Data from a phase 1/2 dose escalation study investigating BDC-10001 plus nivolumab in HER2-expressing tumors support the advancement of additional phase 2 trials evaluating the novel antibody conjugate.
The investigational immune-stimulating antibody conjugate BDC-1001 demonstrated clinical activity and tolerability alone or in combination with nivolumab (Opdivo) in patients with HER2-expressing solid tumors, according to a press release on topline data from a phase 1/2 trial (NCT04278144) from Bolt Biotherapeutics.
In the trial, BDC-1001 achieved target drug exposure levels at or near the recommended phase 2 dose when administered every other week or weekly to patients. Additionally, BDC-1001 with or without nivolumab yielded multiple partial responses, tumor shrinkage, and long-term stable disease across multiple types of HER2-expressing solid tumors.
Biomarker findings also demonstrated corresponding safety and clinical data related to the agent’s immune-stimulating antibody conjugate mechanism.
These topline data support further research as part of a phase 2 clinical program that includes phase 2 dose expansions of the current phase 1/2 trial with an initial focus on assessing BDC-1001 monotherapy in those with HER2-positive colorectal, endometrial, and gastroesophageal cancer.
Investigators will also initiate a 2-cohort phase 2 trial evaluating BDC-1001 on its own and in combination with pertuzumab (Perjeta) for patients who have HER2-positive metastatic breast cancer with disease progression following prior treatment with trastuzumab deruxtecan (Enhertu). Preclinical research has demonstrated enhanced anti-tumor efficacy in multiple models when combining pertuzumab with a BDC-1001 surrogate.
“While we have made remarkable progress in developing new treatments for patients with HER2-expressing cancers, there remains an urgent need for innovation,” lead investigator Bob T. Li, MD, PhD, MPH, physician ambassador to China and Asia-Pacific at Bobst International Center, co-director of the Thoracic Liquid Biopsy Program, and chief scientific officer at Memorial Sloan Kettering (MSK) Direct, MSK Cancer Center, said in the press release.
“In this international dose-escalation trial, BDC-1001 leveraged a novel mechanism of HER2-targeted immune stimulating antibody conjugate and demonstrated encouraging evidence of efficacy and manageable safety, providing hope of a potential new treatment option for patients with HER2-expressing tumors.”
The first-in-human, dose-escalation phase 1/2 trial included more than 100 patients with 16 types of HER2-expressing solid tumors. All patients who enrolled on the study had evidence of tumor progression following standard-of-care treatment, and many were heavily pre-treated.
In the study, patients received BDC-1001, which included an anti-HER2 monoclonal antibody conjugated to a TLR 7/8 dual agonist, with or without nivolumab.
The primary end points of the trial included adverse effects (AEs) and serious AEs, dose-limiting toxicities, potential immune-related toxicities, determining the maximum tolerated dose, and objective response rate. The secondary end points included BDC-1001’s pharmacokinetics, disease control rate, and progression-free survival.
Patients 18 years or older who had an advanced solid tumor with documented HER2 expression or gene amplification for which therapies are not clinically indicated were eligible to enroll on the trial. Additional inclusion criteria included having measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and tumor tissue available for exploratory biomarker evaluation.
Patients who had a hypersensitivity to any ingredient of the study drugs including trastuzumab or other monoclonal antibodies were not eligible for enrollment on the trial. Patients were also unsuitable for enrollment if they had received previous treatment with a TLR 7, TLR 8, or a TLR 7/8 agonist. Additional exclusion criteria included impaired cardiac function or history of clinically significant cardiac disease or human immunodeficiency virus or active hepatitis B or C infection. Presence of untreated central nervous system metastases or an active COVID-19 infection were also grounds for exclusion.
Bolt Biotherapeutics announces positive topline data from BDC-1001 phase 1 dose-escalation trial in HER2-expressing tumors, supporting advancement to phase 2 clinical studies. News release. Bolt Biotherapeutics. March 29, 2023. Accessed April 5, 2023. bit.ly/3KkCjii