Showing papers on "Pertuzumab published in 2007"

HER2-positive breast cancer: current and future treatment strategies.

Abstract: In the year 2006, breast cancer was estimated to affect >200 000 American women and cause nearly 56 000 deaths. Furthermore, breast cancer is the most common cancer diagnosed and second most common cause of cancer-related deaths in women. The current treatment armamentarium for breast cancer includes chemotherapy, endocrine therapy and biological therapy. Treatment has become more individualised based on characteristics of the tumour including overexpression of the human epidermal growth factor receptor (HER)-2. Between 20 and 30% of all breast cancers overexpress HER2, which means 40 000–60 000 patients will have this type of cancer. Previously, overexpression of HER2 was a negative prognostic and predictive risk factor for survival; however, with the advent of trastuzumab, patients’ prognosis is improving in all treatment settings. Much controversy exists in the use of trastuzumab, including (i) the sequence of adjuvant trastuzumab (concurrent with chemotherapy or sequential); (ii) the treatment duration (<1 year, 1 year or 2 years); and (iii) the treatment choice upon disease progression (whether to continue or not with trastuzumab and add another cytotoxic agent). Current trials are ongoing to help answer these questions. Furthermore, there has been interest in predicting which HER2-positive patients would require anthracycline therapy, and which could avoid anthra-cycline therapy and its toxicities. Novel therapeutics, such as lapatinib, an oral tyrosine kinase inhibitor, which blocks both the epidermal growth factor receptor and HER2 receptor has recently been approved by the US FDA. Whereas pertuzumab, a humanised monoclonal antibody, directed against heterodimerisation of HER2 and HER3 has entered phase II and III clinical trials.

Treatment of Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy

Abstract: BACKGROUND Human epidermal growth factor receptor 2 (HER2) is a member of the HER signaling pathway. HER inhibitors partially block HER signaling and tumor growth in preclinical breast cancer models. We investigated whether blockade of all HER homo- and heterodimer pairs by combined treatment with several inhibitors could more effectively inhibit tumor growth in such models. METHODS Mice carrying xenograft tumors of HER2-overexpressing MCF7/HER2-18 (HER2-transfected) or BT474 (HER2-amplified) cells were treated with estrogen supplementation or estrogen withdrawal, alone or combined with tamoxifen. One to three HER inhibitors (pertuzumab, trastuzumab, or gefitinib) could also be added (n > or = 8 mice per group). Tumor volumes, HER signaling, and tumor cell proliferation and apoptosis were assessed. Results were analyzed with the t test or Wilcoxon rank sum test and survival analysis methods. All statistical tests were two-sided. RESULTS Median time to tumor progression was 21 days for mice receiving estrogen and 28 days for mice receiving estrogen and pertuzumab (difference = 7 days; P = .001; hazard ratio [HR] of progression in mice receiving estrogen and pertuzumab versus mice receiving estrogen = 0.27, 95% confidence interval [CI] = 0.09 to 0.77). Addition of gefitinib and trastuzumab to estrogen and pertuzumab increased this time to 49 days (difference = 21 days; P = .004; HR of progression = 0.28, 95% CI = 0.10 to 0.76). MCF7/HER2-18 tumors disappeared completely and did not progress (for > or = 189 days) after combination treatment with pertuzumab, trastuzumab, and gefitinib plus tamoxifen (19 of 20 mice) or plus estrogen withdrawal (14 of 15 mice). Both combination treatments induced apoptosis and blocked HER signaling and proliferation in tumor cells better than any single agent or dual combination. All BT474 tumors treated with pertuzumab, trastuzumab, and gefitinib disappeared rapidly, regardless of endocrine therapy, and no tumor progression was observed for 232 days. CONCLUSION Combined treatment with gefitinib, trastuzumab, and pertuzumab to block signals from all HER homo- and heterodimers inhibited growth of HER2-overexpressing xenografts statistically significantly better than single agents and dual combinations.

Open-Label Phase II Study Evaluating the Efficacy and Safety of Two Doses of Pertuzumab in Castrate Chemotherapy-Naive Patients With Hormone-Refractory Prostate Cancer

Abstract: Purpose To determine the prostate-specific antigen (PSA) 50% decline rate within 24 weeks of starting treatment with single-agent pertuzumab in castrate patients with hormone-refractory prostate cancer (HRPC). Patients and Methods Two independent Simon's two-stage designs were used to evaluate two doses of pertuzumab administered intravenously once every 3 weeks. An interim analysis of the first 23 assessable patients in the first cohort treated at 420 mg (loading dose of 840 mg) allowed termination of additional enrollment if ≤ three patients had a ≥ 50% decline in PSA after all patients had completed at least three cycles of therapy or withdrew due to insufficient therapeutic response, death, or study-related toxicity before completing three cycles. A second cohort of patients treated at 1,050 mg could be enrolled with the same design, and if more than three patients had a ≥ 50% decline in PSA, 27 more patients would be treated at 1,050 mg. Results Sixty-eight castrate, chemotherapy-naive men with HRPC ...

Pertuzumab, a novel HER dimerization inhibitor, inhibits the growth of human lung cancer cells mediated by the HER3 signaling pathway.

Abstract: A humanized anti-HER2 monoclonal antibody pertuzumab (Omnitarg, 2C4), binding to a different HER2 epitope than trastuzumab, is known as an inhibitor of heterodimerization of the HER receptors. Potent antitumor activity against HER2-expressing breast and prostate cancer cell lines has been clarified, but this potential is not clear against lung cancers. The authors investigated the in vitro anti-tumor activity of pertuzumab against eight non-small cell lung cancer cells expressing various members of the HER receptors. A lung cancer 11_18 cell line expressed a large amount of HER2 and HER3, and its cell growth was stimulated by an HER3 ligand, heregulin (HRG)-alpha. Pertuzumab significantly inhibited the HRG-alpha-stimulated cellular growth of the 11_18 cells. Pertuzumab blocked HRG-alpha-stimulated phosphorylation of HER3, mitogen-activated protein kinase (MAPK), and Akt. In contrast, pertuzumab failed to block epidermal growth factor (EGF)-stimulated phosphorylation of EGF receptor (EGFR) and MAPK. Immunoprecipitation showed that pertuzumab inhibited HRG-alpha-stimulated HER2/HER3 heterodimer formation. HRG-alpha-stimulated HER3 phosphorylation was also observed in the PC-9 cells co-overexpressing EGFR, HER2, and HER3, but the cell growth was neither stimulated by HRG-alpha nor inhibited by pertuzumab. The present results suggest that pertuzumab is effective against HRG-alpha-dependent cell growth in lung cancer cells through inhibition of HRG-alpha-stimulated HER2/HER3 signaling.

Efficacy and Safety of Single-Agent Pertuzumab (rhuMAb 2C4), a Human Epidermal Growth Factor Receptor Dimerization Inhibitor, in Castration-Resistant Prostate Cancer After Progression From Taxane-Based Therapy

Abstract: Purpose Pertuzumab represents a new class of targeted anticancer agents, human epidermal growth factor receptor (HER) dimerization inhibitors. The aim of this single-arm phase II clinical study was to assess the efficacy and safety of single-agent pertuzumab in castration-resistant prostate cancer (CRPC) patients who had experienced progression after prior chemotherapy. Patients and Methods Patients received pertuzumab every 3 weeks. All castration-resistant patients had experienced progression after at least one taxane-based regimen. Patients received a loading dose of 840 mg pertuzumab (cycle 1) followed by 420 mg for subsequent cycles. The primary end point was overall response and safety. A separate retrospective analysis of actual survival time versus predicted survival time for a patient population with comparable prognostic features was performed. Results Patients were enrolled (N = 42) and treated (n = 41). No patients had complete or partial response (as defined by Response Evaluation Criteria in...

Efficacy and Safety of Single-Agent Pertuzumab, a Human Epidermal Receptor Dimerization Inhibitor, in Patients with Non–Small Cell Lung Cancer

Abstract: Purpose: Pertuzumab, a first-in-class human epidermal receptor 2 (HER2) dimerization inhibitor, is a humanized monoclonal anti-HER2 antibody that binds HER29s dimerization domain and inhibits HER2 signaling. Based on supporting preclinical studies, we undertook a Phase II trial of pertuzumab in patients with recurrent non–small cell lung cancer (NSCLC). Experimental Design: Patients with previously treated NSCLC accessible for core biopsy and naive to HER pathway inhibitors were treated with pertuzumab i.v. once every 3 weeks. Tumor assessments were done at 6 and 12 weeks and then every 3 months thereafter. The primary efficacy end point was overall response rate by Response Evaluation Criteria in Solid Tumors. Measurement of tumor glucose metabolism (SUV max ) by F-18-fluorodeoxyglucose positron emission tomography was used as an exploratory pharmacodynamic marker of drug activity. Results: Of 43 patients treated with pertuzumab, no responses were seen; 18 of 43 (41.9%) and 9 of 43 (20.9%) patients had stable disease at 6 and 12 weeks, respectively. The median and 3-month progression-free survival rates (PFS) were 6.1 weeks (95% confidence interval, 5.3-11.3 weeks) and 28.4% (95% confidence interval, 14.4-44.2%), respectively. Of 22 patients who underwent F-18-fluorodeoxyglucose positron emission tomography, six (27.3%) had a metabolic response to pertuzumab as evidenced by decreased SUV max . These patients had prolonged PFS (HR = 0.11, log-rank P value = 0.018) compared with the 16 patients who had no metabolic response. Four patients (9.3%) experienced a grade 3/grade 4 adverse event judged related to pertuzumab; none exhibited grade 3/grade 4 cardiac toxicity. Conclusions: Pertuzumab is well tolerated as monotherapy. Pharmacodynamic activity correlated with prolonged PFS was detected in a moderate percentage of patients (27.3%). Further clinical development of pertuzumab should focus on rational combinations of pertuzumab with other drugs active in NSCLC.

Differential impact of Cetuximab, Pertuzumab and Trastuzumab on BT474 and SK‐BR‐3 breast cancer cell proliferation

Abstract: Objectives: The potential of epidermal growth factor receptor (EGFR)- and Her2-targeted antibodies Cetuximab, Pertuzumab and Trastuzumab, used in combination to inhibit cell proliferation of breast cancer cells in vitro, has not been extensively investigated It is anticipated that there would be differences between specific erbB receptor co-expression profiles that would affect tumour cell growth Materials and methods: We have examined the effects of Cetuximab, Pertuzumab and Trastuzumab, applied separately or in combination, on cell proliferation of BT474 and SK-BR-3 breast cancer cell lines Cell cycle progression of BT474 and SK-BR-3 cells was statically and dynamically assessed using flow cytometry In order to discover a potential influence of differential EGFR co-expression on sensitivity to antibody treatment, EGFR was down-regulated by siRNA in SK-BR-3 An annexinV/propidium iodide assay was used to identify potential induction of apoptosis Results: Treatment with Pertuzumab and Trastuzumab, both targeted to Her2, resulted in a reduced fraction of proliferating cells, prolongation of G1 phase and a great increase in quiescent BT474 cells Cetuximab had no additional contribution to the effect of either Pertuzumab or Trastuzumab when administered simultaneously Treatment with the antibodies did not induce an appreciable amount of apoptosis in either BT474 or SK-BR-3 cells In contrast to SK-BR-3, the BT474 cell line appears to be more sensitive to antibody treatment due to low EGFR content besides Her2 overexpression Conclusion: The extent of decelerated or blocked cell proliferation after antibody treatment that is targeted to EGFR and to Her2 depends both on EGFR and Her2 co-expression and on antibody combination used in the treatment setting Cetuximab did not enhance any inhibitory effect of Trastuzumab or Pertuzumab, most probably due to the dominant overexpression of Her2 Cell susceptibility to Trastuzumab/Pertuzumab, both targeted to Her2, was defined by the ratio of EGFR/Her2 co-expression

Objective response rate in a phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T

Abstract: 1004 Background: T and P bind to different epitopes on the extra cellular domain of HER2. Unlike T, P binds to the dimerization domain and blocks homo- and hetero-dimerization of HER2 with other HE...

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours.

Abstract: Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m−2) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m−2) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m−2 in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m−2 in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug–drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m−2 and 420 mg pertuzumab following a loading dose of 840 mg.

Peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo.

Abstract: Human epidermal growth factor receptor-2 (HER-2)/ neu (ErbB2), a member of the epidermal growth factor family of receptors, is overexpressed in 20–30% of breast cancers. It is an attractive target for receptor-directed antitumor therapy using mAbs. Unlike other epidermal growth factor receptor family members, HER-2/ neu does not bind a high-affinity ligand, but rather functions as the preferred dimerization partner. Pertuzumab (Omnitarg) is a humanized mAb directed against the HER-2/ neu dimerization domain that inhibits receptor signaling. The recent definition of the crystal structure of the HER-2/ neu -pertuzumab complex demonstrated that the receptor dimerization region encompassed residues 266–333. Based on the three-dimensional structure of the complex, we have designed three conformational peptide constructs (sequences 266–296, 298–333, and 315–333) to mimic regions of the dimerization loop of the receptor and to characterize their in vitro and in vivo antitumor efficacy. All the constructs elicited high-affinity peptide Abs that inhibited multiple signaling pathways including HER-2/ neu -specific inhibition of cellular proliferation and cytoplasmic receptor domain phosphorylation. All the peptide Abs showed Ab-dependent cellular cytotoxicity to varying degrees with the 266–296 constructs being equally effective as compared with Herceptin. The 266–296 peptide vaccine had statistically reduced tumor onset in both transplantable tumor models (FVB/n and BALB/c) and significant reduction in tumor development in two transgenic mouse tumor models (BALB- neu T and VEGF +/− Neu2–5 +/− ). The 266–296 construct represents the most promising candidate for antitumor vaccination and could also be used to treat a variety of cancers with either normal or elevated expression of HER-2 including breast, lung, ovarian, and prostate.

Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling

Abstract: Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response to this agent in a model of ovarian cancer. A panel of 13 ovarian cancer cell lines was treated with heregulin β1 (HRGβ1) or transforming growth factor-α, and cell proliferation was assessed. Both agents increased cell number in the majority of cell lines studied, the response to both being similar ( r = 0.83; P = 0.0004, Pearson test). HRGβ1 stimulation could be partially reversed by pertuzumab in 6 of 13 cell lines, with complete reversal in PE04 and PE06 cells. Addition of pertuzumab to transforming growth factor-α−stimulated cells produced growth inhibition in 3 of 13 cell lines (PE01, PE04, and PE06). The magnitude of HRGβ1-driven growth stimulation correlated significantly with an increase in extracellular signal-regulated kinase 2 ( P = 0.037) but not Akt ( P = 0.99) phosphorylation. Such HRGβ1-driven phosphorylation of extracellular signal-regulated kinase 1/2 and Akt could be reduced with pertuzumab, accompanied by changes in cell cycle distribution. In cell lines responsive to pertuzumab, HRGβ1-enhanced phosphorylation of HER2 (Tyr877) was reduced. Estrogen-stimulated changes in growth, cell cycle distribution, and signaling were reversed by pertuzumab, indicating cross-talk between HER2 and estrogen signaling. These data indicate that there is a subset of ovarian cancer cell lines sensitive to pertuzumab and suggest possible predictors of response to identify patients who could benefit from this therapy. Furthermore, we have identified an interaction between HER2 and estrogen signaling in this disease. [Mol Cancer Ther 2007;6(1):93–100]

[177Lu]Pertuzumab: Experimental Therapy of HER-2–Expressing Xenografts

Abstract: Pertuzumab (Omnitarg) is a novel antibody against HER-2, domain II. HER-2 is a tyrosine kinase receptor that is overexpressed in several carcinomas, especially breast cancer. Pertuzumab, labeled wi ...

Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer.

Abstract: Tamoxifen resistance is common for estrogen receptor alpha (ERalpha) positive breast cancer. Second-line therapies include aromatase inhibitors or fulvestrant. We have shown previously that fulvestrant reversed 17beta-estradiol-induced tumor regression of tamoxifen-stimulated MCF-7 xenografts (MCF-7TAMLT) treated for >5 years with tamoxifen in athymic mice and paradoxically stimulated growth. We investigated mechanisms responsible for growth by fulvestrant in the presence of physiologic estradiol and therapeutic strategies in vivo. The results demonstrated that only estradiol increased expression of the estrogen-responsive genes, c-myc, igf-1, cathepsin D, and pS2 mRNAs, in MCF-7E2 and MCF-7TAMLT tumors. Tamoxifen or fulvestrant decreased the estradiol-induced increase of these mRNAs in both tumor models. However, tyrosine-phosphorylated HER2/ neu, HER3, phospho-extracellular-regulated kinase-1/2 (ERK-1/2), and phospho-glycogen synthetase kinase 3alpha (GSK3alpha) and beta proteins were increased in MCF-7TAMLT tumors treated with fulvestrant compared to estradiol, control, or tamoxifen. Phospho-HER2/neu interacted with HER3 protein in MCF-7TAMLT tumors. In order to determine whether the functional interaction of HER2/neu with HER3 is critical for growth of fulvestrant-stimulated MCF-7TAMLT tumors, pertuzumab (an antibody that blocks HER2/neu-HER3 interaction) was used in an in vivo xenograft growth assay. Only growth of fulvestrant-treated MCF-7TAMLT xenografts was decreased significantly by 37.2% in response to pertuzumab (P=0.004). Pertuzumab specifically decreased the interaction of HER2/neu protein with HER3 in fulvestrant-stimulated MCF-7TAMLT tumors. These results suggested growth of MCF-7TAMLT tumors by tamoxifen or fulvestrant is potentially independent of ERalpha transcriptional activity as evidenced by lack of induction of four estrogen-responsive genes. The results suggested that growth of MCF-7TAMLT tumors treated with fulvestrant in the presence of physiologic estradiol is in part mediated through enhanced signaling from the HER2/neu-HER3 pathway as pertuzumab partially inhibited growth and the interaction of HER2/neu with HER3 in vivo.

Targeting HER2 in prostate cancer: where to next?

Abstract: Medical oncology is a young field. Historically, cancer chemotherapies have been developed by targeting processes such as cell proliferation, DNA synthesis, and purine or pyrimidine metabolism that are present in all cells and are required for their growth. Given that these cytotoxics often show broad-spectrum activity, it has been common practice in oncology to test empirically agents that show activity in one disease in all tumor types. The first human oncogenes were discovered 25 years ago, and the first therapies deliberately directed against the molecular aberrations required for cancer growth entered clinical trials much more recently. On the basis of historical practices, it is therefore not surprising that when therapies targeted to molecular lesions in specific tumors are successful in one cancer type, that these therapies are then tested in all cancers, especially if they have only modest toxicity. The broad testing of imatinib and all-trans-retinoic acid in tumors without the relevant mutations provide good examples of the limitations of this approach. The HER kinase family, which includes epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), are receptorand receptor-like transmembrane proteins that are activated in some human tumors. The gene encoding the HER2 protein is amplified in 20% to 25% of breast cancer patients and an anti-HER2 antibody, trastuzumab, has proven to be extremely useful in their treatment. Subsequently, intense effort was devoted to the testing of trastuzumab in other cancers and the development of other modalities for inhibiting both EGFR and HER2. Structural studies reveal that binding of ligand to EGFR or HER3 induces a conformational change within the receptor that facilitates receptor homoand heterodimerization. Dimerization leads to activation of the receptors’ intrinsic kinase activity followed by transphosphorylation of specific tyrosine residues located within the cytoplasmic tails. These tyrosine residues serve as docking sites and their phosphorylation regulates the activation of intracellular signaling cascades. HER2 is unique within the family in that it has a fixed open conformation. Because of this fixed conformation, ligand binding is not required for HER2 dimerization and HER2 is always available to dimerize with other ligand-bound HER kinase receptors, for which it serves as the preferred dimerization partner. Both EGFR and HER2 have been validated as therapeutic targets in several epithelial malignancies, including those of breast, lung, and colon origin. Clinical activity has been demonstrated with anti-HER2 (trastuzumab) and anti-EGFR (cetuximab and panitumumab) monoclonal antibodies and anti-EGFR kinase inhibitors (erlotinib and gefitinib). Lapatinib, a HER2 kinase inhibitor, has also recently demonstrated promising activity in patients with breast cancer. Given that HER2 was found to be overexpressed in some prostate cancers, trastuzumab was also tested for activity in this disease, but failed to demonstrate meaningful activity. Clinical trials of gefitinib and erlotinib were also negative in patients with prostate cancer. In this issue of the Journal of Clinical Oncology, de Bono et al report the results of a phase II trial of the second-generation anti-HER2 antibody pertuzumab in patients with hormonerefractory prostate cancer. Pertuzumab and trastuzumab bind to different epitopes of the HER2 extracellular domain. Specifically, pertuzumab binds to the HER2 dimerization domain and thus prevents HER2 dimerization with the other HER kinase family members. There may be a class of nonamplified, low-level HER2-expressing tumors in which HER2-containing heterodimers drive tumor growth or progression. Such tumors may be resistant to trastuzumab but sensitive to pertuzumab. Consistent with this hypothesis, pertuzumab was found to have activity in ovarian cancer in a recently reported phase II clinical trial. HER2 amplification has been reported in a small subset of ovarian tumors but was not detected in tumor samples derived from patients enrolled onto this trial. Notably, responses to pertuzumab correlated with HER2 activation (in tumors without HER2 gene amplification) in pretreatment samples as measure by an enzyme-linked immunosorbent assay. In contrast to the results reported in ovarian cancer, in the trial by de Bono et al, not a single patient with prostate cancer achieved the primary end point of a greater than 50% decline in prostate-specific antigen. Therefore, consistent with the experience of trastuzumab and the EGFR kinase inhibitors, the HER2 dimerization inhibitor pertuzumab as a single agent was found to be ineffective in patients with hormone-refractory prostate cancer. Why have HER-kinase inhibitors been so ineffective in prostate cancer? One possibility is that insufficient target inhibition was achieved at the dose levels studied. Though the activity of pertuzumab, trastuzumab, and erlotinib in ovarian, breast, and lung cancer, respectively, suggests that target inhibition was likely achieved with these agents in patients with prostate cancer, it is possible that the level of target inhibition required to induce an antitumor response may be different in these tumor types. Such a possibility could be explained by differences in drug-to-target affinity in mutant versus wild-type cells, as has been observed with gefitinib and EGFR, or differences in drug penetration to various JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 3 JANUARY 2

Tumor therapy with a combination of anti-her2 antibodies

Abstract: Method of treating a patient suffering from HER2 positive cancer, which does not respond to a monotherapy with the anti-HER2 antibodies trastuzumab or pertuzumab, with a combination of trastuzumab and pertuzumab. Articles of manufacture comprising both trastuzumab and pertuzumab.

Extending survival of cancer patients with elevated levels of egf or tgf-alpha

Abstract: The present application describes extending survival in a cancer patient, where the patient is producing an elevated level of EGF or TGF-alpha, by treating the patient with a HER dimerization inhibitor, such as pertuzumab.

Results from a phase II randomized, placebo-controlled, double-blind trial suggest improved PFS with the addition of pertuzumab to gemcitabine in patients with platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer

Abstract: 5507 Background: Pertuzumab (P) is a humanized monoclonal antibody that blocks the ability of HER2 to heterodimerize with other HER/ErbB receptors. As a single agent, P has demonstrated clinical ac...

Management of hormone refractory prostate cancer.

Abstract: Purpose of review This review highlights the most interesting developments and outstanding issues surrounding the management of hormone-refractory prostate cancer published in the medical literature during the past year. Recent findings Recent research has reported poor health-related quality-of-life outcomes for patient with hormone-refractory prostate cancer treated in standard clinical practices. In addition, age-related differences in survival appear to exist for patients with hormone-refractory prostate cancer. Two potential future therapies for hormone-refractory prostate cancer, sipuleucel-T and the combination regimen of docetaxel and DN-101, demonstrate promising preliminary clinical data in terms of improving survival while minimizing toxicity. A variety of novel agents has been tested for hormone-refractory prostate cancer, including pertuzumab and BMS-275291, which may stabilize disease with minimal toxicity. In terms of bone-related health, skeletal-related events have been found to be associated with worse survival and health-related quality of life outcomes. Summary Data reported during the past year have implications for future research directions. This direction includes the need for continued exploration of health-related quality of life and age-related outcomes, further study of the disease-stabilizing effects of novel therapies and their translation into improved survival, as well as directed efforts to continue preventing skeletal-related events, which may impact survival and health-related quality of life.

Validation of the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) Symptom Index (FOSI) in a phase II clinical trial of pertuzumab in patients with advanced ovarian cancer

Abstract: 16021 Background: The FOSI is a very brief(8-item) index derived from the FACT-O to measure symptom response to treatment for ovarian cancer(OC). We evaluated its performance in a single arm Phase ...

New agents in development for breast cancer.

Abstract: Purpose of review This review summarizes the continuing value of some therapeutic drugs and new agents under development for the treatment of breast cancer. Recent findings Overexpression and activation of various growth factor receptors occurs frequently in human breast cancer. Therapeutic approaches mainly involve the epidermal growth factor receptor family, insulin-like growth factor receptor and vascular endothelial growth factor receptor. Therapeutic agents targeting these receptors include the monoclonal antibodies trastuzumab and pertuzumab, and the small-molecule inhibitors gefitinib and erlotinib. Other small-molecule and dual inhibitors are in development, some of which have been demonstrated to have higher efficacy in the treatment of breast cancer. The selective estrogen receptor modulators and aromatase inhibitors continue to be valuable in the endocrine therapy of breast cancer. These drugs have been shown to have higher efficacy than conventional therapy agents, and to have extensive potential, especially in the treatment of postmenopausal women with advanced breast cancer. Summary Approved agents including epidermal growth factor receptor-targeted inhibitor, selective estrogen receptor modulators and aromatase inhibitors continue to be valuable in treating breast cancer. To overcome the acquired resistance caused by these agents and to enhance the therapy effect, the development of new and specific dual inhibitors targeting various growth factor receptors will be important in the future.

Induction of erbB3/EGFR heterodimers mediates resistance to pertuzumab in a tamoxifen-resistant MCF-7 breast cancer cell line [Abstract]

Abstract: A118 Pertuzumab (‘Omnitarg’) is a novel erbB2-specific, recombinant, humanized monoclonal antibody, that prevents heterodimerization of erbB2 with other erbB family members. We have previously demonstrated that elevated levels of epidermal growth factor receptor (EGFR)/erbB2 heterodimers drive tamoxifen-resistant growth of an MCF-7 breast cancer cell line (Tam-R). In the present study we have examined the short- and long-term effects of pertuzumab in Tam-R cells to evaluate response and resistance to this novel therapeutic agent. Tam-R cells were exposed to pertuzumab (100 nM) for either 1 hour or continuously for 3 months and effects on c-erbB signalling pathways were determined by immunoprecipitation/Western blotting. Pertuzumab blocked basal expression of EGFR/erbB2 heterodimers, EGFR, AKT and ERK1/2 activity and significantly inhibited basal cell growth, whereas, basal erbB3/EGFR heterodimer expression and erbB2 activity were increased in response to this antibody. Basal erbB2/erbB3 heterodimers were not detected in this cell line so no effect of pertuzumab could be assessed on this complex. EGF (10 ng/ml) overcame the growth inhibitory effects of pertuzumab through activation of EGFR/erbB3 heterodimers and phosphorylation of AKT and ERK1/2, whilst EGF-induced erbB2 activity was inhibited by this antibody. Similar findings were also observed following stimulation of pertuzumab-treated Tam-R cells with heregulin β1 (HRGβ1). Continuous culture of Tam-R cells with pertuzumab resulted in growth inhibition which was maintained for 1 month prior to regrowth of the cells due to acquisition of pertuzumab resistance. A stable pertuzumab-resistant subline (Tam/Omni-R) was established after a further 2 months with a growth rate identical to the parental Tam-R cell line. Tam/Omni-R cells demonstrated increased levels of EGFR/erbB3 heterodimers and elevated EGFR and MAPK activity but reduced levels of EGFR/erbB2 heterodimers. Like Tam-R cells, Tam/Omni-R cells were highly sensitive to the growth inhibitory effects of EGFR and MAPK blockade. In conclusion, under basal growth conditions pertuzumab is an effective inhibitor of EGFR/erbB2-driven signalling and growth in our Tam-R cell line. However, pertuzumab also promoted the rapid formation of erbB3/EGFR heterodimers in this cell line providing a mechanism whereby EGF and HRGβ1 stimulation could circumvent the growth inhibitory effect of this agent. Moreover, erbB3/EGFR heterodimer levels were increased in Tam/Omni-R cells further suggesting that pertuzumab-induced EGFR/erbB3 heterodimerization may play a central role in the rapid acquisition of resistance to this agent in Tam-R cells.

Downregulation of HER3: A potential surrogate for activation of HER2 through heterodimerization may predict clinical benefit in ovarian cancer from pertuzumab, a HER dimerization inhibiting antibody

Abstract: C141 Pertuzumab is a humanized monoclonal antibody designed to block HER2’s ability to dimerize with ligand activated HER receptors like HER3. Pre-clinical studies indicated that pertuzumab may have activity in a subset of tumors where HER2 is activated through ligand-induced heterodimerization. Furthermore, these studies indicate that mRNA expression levels of HER2 and/or HER3 might serve as surrogate markers for HER2 pathway activity. To avoid an invasive tumor biopsy, a qRT-PCR assay was developed for mRNA expression analysis of HER pathway genes using archival formalin fixed paraffin embedded tissue (FFPET). To explore the activity of pertuzumab, particularly in patient subsets defined by potential diagnostic biomarkers, a randomized phase II trial in platinum-resistant ovarian cancer, comparing gemcitabine + placebo to gemcitabine + pertuzumab was conducted (N=130) (ASCO 2007, abstract #5507). The overall treatment benefit from adding pertuzumab to gemcitabine was modest, with a PFS hazard ratio (HR) of 0.66 (95% CI: 0.43-1.03, p=0.07) and a median duration PFS of 2.6 vs. 2.9 months. mRNA expression data from archival tumor tissues, analyzing EGFR, HER2, HER3 and several HER ligands was generated from 122/130 patients’ tumors and compared to clinical outcomes. The PFS hazard ratio of 0.13 (95% CI: 0.04-0.41, p=

Combinations of trastuzumab with either pertuzumab or bevacizumab show higher efficacy than lapatinib-based combinations against HER2-positive breast cancer xenografts progressing on trastuzumab monotherapy

Abstract: B102 The humanized monoclonal antibody (mab) trastuzumab, which specifically binds to the extra-cellular domain of HER2 has become standard of care for patients with HER2-positive breast cancer. Unfortunately, some patients progress while on trastuzumab and chemotherapy combination treatment. One way to avoid progression is to block HER pathways more completely by targeting other HER-family growth factor receptors like HER1/EGFR or HER3. We investigated whether HER2-positive tumours progressing under trastuzumab therapy can be inhibited by the combination of trastuzumab in multiple lines with other HER-family receptor targeting agents (pertuzumab and lapatinib) that are in clinical development, and together with clinically established cytotoxic drugs (paclitaxel and 5-FU). Since up-regulation of VEGF has been suggested to promote tumour progression, we also tested the combination of trastuzumab with the anti-huVEGF targeting mab bevacizumab. We used the HER2-positive human breast cancer xenograft model KPL-4 which is known to shed the extra-cellular domain of HER2 and to co-express HER1 and HER3. Mice carrying well established KPL-4 xenograft tumours of about 100-120 mm 3 size were treated once weekly (q7d) with 15mg/kg i.p. trastuzumab, following an initial 2-fold loading dose. After 2 weeks of trastuzumab treatment, those mice with progressively growing tumours of about 160-250 mm 3 in size were randomly distributed into various groups in order to test different treatment options. The compounds used for second line treatment included: (1) pertuzumab (15mg/kg, i.p. q7d), a novel HER dimerisation inhibitor; (2), bevacizumab (5mg/kg, q3d, i.p.) which inactivates huVEGF-A; (3) lapatinib (25mg/kg, 2qd, p.o.), which is described as a dual HER1 and HER2 tyrosine kinase inhibitor, and two cytotoxic drugs, (4) paclitaxel (15mg/kg, q7d, i.v.) and (5) 5-FU (50mg/kg, q7d, i.v.). While trastuzumab treatment was continued after progression, the addition of either pertuzumab or bevacizumab for combined second line treatment demonstrated significant antitumour activity compared to untreated or trastuzumab single agent controls. Adding paclitaxel or 5-FU on top of the dual antibody combinations was clearly superior, resulting in complete tumour remissions and long term survival. In contrast, various combinations of trastuzumab with lapatinib were not efficacious and less well tolerated, especially with the addition of paclitaxel or 5-FU. In summary, our data indicate that there are several effective treatment options for HER2 positive tumours to be used for treatment in multiple lines of trastuzumab with monoclonal antibodies targeting HER-family receptors and/or angiogenesis. The addition to continued trastuzumab therapy of either the HER dimerisation inhibitor pertuzumab or the anti-VEGF mab bevacizumab together with cytotoxic drugs, resulted in superior antitumour activity with complete tumour remission and long term survival, compared to lapatinib-based combinations.

A report of cardiac events in a phase II clinical study using trastuzumab combined with pertuzumab in HER2-positive metastatic breast cancer (MBC)

Abstract: 1028 Background: T and P are humanized recombinant monoclonal antibodies (MoAB) that target different epitopes of HER2 extracellular domain. P blocks HER2’s ability to heterodimerize with other HER...

Controversies of chemotherapy for the treatment of metastatic breast cancer

Abstract: Metastatic breast cancer (MBC) remains an incurable disease. The aims of treatment include tumour shrinkage, symptom control, delay of disease progression and prolongation of survival while maintaining an acceptable quality of life. In the last decade, a decline in mortality has been observed. Combination chemotherapy generally provides some survival advantage over single-agent chemotherapy. Taxanes and antimetabolites are among the most effective agents, providing a balance between efficacy and tolerability. Increasing numbers of patients are receiving adjuvant anthracycline and taxane therapy. In these patients, treatment options include cytotoxic agents not used in adjuvant treatment, re-challenge with anthracycline and taxanes, or new targeted agents such as pertuzumab, lapatinib or bevacizumab. Biology of the disease at cell level plays a major role in treatment choice. Key points in the intracellular signal transduction pathways relevant for cell proliferation, apoptosis and the angiogenesis/metastasis process, represent possible targets for new target-specific agents. Tailored therapies are a step forward in improving patients' prognosis.