BDC-1001 With/Without Nivolumab Elicits Clinical Responses Across Solid Tumors


Data from a phase 1/2 study of BDC-1001 alone or with nivolumab supports selection of a recommended phase 2 dose, advancement of further phase 2 studies, and assessment of the agent in combination with pertuzumab.

Image Credit: © []

Image Credit: © []

Treatment with BDC-1001 as a monotherapy or in combination with nivolumab (Opdivo) led to objective clinical responses that included multiple partial responses (PRs) and long-term stable disease across a diverse set of solid tumor types, according to positive topline data from recently completed phase 1/2 dose-escalation study (NCT04278144).1

These data support selection of a recommended phase 2 dose (RP2D) and advancement into phase 2 studies for patients with breast, colorectal, endometrial, and gastroesophageal cancers.

BDC-1001 is an investigational Immune-Stimulating Antibody Conjugate (ISAC). Investigators are developing the agent for the treatment of patients with HER2-expressing cancers. Further data will be presented at an upcoming medical meeting.

“We are enthusiastic to be taking the next step in investigating the therapeutic promise of BDC-1001. In the study, we not only achieved target exposure levels for BDC-1001, but at those levels we saw promising signs of clinical activity as a single agent and in combination with nivolumab,” said Edith A. Perez, MD, chief medical officer of Bolt Biotherapeutics, in a press release. “We look forward to sharing full data at an upcoming major medical conference, and to initiating a focused phase 2 program working with a diverse group of investigators in the [United States]. and internationally. I’d like to express my gratitude to all the patients and investigators who are participating in our trial and to the incredible team at Bolt for their hard work and dedication.”

In the phase 1/2 study, investigators assessed BDC-1001 as a single agent and in combination with nivolumab in patients with advanced HER2-expressing solid tumors. The study had 4 parts: a dose-escalation part (part 1) with BDC-1001 alone to determine the maximum tolerated dose (MTD), RP2D, or maximum protocol dose (MPD) recommended for part 3; a dose-escalation part (part 2) of BDC-1001 in combination with nivolumab to determine the MTD, RP2D, or MPD for part 4; part 3 where the RP2D from part 1 will be administered as monotherapy to patients with selected advanced malignancies; and part 4 where the selected dose from part 2 will be administered in combination with nivolumab.2

The trial enrolled over 100 patients with 16 different HER2-expressing solid tumor types who were aged 18 years and older and had evidence of tumor progression following prior standard of care treatments. The majority of the patients were heavily pre-treated. Additionally, patients must have had an ECOG performance status of 0 or 1, measurable disease as determined by RECIST v.1.1., and tumor tissue available for exploratory biomarker evaluation.

In the escalation portion of the trial, primary end points included incidence of adverse events (AEs) and serious AEs, nature of dose-limiting toxicities, potential-immune related toxicities, and to determine the MTD. Secondary end points were pharmacokinetics and objective response rate (ORR). For the expansion portion, the primary end points is ORR with secondary end points of incidence of AEs, and potential-immune related toxicities. Among both parts, other secondary end points evaluated duration of response, disease control rate, progression-free survival, and incidence of anti-BDC-1001 antibodies.

Topline findings from this trial indicate that BDC-1001 was well tolerated at all dose levels and schedules evaluated, both as monotherapy and in combination with nivolumab. Target drug exposure levels were achieved at or near the recommended phase 2 dose (RP2D) by more frequent administration including every other week (q2w) and weekly (q1w) administration schedules.

With the agent, patients had anti-tumor activity in the form of multiple PRs, tumor shrinkage, and long-term stable disease at or near the RP2D across multiple HER2-expressing solid tumor types in monotherapy and in combination with nivolumab. Additionally, biomarker data showed that corresponding clinical and safety data are related to the ISAC mechanism.

With this positive data, the selection of a RP2D is supported by investigators, and the agent will be advanced to be evaluated in additional phase 2 studies.1

​​“While we have made remarkable progress in developing new treatments for patients with HER2-expressing cancers, there remains an urgent need for innovation,” said Bob T. Li, MD, PhD, MPH, medical oncologist, and principal investigator at Memorial Sloan Kettering Cancer Center, in a 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.”

In addition to these promising findings, Bolt Biotherapeutics also announced that they have entered into a clinical supply agreement with Roche to evaluate the combination of pertuzumab (Perjeta) and BDC-1001 in a phase 2 trial for metastatic breast cancer.

According to preclinical research that combined pertuzumab with a BDC-1001-surrogate, enhanced anti-tumor efficacy was observed in multiple models as well as a compelling mechanistic rationale for conducting a clinical trial to evaluate a potential impact on patients.

Pertuzumab binds a distinct HER2 epitope from the trastuzumab component of BDC-1001. The agent may increase the amount of clustered Fc on the surface of the tumor and looks to trigger enhanced antibody-dependent cellular phagocytosis, which is a key element of the BDC-1001 mechanism of action. This leads to further propagation of BDC-1001-driven immune activation and anti-tumor efficacy.

1. 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, Inc. March 29, 2023. Accessed April 3, 2023.
2. First-in-human study using BDC-1001 as a single agent and in combination with nivolumab in advanced HER2-expressing solid tumor. Updated February 21, 2023. Accessed April 3, 2023.
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