A novel antibody-drug conjugate targeting the HER3 receptor has demonstrated encouraging efficacy in patients with advanced solid tumors, particularly those with EGFR-mutant non-small cell lung cancer (NSCLC), according to results from an international clinical trial led by Dr. Aaron Lisberg at UCLA Health Jonsson Comprehensive Cancer Center.
The investigational drug DB-1310 showed a 44% objective response rate among patients with EGFR-mutated NSCLC, achieving a median progression-free survival of seven months and a median overall survival of 18.9 months. These results are particularly significant given that the patients had already undergone multiple rounds of standard treatments and their cancers had become resistant to FDA-approved therapies.
Clinical Trial Results
The Phase 1/2a trial enrolled 172 patients with advanced solid tumors who had previously received multiple lines of therapy, including chemotherapy and targeted treatments. Among these patients, 108 had NSCLC, with 62 carrying EGFR mutations. The study also included 24 patients with brain metastases, representing a particularly challenging patient population.
Across all cancer types in the trial, 31% of patients responded to DB-1310 treatment, with an average progression-free survival of 5.5 months and a median overall survival of 14.4 months. The drug was administered intravenously every three weeks at varying dose levels to determine the optimal balance between safety and efficacy.
Mechanism of Action
DB-1310 represents an innovative approach to cancer treatment as an antibody-drug conjugate that combines a laboratory-engineered antibody recognizing HER3 with a powerful cancer-killing agent. HER3, a protein commonly found on the surface of cancer cells and a member of the EGFR receptor family, plays a pivotal role in oncogenic signaling pathways that promote tumor cell proliferation and survival.
The targeted delivery mechanism allows DB-1310 to deliver chemotherapy directly to cancer cells while minimizing damage to healthy tissue, potentially improving treatment precision and reducing side effects associated with traditional chemotherapy.
Safety Profile
The safety profile of DB-1310 was generally manageable, with the most common side effects being cytopenias such as low blood cell counts and mild to moderate nausea. These findings suggest that the ADC's targeted mechanism successfully reduces off-target effects compared to conventional chemotherapy.
"On this Phase 1/2a trial, DB-1310 has shown real potential as a new treatment option for patients with advanced solid tumors that have progressed after standard therapies," said Dr. Aaron Lisberg, assistant professor of medicine and thoracic medical oncologist at the David Geffen School of Medicine at UCLA. "These were patients who were heavily pretreated and whose cancers had become resistant to FDA-approved treatments, yet DB-1310 offered a meaningful extension of life with a very tolerable side effect profile."
Clinical Significance
The results are particularly encouraging for patients with EGFR-mutant lung cancer, who face limited treatment options after standard therapies fail. EGFR mutations are known driver alterations that often confer poor prognosis and resistance to conventional therapies, making this patient population especially challenging to treat.
The study's inclusion of patients with brain metastases addresses a critical unmet need, given the poor prognosis typically associated with central nervous system involvement and the protective nature of the blood-brain barrier that limits effective systemic treatment options.
Future Development
Study enrollment remains ongoing, with the Phase 1 portion continuing to evaluate different dose levels to identify the safest and most effective dose. The Phase 2 portion will evaluate additional patients with tumor types of interest to assess the drug's effectiveness in treating various cancers.
The implications of DB-1310 extend beyond lung cancer, suggesting potential applications for targeting HER3-positive malignancies prevalent in multiple solid tumors such as breast, head and neck, and gastrointestinal cancers.
Dr. Lisberg presented these findings at the American Society of Clinical Oncology annual meeting during the Oral Abstract Session of the Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology Track. The study was sponsored by Duality Biologics and represents a collaborative effort among clinicians and researchers at UCLA and internationally.
