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

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

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