tumor signals in heavily pretreated patients with TROP2-expressing solid tumors who had failed standard therapy."
The fast track designation follows the December 2023 FDA breakthrough therapy designation granted to BNT323/DB-1303 for use in patients with advanced endometrial cancer who had progressed on or following immune checkpoint inhibitors, highlighting the continued development of innovative ADC therapies in the BioNTech-DualityBio collaboration.
