Positive Topline Data from BDC-1001 Phase 1 Dose-Escalation Trial in HER2-Expressing Tumors Supports Advancement to Phase 2 Clinical Studies

Positive top-line data from a recently completed dose-escalation study of BDC-1001 in HER2-expressing solid tumors support the drug to advance into two Phase 2 studies in breast, colorectal, endometrial, and gastroesophageal cancers.

In the study BDC-1001 elicited objective clinical responses, including multiple PRs and long-term stable disease, across a diverse set of solid tumor types in monotherapy and in combination with nivolumab

The data from the trial will be presented at an upcoming medical society meeting.

BDC-1001, an investigational Immune-Stimulating Antibody Conjugate (ISAC) being developed by Bolt Biotherapeutics, is a human epidermal growth factor receptor 2 (HER2-) targeting trastuzumab biosimilar conjugated with a non-cleavable linker to an innovative TLR7/8 agonist.

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Preliminary results of the first-in-human monotherapy dose escalation (Part 1) of the study, presented during the annual meeting of the American Society of Clinical Oncology (ASCO), showed that patients with advanced metastatic HER2-expressing (IHC2/3+) or amplified solid tumors who received BDC-1001 IV q3w in a 3+3 design w/ 12 patient/cohort demonstrated potent and durable immune-mediated antitumor efficacy. [1]

Well tolerated
Topline findings from the phase 1 dose-escalation study demonstrated that BDC-1001 was well tolerated at all dose levels and schedules evaluated, both as monotherapy and in combination with nivolumab (Opdivo®; Bristol-Myers Squibb).

The study results showed that 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. Anti-tumor activity was observed in the form of multiple partial responses (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. Moreover, biomarker data demonstrate that corresponding clinical and safety data are related to the ISAC mechanism. These data support the selection of a RP2D and advancement to Phase 2 studies.

“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,” noted Edith A. Perez, M.D., Chief Medical Officer of Bolt Biotherapeutics.

“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 U.S. and internationally,” Perez added.

“While we have made remarkable progress in developing new treatments for patients with HER2-expressing cancers, there remains an urgent need for innovation,” explained Bob T. Li, M.D., Ph.D., MPH, medical oncologist, and principal investigator at Memorial Sloan Kettering Cancer Center (MSK).

“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,” Li added.

The phase 1 dose-escalation trial enrolled more than 100 patients with 16 different HER2-expressing solid tumor types. At enrollment, all patients entered in the study had evidence of tumor progression following prior standard of care treatments, and a majority of the patients were heavily pre-treated.

New Agreement
Unrelated to the recent data from the Phase 1 study Bolt Biotherapeutics also announced today that it has entered into a clinical supply agreement with Roche to evaluate pertuzumab (Perjeta®; Genentech/Roche) in combination with BDC-1001. Through a supply agreement, Roche will provide pertuzumab in support of a Phase 2 metastatic breast cancer trial.

Preclinical research combining pertuzumab with a BDC-1001-surrogate demonstrated enhanced anti-tumor efficacy in multiple models and a compelling mechanistic rationale for conducting a clinical trial to evaluate a potential impact on patients. Pertuzumab, which binds a distinct HER2 epitope from the trastuzumab component of BDC-1001, may increase the amount of clustered Fc or “eat me signals” on the surface of the tumor. This appears to trigger enhanced antibody-dependent cellular phagocytosis, a key element of the BDC-1001 mechanism of action, resulting in further propagation of BDC-1001-driven immune activation and anti-tumor efficacy.

BDC-1001 Phase 2
Bolt’s Phase 2 clinical plan includes two distinct studies, each using a Simon two-stage design. These studies will build upon Bolt’s existing clinical sites and clinical trial centers of excellence in the U.S. and South Korea, expanding into multiple countries in Europe, and include:

• Phase 2 dose expansions of the current Phase 1/2 trial will initially focus on investigating BDC-1001 as a monotherapy, given the positive single-agent clinical data seen in the Phase 1 trial, enrolling HER2-positive colorectal, endometrial, and gastroesophageal cancer patients. Combination arms with nivolumab are expected to initiate in each indication following demonstration of monotherapy anti-tumor activity. Bristol Myers Squibb, Bolt’s clinical collaborator for this study, will continue to supply nivolumab at no cost for such expansion cohorts.
• Initiation of a two-cohort Phase 2 clinical trial exploring BDC-1001 as monotherapy and BDC-1001 in combination with pertuzumab in patients with HER2-positive metastatic breast cancer who have developed tumor progression following treatment with Enhertu.

Clinical trials
A First-in-human Study Using BDC-1001 as a Single Agent and in Combination With Nivolumab in Advanced HER2-Expressing Solid Tumors – NCT04278144

Highlights of prescribing information
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescription Information]
Pertuzumab (Perjeta®; Genentech/Roche)[Prescribing Information]

Reference
[1] Sharma M, Carvajal RD, Hanna GJ, Li BT, Moore KN, Pegram MD, Rasco DW, Spira AI, et al. Preliminary results from a phase 1/2 study of BDC-1001, a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), in patients (pts) with advanced HER2-expressing solid tumors. J Clin Oncol 39, 2021 (suppl 15; abstr 2549) DOI 10.1200/JCO.2021.39.15_suppl.2549

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