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The FDA has granted fast track designation to the next-generation HER3-targeting antibody-drug conjugate (ADC) DB-1310 for the treatment of adult patients with advanced, unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring an EGFR exon 19 deletion or exon 21 L858R mutation who experienced disease progression on or after treatment with a third-generation EGFR TKI and platinum-based chemotherapy.1
The agent is currently being evaluated in the phase 1/2a DB-1210-O-1001 trial (NCT05785741) in patients with advanced solid tumors.
“DB-1310 demonstrated encouraging clinical efficacy and manageable safety in patients with EGFR-mutated nonsquamous NSCLC and multiple solid tumors,” Hua Mu, MD, PhD, global chief medical officer of DualityBio, stated in a news release. “It is noteworthy that preclinical investigations of DB-1310 in combination with EGFR TKIs and other anticancer agents have also demonstrated robust synergistic tumor suppression activity. We will spare no effort to accelerate the clinical development of DB-1310 and look forward to its potential, as a next-generation HER3 ADC, to become a novel therapeutic option for a broad population of [patients with] cancer.”
Findings from the phase 1/2a trial, which were presented at the 2025 ASCO Annual Meeting, demonstrated that in safety-evaluable patients with EGFR-mutated NSCLC (n = 62), any-grade and grade 3 or higher TEAEs occurred at respective rates of 95.2% and 46.8%. The rates of any-grade and grade 3 or higher TRAEs were 91.9% and 35.5%, respectively. TRAEs led to dose interruption, dose reduction, and treatment discontinuation in 21.0%, 9.7%, and 3.2% of patients, respectively.
In efficacy-evaluable patients with EGFR-mutated NSCLC (n = 46), the unconfirmed and confirmed ORRs were 28.3% and 43.5%, respectively, and the DCR was 91.3%. The median DOR was 5.80 months (95% CI, 2.73-NE), the median PFS was 7.03 months (95% CI, 4.14-8.41), and the median OS was 18.89 months (95% CI, 11.63-NE).
Efficacy and Safety Data Across Solid Tumors
Investigators also presented data from the overall population (n = 172) of patients with various solid tumor types. Any-grade treatment emergent adverse effects (TEAEs) occurred in 95.9% of patients across all dose levels, including grade 3 or higher TEAEs in 50.0% of patients. Treatment-related AEs (TRAEs) of any grade were reported in 88.4% of patients, including 36.0% who had grade 3 or higher TRAEs. TRAEs led to dose interruption, dose reduction, and treatment discontinuation in 15.1%, 12.2%, and 3.5% of patients, respectively.
Regarding efficacy, at a median follow-up of 7.52 months (range, 1.6-18.9), evaluable patients with various tumor types (n = 123) experienced an overall response rate (ORR) of 30.9%, including a confirmed ORR of 20.3% with 8 patients awaiting confirmation of response. The disease control rate (DCR) was 83.7%. The median duration of response (DOR) was 6.28 months (95% CI, 4.14-not evaluable [NE]), the median progression-free survival (PFS) was 5.49 months (95% CI, 4.30-6.93), and the median overall survival (OS) was 14.42 months (95% CI, 10.68-NE).
DB-1210-O-1001 Study Design
The first-in-human, multicenter trial enrolled patients at least 18 years of age with advanced or metastatic solid tumors that had progressed on or after standard systemic therapy. Key exclusion criteria comprised at least 1 measurable lesion per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function. Patients with treated and asymptomatic brain metastases were allowed to enroll; however, prior treatment with HER3-targeted therapy or an ADC with a topoisomerase I inhibitor payload precluded patients from participation.
During the phase 1 dose escalation, DB-1310 was evaluated at doses of 1.5 mg/kg, 3.0 mg/kg, 4.5 mg/kg, 5.5 mg/kg, 6.0 mg/kg, and 6.5 mg/kg given once every 3 weeks. Backfilling was prioritized for patients with EGFR-mutated NSCLC at doses of 5.0 mg/kg and 5.5 mg/kg.
The incidence of dose-limiting toxicities, determination of the maximum tolerated dose, and safety served as the trial’s primary end points. Secondary end points included ORR, DCR, DOR, PFS, OS, pharmacokinetics, and anti-drug antibodies.
Common TRAEs in the Overall Population
Further safety data from the trial’s overall population, irrespective of tumor type, showed that the most common TRAEs reported in at least 15% of patients across all dose levels included anemia (grade 1/2, 37.2%; grade ≥3, 4.7%), decreased neutrophil count (21.0%; 20.9%), nausea (37.8%; 0.6%), decreased platelet count (26.8%; 11.6%), decreased white blood cell count (26.8%; 8.7%), decreased appetite (25.6%; 0.6%), vomiting (22.7%; 0%), alopecia (20.3%; 0%), hypoalbuminemia (19.8%; 0%), hyponatremia (17.4%; 0%), increased aspartate aminotransferase levels (17.4%; 0%), and decreased lymphocyte count (10.5%; 6.4%).
Unadjudicated interstitial lung disease (ILD)/pneumonitis was reported in 5.2% of patients (n = 9); 8 of these patients experienced grade 1 ILD/pneumonitis, and 1 instance of grade 2 ILD/pneumonitis was reported in a patient treated at the 5-mg/kg dose level.
References
- DualityBio’s next-generation HER3 ADC DB-1310 granted FDA fast track designation. News release. DualityBio. July 22, 2025. Accessed July 22, 2025. https://en.dualitybiologics.com/news/592.html
- Lisberg A, Lu S, Hamilton E, et al. DB-1310, a HER3-targeted ADC, in pts with advanced solid tumors: Preliminary results from the phase 1/2a trial. J Clin Oncol. 2025;43(suppl 16):3000. doi:10.1200/JCO.2025.43.16_suppl.3000