BDC-1001 Monotherapy Under Further Evaluation in Phase 2 Trial in HER2+ Cancers

Edith A. Perez, MD

The first patients have been dosed in the phase 2 portion of a phase 1/2 trial (NCT04278144) evaluating BDC-1001 monotherapy in patients with HER2-positive colorectal cancer (CRC), endometrial cancer, and gastroesophageal cancer.¹

The multicenter, open-label, phase 2 study will evaluate the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of intravenous BDC-1001 given at 20 mg/kg once every 2 weeks.

“This is an important milestone for our company that builds on the positive signal of monotherapy activity that we observed in the phase 1 portion of the study,” Edith A. Perez, MD, chief medical officer of Bolt Biotherapeutics, stated in a news release. “Despite considerable advances in anti-cancer therapy, HER2-positive tumors remain difficult to treat, and new therapeutic options are urgently needed. Our immune-stimulating antibody conjugate [ISAC] platform brings a novel mechanism with the potential to address refractory and recurrent disease to the treatment of HER2-positive cancers, and BDC-1001 has demonstrated promise. We are committed to advancing this study for the benefit of the many patients in need.”

BDC-1001 is an ISAC consisting of a HER2-targeting biosimilar of trastuzumab (Herceptin) conjugated with a non-cleavable linker to a proprietary TLR 7/8 agonist.

In the phase 1, dose-escalation portion of the study, 6 patients experienced partial responses (PRs) across all dose levels of BDC-1001 given alone or in combination with nivolumab (Opdivo), including 3 patients with CRC and 1 each with ovarian cancer, biliary tract cancer, and salivary gland cancer.²

Four PRs were observed among patients treated with 20 mg/kg of BDC-1001 every 2 weeks, including 2 patients in the monotherapy group and 2 patients in the combination group. In patients treated with BDC-1001 monotherapy at 20 mg/kg every 2 weeks (n = 7), the overall response rate (ORR) was 29%, and the stable disease (SD) rate was 43%. Fifty-seven percent of patients experienced tumor shrinkage, and the disease control rates (DCRs) of at least 6 weeks and at least 24 weeks were 71% and 43%, respectively.

In patients treated with 20 mg/kg of BDC-1001 every 2 weeks in combination with nivolumab (n = 8), the ORR was 25%. Fifty percent of patients had SD, and the DCRs of at least 6 weeks and at least 24 weeks were 75% and 50%, respectively.

Regarding safety, the maximum-tolerated dose was not reached, and 1 dose-limiting toxicity of grade 3 supraventricular tachycardia was reported in a patient treated with 8 mg/kg of BDC-1001 per week in combination with nivolumab. One grade 4 drug-related adverse effect (AE) was reported, and there were no grade 5 drug-related AEs. The most common drug-related AEs were grade 1/2 infusion-related reactions (29.0%). One patient treated with 12 mg/kg of BCD-1001 once per week experienced grade 1 cytokine release syndrome.

Left ventricular ejection fraction (LVEF) was decreased in 6 patients (grade 2, n = 4; grade 3, n = 2). These events occurred in 5 patients treated with BDC-1001 monotherapy at 12 mg/kg once per week (n = 1), 20 mg/kg once per week (n = 2), 5 mg/kg once every 3 weeks (n = 1), and 8 mg/kg once every 2 weeks (n =1), as well as 1 patient treated with 8 mg/kg of BDC-1001 once per week in combination with nivolumab. Two patients discontinued treatment due to decreased LVEF.

The phase 2 portion of the study is enrolling patients with advanced CRC, endometrial cancer, and gastroesophageal cancer with documented HER2-protein expression or gene amplification for which approved therapies have been exhausted or are not clinically indicated.³ Patients are also required to have measurable disease per RECIST v.1.1 and an ECOG performance status of 0 or 1.

Key exclusion criteria included previous treatment with a TLR 7, TLR 8 or a TLR 7/8 agonist; impaired cardiac function or history of clinically significant cardiac disease; and untreated central nervous system metastases, epidural tumor or metastasis, or brain metastasis.

An additional randomized, 2-arm phase 2 trial (NCT05954143) will evaluate BDC-1001 with or without pertuzumab (Perjeta) in patients with HER2-positive metastatic breast cancer who experienced disease progression following treatment with fam-trastuzumab deruxtecan-nxki (Enhertu).¹

References

1. Bolt Biotherapeutics initiates phase 2 clinical studies of BDC-1001 in patients with HER2-positive cancer. News release. Bolt Biotherapeutics. August 3, 2023. Accessed August 10, 2023. https://investors.boltbio.com/news-releases/news-release-details/bolt-biotherapeutics-initiates-phase-2-clinical-studies-bdc-1001
2. Li BT, Pegram MD, Lee KW, et al. A phase 1/2 study of a first-in-human immune-stimulating antibody conjugate (ISAC) BDC-1001 in patients with advanced HER2-expressing solid tumors. J Clin Oncol. 2023;41(suppl 16):2538. doi:10.1200/JCO.2023.41.16_suppl.2538
3. A first-in-human study using BDC-1001 as a single agent and in combination with nivolumab in advanced HER2-expressing solid tumors. ClinicalTrials.gov. Updated February 21, 2023. Accessed August 10, 2023. https://www.clinicaltrials.gov/study/NCT04278144