scispace - formally typeset
Search or ask a question
Topic

Pertuzumab

About: Pertuzumab is a research topic. Over the lifetime, 1453 publications have been published within this topic receiving 73219 citations. The topic is also known as: 2C4 Antibody & MOAB 2C4.


Papers
More filters
Proceedings ArticleDOI
TL;DR: XMT-1522 will soon enter clinical testing in breast cancer patients with both HER2-positive tumors and HER2 low-expressing (IHC 1+ and 2+/FISH-) tumors, and in vivo the combination of low dose XMT- 1522 with full dose trastuzumab and pertuzumAB is synergistic in a Her2-driven model.
Abstract: XMT-1522 is an anti-HER2 antibody-drug conjugate (ADC) comprised of a novel anti-HER2 antibody (HT-19) and the Dolaflexin ADC platform, which allows for conjugation of 12-15 proprietary auristatin drug payload molecules per antibody without aggregation or detrimental impact on pharmacokinetics. The HT-19 antibody binds to a novel HER2 extracellular domain epitope and does not compete for HER2 binding with trastuzumab or pertuzumab. In vitro, XMT-1522 has sub-nanomolar potency in cell lines expressing as few as 25,000 HER2 antigens per cell, and is ∼100X more potent than ado-trastuzumab emtansine (T-DM1) across a panel of 25 cell lines representing a range of tumor indications and HER2 expression levels. In the BT-474 HER2-positive breast cancer model, treatment with the HT-19 antibody alone at a single 5 mg/kg dose is inactive, while XMT-1522 ADC at a single 2 mg/kg or 5 mg/kg dose induces durable complete tumor regression, indicating that the primary mechanism of XMT-1522 is cytotoxic payload delivery, not inhibition of HER2 signaling. T-DM1 at a single 5 mg/kg dose in the same model is inactive, consistent with the significant improvement in potency of XMT-1522 compared to T-DM1. Biodistribution studies using a HER2-targeted Dolaflexin ADC in the BT-474 model demonstrate accumulation of intact ADC and released active drug payload in tumor at levels significantly higher than normal tissues. In a HER2-positive patient-derived xenograft (PDX) model, XMT-1522 induces durable complete tumor regression after a single 1 mg/kg dose, while T-DM1 at a 10 mg/kg dose achieves tumor growth delay without regression. In a HER2 1+ PDX model without HER2 gene amplification, a single 3 mg/kg dose of XMT-1522 achieves partial tumor regression where a 10 mg/kg dose of T-DM1 is inactive. Combination of XMT-1522 with trastuzumab does not block the ability of the ADC to bind HER2 or efficiently internalize, and in vivo the combination of low dose XMT-1522 with full dose trastuzumab and pertuzumab is synergistic in a HER2-driven model. The exposure achieved with XMT-1522 at well-tolerated doses in cynomolgus monkey is several fold higher than the exposure needed in mice to achieve complete tumor regressions across models representing a range of HER2 expression and tumor indications. Based on these data, XMT-1522 will soon enter clinical testing in breast cancer patients with both HER2-positive tumors and HER2 low-expressing (IHC 1+ and 2+/FISH-) tumors. Citation Format: Bergstrom DA, Bodyak N, Park PU, Yurkovetskiy A, DeVit M, Yin M, Poling L, Thomas JD, Gumerov D, Xiao D, Ter-Ovanesyan E, Qin L, Uttard A, Johnson A, Lowinger TB. XMT-1522 induces tumor regressions in pre-clinical models representing HER2-positive and HER2 low-expressing breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-28.

18 citations

Journal ArticleDOI
TL;DR: The development of trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor 2 (HER2), revolutionized outcomes of patients with HER2- positive breast cancer; however, many patients with Her2-positive metastatic breast cancer eventually become resistant to it.
Abstract: Overexpression of human epidermal growth factor occurs in approximately 20–25 % of invasive breast cancers. This subtype of breast cancer has been associated with poor clinical outcomes. The development of trastuzumab, a humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor 2 (HER2), revolutionized outcomes of patients with HER2-positive breast cancer; however, many patients with HER2-positive metastatic breast cancer eventually become resistant to it. Several newer anti-HER2 agents have been developed, including lapatinib, pertuzumab, and trastuzumab emtansine. These exciting advances in drug development for HER2-positive breast cancer have also led to many challenges, including how to optimally sequence and combine HER2-targeted agents.

18 citations

Journal ArticleDOI
TL;DR: In this paper, the authors evaluated the potential of trastuzumab emtansine (T-DM1) as a monotherapy for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy.
Abstract: Importance Trastuzumab emtansine (T-DM1) is presently approved for treatment of advanced breast cancer and after incomplete response to neoadjuvant therapy, but the potential of T-DM1 as monotherapy is so far unknown. Objective To assess pathologic complete response (pCR) to standard neoadjuvant therapy of combination docetaxel, trastuzumab, and pertuzumab (DTP) vs T-DM1 monotherapy in patients with ERBB2 (formerly HER2)-positive breast cancer. Design, Setting, and Participants This randomized phase 2 trial, conducted at 9 sites in Sweden, enrolled 202 patients between December 1, 2014, and October 31, 2018. Participants were 18 years or older, with ERBB2-positive tumors larger than 20 mm and/or verified lymph node metastases. Analysis was performed on an intention-to-treat basis. Interventions Patients were randomized to receive 6 cycles of DTP (standard group) or T-DM1 (investigational group). Crossover was recommended at lack of response or occurrence of intolerable toxic effects. Assessment with fluorine 18–labeled fluorodeoxyglucose (18F-FDG) positron emission tomography combined with computed tomography (PET-CT) was performed at baseline and after 2 and 6 treatment cycles. Main Outcome and Measures Pathologic complete response, defined as ypT0 or Tis ypN0. Secondary end points were clinical and radiologic objective response; event-free survival, invasive disease-free survival, distant disease-free survival, and overall survival; safety; health-related quality of life (HRQoL); functional and biological tumor characteristics; and frequency of breast-conserving surgery. Results Overall, 202 patients were randomized; 197 (99 women in the standard group [median age, 51 years (range, 26-73 years)] and 98 women in the investigational group [median age, 53 years (range, 28-74 years)]) were evaluable for the primary end point. Pathologic complete response was achieved in 45 patients in the standard group (45.5%; 95% CI 35.4%-55.8%) and 43 patients in the investigational group (43.9%; 95% CI 33.9%-54.3%). The difference was not statistically significant (P = .82). In a subgroup analysis, the pCR rate was higher in hormone receptor–negative tumors than in hormone receptor–positive tumors in both treatment groups (45 of 72 [62.5%] vs 45 of 125 [36.0%]). Three patients in the T-DM1 group experienced progression during therapy. In an exploratory analysis, tumor-infiltrating lymphocytes at 10% or more (median) estimated pCR significantly (odds ratio, 2.76; 95% CI, 1.42-5.36;P = .003). Response evaluation with18F-FDG PET-CT revealed a relative decrease of maximum standardized uptake value by equal to or greater than 68.7% (median) was associated with pCR (odds ratio, 6.74, 95% CI, 2.75-16.51;P Conclusions and Relevance In this study, treatment with standard neoadjuvant combination DTP was equal to T-DM1. Trial Registrations ClinicalTrials.gov Identifier:NCT02568839; EudraCT number:2014-000808-10

18 citations

Journal ArticleDOI
TL;DR: Pertuzumab is able to prevent c‐erbB2 homodimerization and thereby enhance the antiproliferative effect of trastuzuumab when administered in combination.
Abstract: Lateral interaction of c-erbB family receptors resulting in dimer formation is the key event initiating signal transduction Consequently cross-activation and intracellular signaling is triggered with immediate impact on cell proliferation, migration, cell survival, and differentiation In order to elucidate the connection of signal input (receptor activation) and signal output (altered cellular behavior) we dynamically assessed cell proliferation of BT474 and SK-BR-3 breast cancer cell lines We quantitated c-erbB2 receptor homodimerization upon treatment with the therapeutic monoclonal anti-c-erbB2 antibodies trastuzumab (Herceptin®) and pertuzumab by flow cytometric FRET (FCET) measurements on a cell-by-cell basis and calculated the extent of antibody-induced cell cycle exit The results confirm that trastuzumab does not decrease c-erbB2 homodimers despite its strong potency to drive c-erbB2-overexpressing cells into quiescence Pertuzumab, however, is able to prevent c-erbB2 homodimerization and thereby enhance the antiproliferative effect of trastuzumab when administered in combination

18 citations

Journal ArticleDOI
TL;DR: Patients with HER2-positive MBC who received Tmab and Pmab treatment before T- DM1 have fewer benefits from T-DM1, and the best response was lower in the T mab/Pmab group.
Abstract: Trastuzumab emtansine (T-DM1) has been approved since 2013 for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who had received trastuzumab (Tmab) and taxane. However, no clinical trial has evaluated the efficacy of T-DM1 in those who have previously received pertuzumab (Pmab). This study aimed to compare the efficacy of T-DM1 between patients who had received Tmab and Pmab and those who had received Tmab only in Japanese population. We identified all patients with HER2-positive MBC who received T-DM1 between April 1, 2014 and February 28, 2017 in our institution. The patients were divided into the Tmab group (i.e., those who received only Tmab before T-DM1 treatment) and the Tmab/Pmab group (i.e., those who received Tmab and Pmab before T-DM1 treatment), and progression-free survival (PFS) and best response were compared between the two groups. A total of 42 patients were enrolled for outcome analysis. The median follow-up period was 4.8 months, and the median number of prior chemotherapy regimens for metastatic disease before T-DM1 was 1 (range 1–2) in the Tmab/Pmab group and 2 (range 0–6) in the Tmab group. The median PFS was 2.8 months in the Tmab/Pmab group (95% confidence interval [CI] 1.7–4.8 months) and 7.8 months in the Tmab group (95% CI 5.5–15.9 months) (p = 0.0030). The best response was lower in the Tmab/Pmab group (11.1% vs. 25.0%). Patients with HER2-positive MBC who received Tmab and Pmab treatment before T-DM1 have fewer benefits from T-DM1.

18 citations


Network Information
Related Topics (5)
Breast cancer
214.3K papers, 6.4M citations
89% related
Cancer
339.6K papers, 10.9M citations
87% related
Colorectal cancer
71.1K papers, 2.2M citations
84% related
Metastasis
103.6K papers, 3.4M citations
84% related
Carcinogenesis
60.3K papers, 3.1M citations
83% related
Performance
Metrics
No. of papers in the topic in previous years
YearPapers
2023372
2022307
2021158
2020144
2019143
2018130