Novel HER3 ADC Receives FDA Fast Track for Refractory NSCLC

The FDA has granted fast track designation to a novel 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).¹ This designation specifically applies to patients whose tumors harbor an EGFR exon 19 deletion or L858R mutation and who have experienced disease progression on or after treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy.

The fast track designation is a significant regulatory milestone, aiming to expedite the development and review of therapies for serious conditions that address an unmet medical need. For this patient population, whose disease has progressed despite current standard-of-care treatments, new therapeutic options are critically needed.

DB-1310 is an investigational ADC developed using DualityBio's proprietary DITAC platform. It is designed to specifically target HER3, a protein frequently overexpressed in various solid tumors, including NSCLC. The ADC mechanism involves the antibody binding to HER3 on tumor cells, leading to internalization and subsequent release of a potent cytotoxic payload, a DNA topoisomerase I inhibitor, within the cancer cell.

Preclinical data suggest that DB-1310's activity is mediated through multiple mechanisms, including direct payload-mediated cytotoxicity, bystander effect on surrounding tumor cells, and antibody-dependent cellular cytotoxicity. Importantly, preclinical investigations have also indicated synergistic tumor suppression when DB-1310 is combined with EGFR TKIs.

Preliminary results from the ongoing first-in-human phase 1/2a clinical trial (NCT05785741) of DB-1310 were presented in June 2025 at the American Society of Clinical Oncology (ASCO) Annual Meeting by Aaron E. Lisberg, MD, from the University of California, Los Angeles.² These early findings demonstrated encouraging antitumor activity and a manageable safety profile in patients with heavily pretreated advanced solid tumors, particularly in the EGFR-mutated NSCLC cohort.

The phase 1/2a trial enrolled 123 patients with advanced solid tumors who had exhausted standard therapeutic options. Among the 42 efficacy-evaluable patients with EGFR-mutated NSCLC, 92.9% had previously received a third-generation EGFR TKI such as osimertinib (Tagrisso), rociletinib, or lazertinib (Lazcluze), and 92.9% had received platinum-based chemotherapy (commonly cisplatin or carboplatin in combination with another agent).

The unconfirmed overall response rate (ORR) across all tumor types was reported as 25.5% (95% CI, 17.63%–34.65%), with a higher ORR of 35.7% (95% CI, 21.55%–51.97%) observed in the EGFR-mutated NSCLC subgroup. The median progression-free survival (PFS) was 5.4 months overall and 7.0 months for patients with EGFR-mutated NSCLC.

Regarding safety, 30.9% of patients experienced grade ≥3 treatment-related adverse events (TRAEs), and 5.7% had drug-related serious adverse events. TRAEs led to dose reduction in 11.4% of patients and discontinuation in 4.1%. No TRAE leading to death was reported. Common TRAEs (any grade/≥ grade 3) included nausea (36.6%/0.8%), anemia (35.8%/4.1%), decreased neutrophil count (34.1%/17.9%), decreased platelet count (31.7%/9.8%), decreased white blood cell count (29.3%/8.9%), decreased appetite (23.6%/0.8%), and vomiting (21.1%/0%). Interstitial lung disease, a known concern with certain ADCs, occurred in 5.7% of patients (6 grade 1 and 1 grade 2). Pharmacokinetic data indicated increased exposure with dose escalation, low systemic payload exposure, and no accumulation of DB-1310 with repeated administration.

“DB-1310 demonstrated encouraging clinical efficacy and manageable safety in patients with EGFR[-mutant nonsquamous] NSCLC and multiple solid tumors. 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 cancer patients,” said Hua Mu, MD, global chief medical officer of DualityBio, in a press release.¹

REFERENCES:

1. DualityBio's next-generation HER3 ADC DB-1310 granted FDA fast track designation. News release. DualityBio. July 21, 2025. Accessed July 22, 2025. https://tinyurl.com/388av658

2. Lisberg AE, 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. 43(16_suppl),