BDC-1001 +/- Immune Checkpoint Inhibitor Therapy Under Investigation for HER2+ Breast Cancer

Currently, the only immune-based therapy for patients with HER2-driven or expressing cancers are anti-HER2 monoclonal antibodies. More treatment options are needed for patients who develop progressive disease.

A trail in progress presented at the virtual 2020 San Antonio Breast Cancer Symposium suggests that immunostimulatory adjuvants such as toll-like receptor (TLR) 7/8 can help cause T-cells to mediate antitumor activity.

The first-in-human phase 1/2 dose-escalation and dose-expansion study aims to enroll 390 patients with advanced solid tumors that are HER2-expressing or HER2-amplified. In part 1 of the dose escalation arm, the primary objective is to define the safety and tolerability of BDC-1001 as a monotherapy. Part 2 will focus on it as part of a combination with an immune checkpoint inhibitor. BDC-1001 will be administered intravenously over 60 minutes at increasing doses.

Once safety data are available from the study, the dose expansion portion will evaluate the anti-tumor activity of BDC-1001. The primary endpoints of this trial will be duration of response, disease control, and progression free survival.

In an interview with Ecaterina Ileana Dumbrava, MD, assistant professor at the University of Texas MD Anderson Cancer Center, discussed the ongoing study of BDC-1001 as treatment of HER2-positive breast cancer and other solid tumors.

TARGETED ONCOLOGY: Could you explain mechanism of action of this novel agent?

DUMBRAVA: BDC-1001 is a novel HER2 agent targeting TLR7/8 immune stimulating antibody conjugate, or ISAC. This consists of an investigational biosimilar of the humanized monoclonal antibody trastuzumab, which is contributed to a TLR7/8 agonist with a non-cleavable linker that is administered systemically. BDC-100 can initiate an entirely new immune response by activating the human myeloid antigen presenting cells, while retaining antibody mediated effector functions such as antibody dependent cellular cytotoxicity, and phagocytosis. Despite all the advances that have been ongoing in in targeting HER2 for patients with HER2-positive breast cancer, there remains a significant unmet need for to get better approaches and to improve patient outcomes.

The preclinical data for BDC-1001 were recently published, and the preclinical models on trastuzumab (Herceptin) resistance and syngeneic tumors indicated that this HER2-targeted ISAC, BDC-1001, can elicit potent and durable immune mediated anti-tumor efficacy, leading to complete tumor regression in a TLR7/8 in an FC receptor-dependent manner. So, what we are hoping is that these 2 treatments will lead to a strong and localized pro inflammatory response in the tumor and will be able to turn some tumors that they are called to heart and translate into meaningful responses in patients.

TARGETED ONCOLOGY: What would you say is the rationale for combining this agent with an immune checkpoint inhibitor?

DUMBRAVA: In the preclinical models, we have seen synergistic activity and when combined with immune checkpoint inhibitors. There are striking results of combining the BBC-1001 with an anti-PD-1 agent. It leads to T-cell dependent immunologic memory, and epitopes for spreading, and hopefully it will be translated to long-term responses in patients.

TARGETED ONCOLOGY: What methods will be utilized on this study?

DUMBRAVA: This clinical study has 2 parts. One is a dose escalation phase and a second part is a dose expansion. And this is a first in human trial. The studies evaluating BDC-1001 intravenously every 3 weeks with or without an immune checkpoint inhibitor targeted in PD-1 in up to 390 patients with HER2-expressing or HER2-amplifying advanced or metastatic solid tumors.

For the dose-escalation part, we’ll evaluate the base dose of BDC-1001 as monotherapy or in combination with an anti PD-1 antibody, such as pembrolizumab (Keytruda). The design, it's a classical step 3 + 3 dose escalation. HER2 inclusion criteria for part 1 and 2, for the dose escalation, included the virtue expressing by immunohistochemistry, or HER2 positivity by gene amplification.

Once the right doses are identified for these parts, we'll have either the BDC-1001 as monotherapy or in combination with a PD-1 antibody in 3 different cohorts. We will include patients with breast, gastric, other solid tumors that are HER2 positive.

TARGETED ONCOLOGY: Whtat are the key goals of this study?

DUMBRAVA: The primary objective is to determine the safety, tolerability, the recommended phase 2 those of the BDC-1001 as monotherapy and in combination with an anti PD-1 antibody. There are also other secondary objectives, such as evaluating the pharmacokinetic and pharmacodynamic parameters. There are also exploratory anlayses that will help to elucidate the mechanism of action of this drug and identify biomarkers associated with activity or resistance. These are the main goals and I think it's crucial to identify biomarkers that would allow us to better select patients.

TARGETED ONCOLOGY: If the results of the phase 1/2 study are positive, what will be the next steps with this research?

DUMBRAVA: Hopefully, the results will be positive. If the results are positive, of course, it will be a major step forward for patients with breast cancer, with gastric cancer, but also with other tumor types beyond these 2 tumors that had that are HER2 positive. We will really beable to develop a personalized treatment option for them. At MD Anderson Cancer Center, what we have been working on is really trying to develop personalized cancer therapies for these patients. HER2 is a validated biomarker, and we are seeing responses in other tumor types with HER2-targeted therapies. So, it would be very interesting to see the results of this trial and how it will find its place among other HER2 therapies in breast cancer, gastric cancer, but also other tumor types that are not negligible. We cannot neglect them, even if the percentage of HER2 is much lower than in breast and gastric.

TARGETED ONCOLOGY: Are you participating in any other ongoing research efforts in the breast space that you'd like to highlight?

DUMBRAVA: We are in investigational cancer therapeutics. I'm very interested in HER2 and HER2 treatments. So, I know that from the San Antonio Breast Cancer Symposium, I was pleased to see the updated results from the DESTINY-BREAST01 trial (NCT03248492) that we showed the prolonged responses and increased overall survival in patients. That is definitely still in the HER2 space, but HER2 is a very good biomarker that is predictive for responses for the targeted therapies. I hope to see more in the coming years.

_REFERENCE:

_{Dumbrava,E Sharma, M., Carvajal, R., et al. Phase 1/2 study of a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), BDC-1001, as a single agent and in combination with an immune checkpoint inhibitor in patients with advanced HER2-expressing solid tumors [abstract]. Cancer Res 2021;81(Suppl 4):Abstract nr OT-03-02.}