Dr Brufsky on the Unique Design of the Allogeneic SV-BR-1-GM Vaccine in Metastatic Breast Cancer

Adam M. Brufsky, MD, PhD, FACP, professor, medicine, associate division chief, Division of Hematology/Oncology, Department of Medicine, the University of Pittsburgh School of Medicine; medical director, the Magee-Women's Cancer Program, associate director, clinical investigations, codirector, the Comprehensive Breast Cancer Center, UPMC Hillman Cancer Center, discusses the unique design of the allogeneic GM-CSF–secreting breast cancer vaccine SV-BR-1-GM, highlighting how this agent distinguishes itself from other currently available agents in the metastatic setting.

SV-BR-1-GM is a genetically engineered human breast cancer cell line  clinically used as a targeted immunotherapy in advanced metastatic breast cancer, Brufsky begins. The vaccine consists of irradiated allogeneic breast cancer cells derived from the SV-BR-1 cell line and transfected with the granulocyte-macrophage colony-stimulating factor (GM-CSF; CSF2) gene. Unlike CAR T-cell therapy, which involves modifying and reinfusing a patient’s own cells, SV-BR-1-GM is an off-the-shelf allogeneic product, he notes.

SV-BR-1-GM is being evaluated as part of the Bria-IMT regimen in the phase 3 BRIA-ABC trial (NCT06072612). The Bria-IMT regimen includes administering 300 mg/m2 of cyclophosphamide on day -2 or -3 along with 4 intradermal inoculations of SV-BR-1-GM on day 0. The mechanism of action is under investigation, although it is hypothesized that, upon intradermal administration, the genetically modified SV-BR-1-GM cells secrete GM-CSF, potentiating a tumor-specific cytotoxic T-lymphocyte immune response against breast cancer cells. Approximately 90% of patients have a partial HLA match with the product, which allows the vaccine to activate an immune response against their breast cancer cells, Brufsky adds.

Early data reported from the study showed early activity with the regimen, which produced a 71% intracranial objective response rate in patients with heavily pretreated advanced breast cancer and central nervous system (CNS) metastases. Based on these findings, a pre-planned subgroup analysis of patients with CNS metastases in advanced metastatic breast cancer is planned for the phase 3 trial. This analysis could provide additional indications for market approval of Bria-IMT, potentially expanding its use in advanced metastatic breast cancer.

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Adam M. Brufsky, MD, PhD, FACP, discusses the unique design of the allogeneic GM-CSF–secreting breast cancer vaccine SV-BR-1-GM.

Dr Brufsky on Unmet Needs and Unanswered Questions in HR+/HER2– Breast Cancer

Adam M. Brufsky, MD, PhD, FACP, professor, medicine, associate division chief, Division of Hematology/Oncology, Department of Medicine, the University of Pittsburgh School of Medicine; medical director, the Magee-Women's Cancer Program, associate director, clinical investigation, codirector, the Comprehensive Breast Cancer Center, UPMC Hillman Cancer Center, discusses remaining questions and unmet needs following the FDA approval of capivasertib (Truqap) in combination with fulvestrant (Faslodex) in hormone receptor–positive, HER2-negative breast cancer.

On November 16, 2023, 

the FDA approved this treatment combination

 for patients with locally advanced or metastatic hormone receptor–positive, HER2-negative breast cancer harboring 1 or more 

 alterations based on data from the phase 3 CAPItello-291 trial (NCT04305496). With this approval, new unmet needs have surfaced. Investigators continue to question the rationale behind not initiating treatment in the first line and waiting until disease progression. Patients with poor prognostic features, such as recurrence on aromatase inhibitor or within 12 months of stopping adjuvant hormone therapy, or those with 

 mutations, may have a worse prognosis with this approach, Brufsky begins. In response, investigators assessed these patients in a phase 3 study, he states.

Notably, the major adverse effect (AE) observed with the combination was hyperglycemia, which was expected. Although these initial data are intriguing, updates are highly anticipated, he emphasizes. Nevertheless, this could potentially offer an advanced upfront PI3K inhibitor–containing regimen for challenging, primarily endocrine-resistant patients—a population with notable unmet need, Brufsky explains.

Looking to other unmet needs, the sequencing of ADCs also remains a significant concern in breast cancer, particular for patients who develop drug resistance, Brufsky expands. The current sequence of therapy involves hormone therapy, CDK4/6 inhibitors, and an oral selective estrogen receptor degrader, he explains. However, the there is a lack of consensus on what regimens should be administered next after these options are exhausted.

Many oncologists turn to chemotherapy with capecitabine (Xeloda), but the challenge lies in deciding the appropriate sequence thereafter, he continues. For HER2-low patients, fam-trastuzumab deruxtecan-nxki (Enhertu) is an option, and HER2-zero patients may consider sacituzumab govitecan-hziy (Trodelvy), Brufsky imparts. Both are distinct ADCs with different toxicity profiles. One is a 3-week drug with notable AEs, including nausea, hair loss, and potential interstitial lung disease (ILD), he emphasizes. The other is a day 1/ day 8 drug with different AEs like neutropenia, mild nausea, alopecia, and diarrhea. Although managing these toxicities is feasible, uncertainties persist regarding the optimal approach in this setting, he concludes.

Adam M. Brufsky, MD, PhD, FACP, discusses the remaining questions following the FDA approval of capivasertib/fulvestrant in HR+/HER2- breast cancer.

The FDA Approval of Capivasertib Plus Fulvestrant in PIK3CA/AKT1/PTEN-Altered HR+/HER2– Breast Cancer

Adam M. Brufsky, MD, PhD, FACP, professor, medicine, associate division chief, Division of Hematology/Oncology, Department of Medicine, the University of Pittsburgh School of Medicine; medical director, the Magee-Women's Cancer Program, associate director, clinical investigation, codirector, the Comprehensive Breast Cancer Center, UPMC Hillman Cancer Center, discusses the significance of the FDA approval of capivasertib (Truqap) in combination with fulvestrant (Faslodex) for patients with hormone receptor (HR)–positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more 

the FDA approved this combination in this population

 based on data from the phase 3 CAPItello-291 trial (NCT04305496). Findings derived from the randomized, double-blind, placebo-controlled, multicenter trial demonstrated that among 289 patients with 

-altered tumors, treatment with capivasertib and fulvestrant (n = 155) elicited a median progression-free survival (PFS) of 7.3 months (95% CI, 5.5-9.0) vs 3.1 months (95% CI, 2.0-3.7) with placebo and fulvestrant (n = 134; HR 0.50; 95% CI, 0.38, 0.65; 

Patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer with 

 alterations currently require alternative treatment agents to those presently available, and capivasertib, an AKT inhibitor, has emerged as a promising candidate, Brufsky begins. The CAPItello-291 trial revealed a significant PFS improvement with capivasertib plus fulvestrant vs placebo plus fulvestrant, he explains, adding that this positive outcome extended to various patient populations, including those with 

mutations, those without PI3K results for unspecified reasons, and those without 

Notably, benefits with capivasertib plus fulvestrant were observed in patients with 

 mutations in the PI3K pathway and those with less common 

 mutations within the same pathway. Although the FDA approved this combination exclusively for patients with alterations in the PI3K pathway, based on findings from a post hoc analysis that excluded patients with confirmed 

 wild-type disease, the trial's primary end point success across all prespecified patient subgroups suggests broader efficacy, he continues. Despite concerns about potential adverse effects (AEs), such as diarrhea and rash, the latter requiring proactive management with Cetirizine and other H1 blockers, capivasertib's lower toxicity, as indicated in clinical trial results, offers a valuable addition to the breast cancer treatment paradigm, he emphasizes.

Preliminary observations with this combination hint at potential overall survival benefits vs fulvestrant alone, with ongoing patient monitoring expected to provide further insights, Brufsky expands. With its unique 4-days-on, 3-days-off dosing schedule and manageable grade 3 rash occurrences, capivasertib stands as a welcome addition to address unmet needs for patients with HR-positive, HER2-negative metastatic breast cancer, and may be widely adopted among oncologists, Brufsky concludes.

Adam M. Brufsky, MD, PhD, FACP, discusses the significance of the FDA approval of capivasertib in combination with fulvestrant for patients with hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more PIK3CA, AKT1, or PTEN alterations.


Dr Brufsky on the FDA Approval of Capivasertib Plus Fulvestrant in PIK3CA/AKT1/PTEN-Altered HR+/HER2– Breast Cancer 

Adam M. Brufsky, MD, PhD, a professor of medicine, associate chief in the Division of Hematology/Oncology, co-director of the Comprehensive Breast Cancer, and associate director of clinical investigation at the University of Pittsburgh, discusses treatment options for male patients with breast cancer.

Men with breast cancer are treated similarly to postmenopausal women with the disease, Brufsky says. Androgen receptors (ARs) are likely to act as a tumor suppressor in this patient population, Brufsky adds. One upcoming trial will examine the use of an AR agonist in patients with estrogen receptor–positive, AR-positive metastatic breast cancer.

This research could impact the male patient population due to the potential role of ARs in male breast cancer, Brufsky says. Additionally, male patients tend to present with more advanced disease, namely stage II or higher; earlier-stage disease is uncommon, although cases are beginning to rise, Brufsky notes. 

A handful of treatment options are available for this population, including neoadjuvant and adjuvant chemotherapy, mastectomy, radiation, and tamoxifen. Aromatase inhibitors have also been considered for use, although some experts believe they may boost testosterone levels, which could either help or hinder the treatment of this patient population, Brufsky concludes.

Adam M. Brufsky, MD, PhD, discusses treatment options for male patients with breast cancer.

Dr. Brufsky on Treatment Options for Male Breast Cancer

Adam M. Brufsky, MD, PhD, a professor of medicine, associate chief in the Division of Hematology/Oncology, co-director of the Comprehensive Breast Cancer, and associate director of clinical investigation at University of Pittsburgh, discusses the role of neoadjuvant chemotherapy in triple-negative breast cancer (TNBC).

It is important to consider whether neoadjuvant therapy should be used in this population, according to Brufsky. As most patients with TNBC will require chemotherapy at some point during their treatment, it is acceptable to treat them with this approach up front, according to Brufsky; this provides several benefits. For example, neoadjuvant chemotherapy can help shrink large tumors, lead to less extensive surgery, and allow more time to prepare for surgeries like mastectomy or reconstruction. Additionally, if a patient has a family history of disease, this also allows for time to test for 

 mutations and make surgical decisions accordingly.

Neoadjuvant therapy can also indicate whether the chemotherapy is effective in a patient, and can provide insight into whether another agent, such as capecitabine (Xeloda), is needed. Generally, neoadjuvant therapy is considered for tumors greater than 1 cm for patients with TNBC. Some practices will use this strategy for tumors that are 2 cm or T2, but neoadjuvant chemotherapy should be considered for tumors that are T1 and below, Brufsky concludes.

Adam M. Brufsky, MD, PhD, discusses the role of neoadjuvant chemotherapy in triple-negative breast cancer.

Dr. Brufsky on the Role of Neoadjuvant Chemotherapy in TNBC

Adam M. Brufsky, MD, PhD, a professor of medicine, associate chief in the Division of Hematology/Oncology, and co-director of Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine, discusses the treatment of early-stage, HER2-positive breast cancer.

Generally, patients with early-stage, metastatic HER2-positive breast cancer are treated depending on the size of their tumor, says Brufsky. If the tumor is greater than 2 cm, patients will receive neoadjuvant chemotherapy, usually with trastuzumab (Herceptin) and pertuzumab (Perjeta). If the patient achieves a pathologic complete response, they will then receive trastuzumab or pertuzumab for 1 year; if they do not, they will receive ado-trastuzumab emtansine (T-DM1; Kadcyla).

For patients with tumors of less than 1 cm, they will undergo surgery and then a decision will be made on next steps. If they have tumors that are less than 2 cm and are node negative, they will likely receive adjuvant paclitaxel and trastuzumab for 12 cycles or 12 weeks. Some will give T-DM1 for 1 year, but that decision is a little controversial right now, concludes Brufsky.

Adam M. Brufsky, MD, PhD, discusses the treatment of early-stage, HER2-positive breast cancer.

Adam Brufsky,MD

Articles

Dr Brufsky on the Unique Design of the Allogeneic SV-BR-1-GM Vaccine in Metastatic Breast Cancer

Dr Brufsky on Unmet Needs and Unanswered Questions in HR+/HER2– Breast Cancer

Dr Brufsky on the FDA Approval of Capivasertib Plus Fulvestrant in PIK3CA/AKT1/PTEN-Altered HR+/HER2– Breast Cancer

Dr. Brufsky on Treatment Options for Male Breast Cancer

Dr. Brufsky on the Role of Neoadjuvant Chemotherapy in TNBC

Dr. Brufsky on Treatment Approaches for Early-Stage HER2+ Breast Cancer