The safety/modified intention-to-treat population included all patients that received inoculation of nelipepimut-S or placebo and was utilized for comparing rates of adverse events

The safety/modified intention-to-treat population included all patients that received inoculation of nelipepimut-S or placebo and was utilized for comparing rates of adverse events. compared to control. At median follow up of 25.7 (interquartile range, IQR: 18.4C32.7) weeks, estimated DFS did not significantly differ between NPS and control (HR 0.62, 95% CI: 0.31C1.25, p=0.18). In a planned exploratory analysis of TNBC individuals, DFS was improved for NPS vs control (HR 0.26, 95% CI: 0.08C0.81, p=0.01). Summary: The combination of NPS with trastuzumab is definitely safe. In HER2 low-expressing breast cancer, no significant difference in DFS was seen in the intention-to-treat analysis; however, significant medical benefit was seen in TNBC individuals. These findings warrant further investigation in a phase III randomized trial. strong class=”kwd-title” Keywords: Breast Tumor, Immunotherapy, Nelipepimut-S, Trastuzumab, BF-168 Vaccine Intro: Trastuzumab, a BF-168 monoclonal antibody focusing on the HER2 protein, has been the backbone of therapy for ladies with HER2 over-expressing (3+ by immunohistochemistry [IHC] or in-situ hybridization [ISH] amplified) breast cancer for two decades.(1C3) While only 15C20% of all breast cancer individuals possess BF-168 HER2 over-expressing tumors, the majority possess tumors that express HER2 to a Rabbit Polyclonal to SMC1 lesser degree.(4) Retrospective data encouraging the use of trastuzumab BF-168 in HER2 IHC 1+ or 2+ breast cancer led to the conduct of the NSABP B-47 adjuvant therapy trial, which randomized patients with HER2 low-expressing tumors (1C2+ by IHC and ISH HER2:CEP17 2.0 or HER2 gene copy quantity 4 per nucleus) to trastuzumab versus placebo.(5) At a median follow-up of 46 weeks, the 5-year invasive disease-free survival (DFS) rate did not differ between organizations: 89.6% for individuals receiving trastuzumab in addition to chemotherapy versus 89.2% for those receiving chemotherapy alone (p=0.90). While passive, monoclonal antibody based HER2-directed therapy alone has not shown clinical activity in patients with HER2 1+ or 2+ tumors, there may be benefit to HER2-targeted active immunotherapy in patients with HER2 low-expressing breast malignancy. Our group has developed HER2-derived peptide vaccines, including nelipepimut-S (NPS), which are combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) as an immunoadjuvant. Promising initial clinical work with this CD8+ T cell-eliciting vaccine led to a phase II trial, which showed a significant improvement in DFS for vaccinated patients versus unvaccinated controls.(6) Based on these results, the phase III PRESENT trial was conducted, randomizing patients with node-positive, HER2 1+ or 2+ breast malignancy to NPS with GM-CSF vs GM-CSF alone.(7) At the time of a planned interim analysis, this trial was terminated for futility due to lack of benefit from the vaccine. Although phase III trials evaluating either trastuzumab or NPS as monotherapy failed to show benefit for patients with HER2 1+ or 2+ breast cancer, preclinical work suggests potential synergy through combining these two therapies.(8C10) To further investigate this promising combination, a multi-center, prospective, randomized, single-blinded, placebo-controlled phase IIb trial of trastuzumab and NPS with GM-CSF versus trastuzumab and placebo with GM-CSF was conducted. Here, we statement the final security, immunologic response, and efficacy results of this trial. Methods Study Design and Patient Eligibility This was a multicenter, randomized, single-blind, placebo-controlled phase IIb trial enrolling at 26 centers in the United States comparing trastuzumab with concurrent NPS with GM-CSF to placebo with GM-CSF. Eligible patients had to be 18 years or older, have histologically confirmed invasive breast malignancy that was HER2 1+ or 2+ (for IHC 2+ tumors, ISH nonamplified), be node positive or estrogen and progesterone receptor unfavorable (triple negative breast cancer [TNBC]), and be clinically disease-free after receiving medical procedures, chemotherapy, and radiation administered as guideline concordant care. Patients receiving neoadjuvant chemotherapy were eligible based on their pretreatment clinical stage or final pathologic stage; individual staging was based on the AJCC 7th edition. Patients began study treatment 3C12 weeks after completion of their breast cancer treatment with the estrogen and/or progesterone receptor-positive patients who initiated endocrine therapy remaining on that treatment per standard practice. Patients were excluded for a history of prior trastuzumab therapy, New York Heart Association stage 3 or 4 4 cardiac disease, left ventricular ejection portion (LVEF) by echocardiogram or radionuclide angiography (MUGA) less than 50% or below the lower limit of normal for the screening institution, active immunosuppression or autoimmune diseases. Eligible patients underwent a two-stage.