BRIA-ABC Trial Explores Novel Post-ADC Strategy for Metastatic Breast Cancer

Efforts to expand the post–antibody-drug conjugate (ADC) arsenal in metastatic breast cancer have led to the development of SV-BR-1-GM (Bria-IMT), a granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting, antigen-presenting immortalized breast cancer cell line.1

“When we talk about later lines of treatment for patients with metastatic breast cancer, [it is often limited to] chemotherapy after chemotherapy. Even with the advent of new ADCs, such as fam-trastuzumab deruxtecan-nxki [Enhertu] and sacituzumab govitecan-hziy [Trodelvy], once patients progress on these ADCs, their treatment [options] are limited,” Saranya Chumsri, MD, a breast medical oncologist in the Department of Oncology and senior associate consultant at Mayo Clinic in Jacksonville, Florida, said in an interview with OncologyLive.

This novel therapeutic approach leverages a distinct mechanism of action and could provide patients who have exhausted all other treatment options with a less toxic, more tolerable therapeutic alternative. With clinical utility as a cellular immunotherapy, the Bria-IMT regimen is currently being evaluated in combination with an immune checkpoint inhibitor in the phase 3 BRIA-ABC trial (NCT06072612).²

“We know that patients who progress on ADCs, regardless of HER2 expression levels, [experience poor survival outcomes]. There’s really no good treatment of choice in a post-ADC world,” Adam M. Brufsky, MD, PhD, said in a separate interview. “If we can show that [this regimen can] improve survival, then we’ve shown that we can do something in this post-ADC world. That’s the big issue here.” Brufsky is a professor of medicine and associate chief in the Division of Hematology/Oncology, Department of Medicine, at the University of Pittsburgh School of Medicine in Pennsylvania. He also serves as medical director of the Magee-Women’s Cancer Program, associate director of clinical investigation, and codirector of the Comprehensive Breast Cancer Center at UPMC Hillman Cancer Center.

Dual Mechanism of Action Drives Immune Responses With Bria-IMT

BriaCell human immortalized cell lines, such as Bria-IMT, are engineered to elicit strong immune responses and deliver efficacy through both adaptive T-cell responses and innate activation of dendritic and natural killer cells. Notably, these cell lines can match patients’ human leukocyte antigens (HLAs) for enhanced effectiveness.^2,3

The Bria-IMT regimen consists of the off-the-shelf targeted immunotherapy SV-BR-1-GM in combination with a checkpoint inhibitor and cyclophosphamide. The SV-BR-1-GM vaccine uses irradiated allogeneic breast cancer cells from the SV-BR-1 cell line. “In other words, it’s not like a CAR T-cell therapy where we’re giving the patient their own cells back. This is a cell line that’s been engineered to express various immune costimulatory molecules on it,” Brufsky said.

Preclinical studies have revealed that Bria-IMT has a dual mechanism of action: It directly enhances antitumor activity through the stimulation of CD4- and CD8-positive T cells, and indirectly through the introduction of tumor antigens and the secretion of GM-CSF, which supports dendritic antigen presentation. Accordingly, the regimen can significantly bolster immune responses when combined with immune checkpoint inhibitors

“Because Bria-IMT can activate both CD4- and CD8-positive [T] cells, we can get both cytotoxic and humoral responses,” Chumsri said. “Besides that, the unique thing about this cell line is that it includes multiple tumor-associated antigens [and] multiple cancer/testis antigens, so it’s almost like you combine multiple vaccines together. It’s also cell based.

“[These preclinical studies showed that] these allogeneic cancer cell–based vaccines [may] be able to stimulate patient immune responses better than an autologous dendritic vaccine,” she continued.

Bria-IMT Shows Early Clinical Activity With/Without Checkpoint Inhibitors

Previously reported data from a preliminary phase 1 study published in 2010 provided the proof of concept for the development of breast cancer vaccine therapies using the SV-BR-1 cell line.⁴ Since then, 2 main clinical studies of Bria-IMT in metastatic breast cancer have been conducted: a phase 1/2a study (NCT03066947) investigating Bria-IMT monotherapy and a phase 1/2 combination study (NCT03328026) assessing Bria-IMT in combination with the checkpoint inhibitor retifanlimab-dlwr (Zynyz) or pembrolizumab (Keytruda) for patients who had progressed on multiple prior lines of therapy (n = 54).⁵

Updated efficacy data from the phase 1 and phase 2 cohorts in the combination study were presented at the 2024 ASCO Annual Meeting and showed that Bria-IMT plus a checkpoint inhibitor produced a 12-week clinical benefit rate (CBR) of 55% across all evaluable breast cancer subtypes (n = 42). Among patients with estrogen receptor (ER)–/progesterone receptor (PR)–positive breast cancer (n = 29), triple-negative breast cancer (TNBC; n = 11), and HER2-positive breast cancer (n = 2), CBRs were 59%, 36%, and 100%, respectively.

The median duration of response was 8.6 months (range, 5.8-9.8) for all patients, 9.7 months (range, 5.8-9.8) for the ER-/PR-positive group, and 7.4-plus months in the HER2-positive group. Bria-IMT elicited overall response rates (ORRs) of 10%, 50%, and 0% in the hormone receptor–positive, HER2-positive, and TNBC groups, respectively.

Further analysis of responses among patients who had developed resistance to prior ADCs (n = 17) showed that 53% of patients achieved a CBR, with an ORR of 12%.5 The median progression-free survival (PFS) was 4.1 months in this population.⁶

Treatment was well tolerated, and no patients discontinued the study due to toxicities associated with SV-BR-1-GM. The most common any-grade adverse effects were fatigue (22%), injection site reaction (31.5%), and nausea (14.8%).⁵

In May 2024, BriaCell also reported that 83% of evaluable patients with intracranial lesions (n = 6) achieved intracranial responses, including complete and partial responses, with the regimen across all BriaCell studies.⁶

Post hoc exploratory data from a pooled analysis of patients in both the monotherapy and combination trials also revealed that heavily pretreated patients experienced benefit with both the monotherapy and combination regimens, regardless of anergy at baseline, as well as induced immune responses in 80% of patients who were anergic. Moreover, patients with a positive delayed-type hypersensitivity (DTH) test experienced favorable PFS outcomes.⁷

Additionally, results from a subsequent exploratory analysis from the monotherapy trial reported in 2024 showed that benefit with HLA matching was observed among patients with advanced refractory breast cancer, particularly if associated with the development of a positive immune response. Although preliminary, investigators also identified a positive correlation between a decrease in circulating cancer-associated macrophagelike cells and survival outcomes.⁸

“It’s neat that a cellular regimen can induce an immune response in these patients,” Brufsky said of the data. “The belief is that these patients didn’t just live because [study investigators] selected patients who would respond to the product; they lived because they had a DTH response and a fall in circulating tumor cells. It appeared that the product did have some therapeutic relevance.”

Overall, results from the combination study informed the design of the ongoing BRIA-ABC trial and supported the FDA's decision to grant fast track designation to Bria-IMT as a potential therapeutic option for patients with metastatic breast cancer in April 2022.⁹

BRIA-ABC Trial Design

BRIA-ABC is a multicenter, randomized, open-label study comparing the efficacy and safety of Bria-IMT plus a checkpoint inhibitor with treatment of physician’s choice in patients with metastatic breast cancer who have exhausted all approved therapeutic alternatives. Eligible patients must have histologically confirmed breast cancer with either locally recurrent unresectable or metastatic lesions.^2,10 The following treatment histories are required based on breast cancer subtype:

• Patients with HER2-positive disease must have been treated with at least 3 regimens, including 2 or more HER2-targeted therapies and at least 1 chemotherapy-containing regimen.
• Patients with ER-/PR-positive tumors must be refractory to 2 or more lines of different hormone therapies.
• Patients with TNBC must have progressed on 2 or more chemotherapies in the neoadjuvant or adjuvant setting.
• Patients harboring actionable mutations, including BRCA, must have received all indicated targeted therapies.
• Patients with HER2-low disease must have received at least 1 HER2-targeted agent.
• Patients with HER2-negative tumors must be refractory to hormonal therapy and had prior exposure to 2 or more chemotherapy regimens.
• Patients with central nervous system metastases are also permitted to enroll, provided that their metastases are clinically stable, do not necessitate steroids for at least 2 weeks, do not impinge on critical brain areas, and have been surgically healed for at least 3 weeks.

“This trial allowed for [broader] inclusion criteria that reflect what we see in real-world practice. It included patients from all 3 types of breast cancer because this vaccine stimulates endogenous immune responses rather than targeting certain things in the tumor cell. This means it can potentially work in any breast cancer subtype,” Chumsri said.

Patients must also have an ECOG performance status of 0 to 2 and must undergo a 2-week washout period between the conclusion of their last therapy and the initiation of study treatment. There is no limit on the number of prior therapies allowed.

Upon enrollment, patients are randomly assigned 1:1:1 to receive Bria-IMT plus a checkpoint inhibitor, treatment of physician’s choice, or Bria-IMT alone. Notably, patients on the latter arm may cross over to the combination arm if they experience disease progression but will not be included in the primary analysis. After the initial 150 patients have enrolled in the study, the monotherapy arm will be discontinued and remaining patients will be randomly assigned 1:1 to the remaining treatment arms.

The Bria-IMT regimen consists of 300 mg/m2 of cyclophosphamide 2 days prior to treatment, followed by 20 million irradiated SV-BR-1-GM cells administered intradermally at 4 sites and subsequent administration of 0.1 mg of interferon-a at each inoculation site. In the combination arm, patients will receive the Bria-IMT regimen and 375 mg of retifanlimab administered intravenously on any 1 of the 3 visit days per 3-week cycle.

The primary end point is overall survival (OS). Key secondary end points include PFS, ORR, CBR, CNS event-free survival, and time without symptoms or toxicities.

An interim analysis is planned after 144 events. If the HR is 0.6 at the time of analysis, investigators will submit a biologics license application; if the HR is higher than 0.6, the study will continue to completion, with an HR target of 0.7. PFS, CBR, and OS will be assessed in the final analysis.

“The problem is going to be that patients progress very rapidly,” Brufsky said. “[However], the nice thing about this is that there will be a lot of immune correlates that will be done with the trial.”

The study was initiated in 2023 and enrollment began in January 2024. Investigators plan to enroll 150 patients globally across approximately 100 sites in the United States, Canada, and the European Union. Enrollment is ongoing at 16 locations.

“These are the kinds of trials we need to do in the post-ADC world…. If this regimen does work, [these data] could lead to the approval of Bria-IMT plus a checkpoint inhibitor as a standard of care post progression on an ADC,” Brufsky said.

Chumsri further contextualized the significance of this regimen in the context of cancer vaccine development. “If you look at the history of cancer vaccine development, there has not been any other additional cancer vaccine approved since sipuleucel-T [Provenge] in prostate cancer 14 years ago. Therefore, this cell-based vaccine could provide us with an entirely novel treatment paradigm.”

References

1. Nangia CS, Calfa CJ, Bayer B, et al. SV-BR-1-GM after progression on ADC in patients with metastatic breast cancer. J Clin Oncol. 2024;42(suppl 16):1087. doi:10.1200/JCO.2024.42.16_suppl.1087
2. Hurvitz SA, Chumsri S, Brufsky A, et al. Study of the Bria-IMT regimen and CPI vs physicians’ choice in advanced metastatic breast cancer (BRIA-ABC). J Clin Oncol. 2024;42(suppl 16):TPS1137. doi:10.1200/JCO.2024.42.16_suppl.TPS1137
3. Bria-IMT cell therapy. BriaCell Therapeutics Corp. Accessed August 22, 2024. https://briacell.com/briaimt/
4. Wiseman CL, Kharazi A. Phase I study with SV-BR-1 breast cancer cell line vaccine and GMCSF: clinical experience in 14 patients. Open Breast Cancer J. 2010;2:4-11. doi:10.2174/1876817201002010004
5. Calfa CJ, Nangia CS, Barve MA, et al. Outcomes of advanced/metastatic breast cancer (aMBC) treated with BRIA-IMT, an allogeneic whole cell immunotherapy. J Clin Oncol. 2024;42(suppl 16):1022. doi:10.1200/JCO.2024.42.16_suppl.1022
6. Ganegoda C. BriaCell doubles progression-free-survival (PFS) and reports clinical benefit data at ASCO 2024. News release. BriaCell Therapeutics Corp. May 24, 2024. Accessed August 22, 2024. https://briacell.com/briacell-doubles-progression-free-survival-pfs-and-reports-clinical-benefit-data-at-asco-2024/
7. Chumsri S, Barve M, Nangia C, et al. Whole cell antigen presenting immune stimulating cells (Bria-IMT) for the treatment of metastatic breast cancer. Cancer Res. 2023;83(suppl 8):CT143. doi:10.1158/1538-7445.AM2023-CT143
8. Wiseman CL, Holmes JP, Calfa C, et al. Results of a phase I/IIa trial of SV-BR-1-GM inoculation with low-dose cyclophosphamide and interferon alpha (Bria-IMT) in metastatic breast cancer. Hum Vaccin Immunother. 2024;20(1):2379864. doi:10.1080/21645515.2024.2379864
9. BriaCell receives FDA fast track approval for targeted breast cancer immunotherapy. News release. BriaCell Therapeutics Corp. April 13, 2022. Accessed August 22, 2024. https://www.globenewswire.com/news-release/2022/04/13/2421857/0/en/BriaCell-Receives-FDA-Fast-Track-Approval-for-Targeted-Breast-Cancer-Immunotherapy.html
10. Study of the Bria-IMT regimen and CPI vs physicians’ choice in advanced metastatic breast cancer. (BRIA-ABC). ClinicalTrials.gov. Updated August 26, 2024. Accessed August 26, 2024. https://clinicaltrials.gov/study/NCT06072612