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.

T-DM1 versus pertuzumab, trastuzumab and a taxane as first-line therapy of early-relapsed HER2-positive metastatic breast cancer: an Italian multicenter observational study

Abstract: Background The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. Patients and methods We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian ‘real-world’ setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. Results Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095). Conclusions Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.

OT1-02-04: Adjuvant Pertuzumab and Herceptin IN IniTial TherapY of Breast Cancer: APHINITY (BIG 4–11/BO25126/TOC4939g).

Abstract: Background Approximately 20% of breast cancer (BC) patients (pts) have HER2−positive tumors. While the adjuvant use of the anti-HER2 humanized monoclonal antibody trastuzumab (T) has been shown to improve disease-free (DFS) and overall survival (OS), not all pts treated with this agent benefit from this therapy. Pertuzumab (P) is a humanized monoclonal antibody that inhibits HER2 dimerization and induces ADCC with a complementary mechanism of action to T. In HER2−positiveadvanced BC, T and P is active in pts who have progressed to T. In the neoadjuvant setting, T and P in combination with chemotherapy (CT) nearly doubled the pathological complete response rate compared to either T or P administered in combination with CT (45.8% vs 29% vs 24%, respectively). Therefore, comprehensive HER2 blockade with two anti-HER2 monoclonal antibodies warrants further investigation in the adjuvant setting. Trial Design : APHINITY is a prospective, randomized, multicenter, double-blind, placebo-controlled study in pts with HER2−positive primary BC who have had an excision of their tumor. Pts will be randomized to one of 2 arms (1:1 ratio). The investigational arm will comprise of a course of adjuvant CT (investigators choice) consisting of either an anthracycline-taxane or taxane-platin containing regimens and T and P for 1 year. The comparator arm will consist of the same adjuvant CT backbone with T and placebo for 1 year. Major Eligibility Criteria : 1. Non-metastatic primary BC histologically confirmed and adequately excised 2. Node-positive or node-negative: for patients with node-positive disease (pN ≥1), any pT except T0; for patients with node-negative disease (pN0), tumor size must be >1.0 cm OR for tumor size between >0.5 cm and ≤1.0 cm, at least one of the following features will be required: histologic grade 3 OR negative for ER and PgR OR age 3. The interval between definitive surgery for BC and randomization must be at least 3 weeks but no more than 7 weeks 4. Baseline LVEF ≥55% 5. HER2−positive BC confirmed by a central laboratory and defined as: IHC 3+ in >10% immunoreactive cells OR HER2 gene amplification by in situ hybridization [ISH] (ratio of HER2 gene signals to centromere 17 signals ≥2) Aims : The primary objective is to compare invasive disease-free survival (IDFS) between both treatment arms. Secondary objectives include comparing IDFS including second non-BC, DFS, OS, recurrence-free interval (RFI), distant RFI, cardiac safety, overall safety and health-related quality of life in the two treatment arms. Statistical Methods : Pts will be stratified based on nodal status, type of adjuvant CT regimen, hormone receptor status and geographical region. The study is designed to have an 80% power to test the null hypothesis of no true difference in risk of an IDFS event (HR = 1) versus the alternative hypothesis of a difference (HR = 0.75) in hazard rates with a 5%, 2-sided significance level. Target accrual: 3806; Present accrual: Start Q4 2011 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-02-04.

Breast Cancer: Blocking both driver and escape pathways improves outcomes.

Abstract: The BOLERO-2 and CLEOPATRA trials evaluated everolimus for estrogen receptor-positive and pertuzumab for HER2-positive metastatic breast cancer. Both agents enhanced the efficacy of standard therapy, were relatively well tolerated and should be approved for therapeutic use. These data confirm that targeting both major driver and escape pathways improves treatment outcomes.

Dual HER2 blockade: preclinical and clinical data

Abstract: The estrogen receptor and human epidermal growth factor receptor (HER) signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, targeting these pathways provides the most effective therapies in appropriately selected patients. However, de novo and acquired resistance remain major obstacles to successful treatment. By increasing the understanding of the molecular mechanisms of combined HER2-targeted therapies, we aim to be better able to select patients who would respond to these treatments and understand some of the mechanisms of resistance to HER2-targeted treatments. Recent studies have demonstrated an increased effectiveness of dual targeted HER2 therapies against HER2-amplified breast cancer as compared with single blockade. These studies have resulted in the recent US Food and Drug Administration approval of the combination of taxane chemotherapy with pertuzumab and trastuzumab in the first-line metastatic setting as well as an accelerated approval in the neoadjuvant setting. Another mechanism for overcoming resistance to HER2 targeted therapies is the antibody-drug conjugate trastuzumab-emtansine, which targets the HER2 receptor conjugated to the potent antimicrotubule agent mertansine, allowing for intracellular release of the cytotoxic drug. Studies evaluating the efficacy of dual blockade with antibody-drug conjugate are currently ongoing. This article reviews recent data on different combinations of anti-HER2 treatments as well as ongoing and future research in this area.