Showing papers on "Pertuzumab published in 2011"
TL;DR: The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer and the risk-benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia.
Abstract: BackgroundTrastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. MethodsWe randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. ResultsAt a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall su...
2,081 citations
TL;DR: Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T- DM1 doses, and a few covariates were shown to affect interindividual variability in T-dm1 exposure and clearance in population-pharmacokinetics analyses.
Abstract: Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)–targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1–containing agents are eagerly awaited. Clin Cancer Res; 17(20); 6437–47. ©2011 AACR .
425 citations
TL;DR: The emerging data for the treatment of trastuzumab-refractory disease with novel agents including lapatinib, neratinIB, pertizumab, trastudumab -DM1, HSP90 and PI3K pathway inhibitors are explored and the future potential for these inhibitors is explored.
Abstract: HER2 amplification is seen in up to 20% of breast cancers and is associated with an aggressive phenotype. Trastuzumab, a monoclonal antibody to HER2, accrues significant clinical benefit in the metastatic and adjuvant settings. However, some patients suffer disease recurrence despite adjuvant trastuzumab therapy, and many patients with metastatic disease do not respond to therapy or develop refractory disease within 1 year of treatment. Given the increased recognition of de novo and acquired resistance to therapy, considerable research has been dedicated to understanding the molecular mechanisms of trastuzumab resistance. Here, we highlight putative models of resistance, including activation of the downstream PI3K-signaling pathway, accumulation of a constitutively active form of HER2, and crosstalk of HER2 with other growth factor receptors. The identification of these specific mechanisms of trastuzumab resistance has provided a rationale for the development of several novel HER2-targeted agents as the mechanisms have largely suggested a continued tumor dependence on HER2 signaling. We explore the emerging data for the treatment of trastuzumab-refractory disease with novel agents including lapatinib, neratinib, pertuzumab, trastuzumab-DM1, HSP90 and PI3K pathway inhibitors, and the future potential for these inhibitors which, if combined with reliable biomarkers of resistance, may ultimately usher in a new era of personalized medicine for this disease.
387 citations
TL;DR: A panel of 38 nanobodies, small HER2‐binding fragments that are derived from heavy‐chain‐only antibodies raised in an immunized dromedary are described, which was found to be stable and to interact specifically with HER2 recombinant protein and Her2‐expressing cells in ELISA, surface plasmon resonance, flow cytometry, and radioligand binding studies with low nanomolar affinities.
Abstract: Accurate determination of tumor human epidermal growth factor receptor 2 (HER2)-status in breast cancer patients is possible via noninvasive imaging, provided adequate tracers are used. In this study, we describe the generation of a panel of 38 nanobodies, small HER2-binding fragments that are derived from heavy-chain-only antibodies raised in an immunized dromedary. In search of a lead compound, a subset of nanobodies was biochemically characterized in depth and preclinically tested for use as tracers for imaging of xenografted tumors. The selected compound, 2Rs15d, was found to be stable and to interact specifically with HER2 recombinant protein and HER2-expressing cells in ELISA, surface plasmon resonance, flow cytometry, and radioligand binding studies with low nanomolar affinities, and did not compete with anti-HER2 therapeutic antibodies trastuzumab and pertuzumab. Single-photon-emission computed tomography (SPECT) imaging quantification and biodistribution analyses showed that (99m)Tc-labeled 2Rs15d has a high tumor uptake in 2 HER2(+) tumor models, fast blood clearance, low accumulation in nontarget organs except kidneys, and high concomitant tumor-to-blood and tumor-to-muscle ratios at 1 h after intravenous injection. These values were dramatically lower for an irrelevant control (99m)Tc-nanobody and for (99m)Tc-2Rs15d targeting a HER2(-) tumor.
244 citations
TL;DR: The notion that HER2 oligomeric states regulate HER2 signaling is confirmed, also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K (phosphoinositide 3-kinase)/AKT pathway.
Abstract: In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers, and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2(+) breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. Trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, the HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with HER2-overexpressing breast cancer. Together, our findings confirm the notion that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K (phosphoinositide 3-kinase)/AKT pathway. A clinical implication of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab.
209 citations
TL;DR: The clinical benefit of combination therapy with pertuzumab and trastuzumAB for patients with HER2-positive gastric cancers is suggested, through the potentiation of cell growth inhibition, apoptosis activity, cell killing activity by ADCC, and antiangiogenic activity.
Abstract: Purpose: We investigated the antitumor activity of the combination of two different humanized monoclonal human epidermal growth factor receptor (HER) 2 antibodies, pertuzumab and trastuzumab, for gastric cancer. Experimental Design: Tumor mouse xenograft models were used to examine antitumor activity. Cell proliferation was examined using crystal violet staining. HER family proteins9 expression was analyzed by ELISA and immunohistochemistry. Phosphorylated proteins and heterodimers were detected by Western blotting and in situ proximity ligation assay (PLA), respectively. Apoptosis activity was examined by caspase 3/7 activity. Antibody-dependent cellular cytotoxicity (ADCC) activity was detected by xCELLigence. Microvessel density was examined by CD31 staining. Results: Pertuzumab in combination with trastuzumab showed significant antitumor activity compared with each monotherapy in NCI-N87, an HER2-positive human gastric cancer xenograft model. The efficacy was stronger than that of the maximum effective dose with each monotherapy. Similar antitumor activity was shown in 4-1ST, another HER2-positive gastric cancer model, but not in MKN-28, an HER2-negative model. Combining pertuzumab with trastuzumab enhanced cell growth inhibition and apoptosis activity by inhibiting EGFR-HER2 heterodimerization and the phosphorylation of these receptors and their downstream factors. This effect was also seen in HER2-HER3 signaling. Furthermore, pertuzumab in combination with trastuzumab potentiated the ADCC activity of those antibodies and reduced tumor microvessel density. Conclusions: We showed the significantly enhanced efficacy of pertuzumab combining with trastuzumab for HER2 overexpressing gastric cancer through the potentiation of cell growth inhibition, apoptosis activity, cell killing activity by ADCC, and antiangiogenic activity. This study suggests the clinical benefit of combination therapy with pertuzumab and trastuzumab for patients with HER2-positive gastric cancers. Clin Cancer Res; 17(15); 5060–70. ©2011 AACR .
152 citations
97 citations
TL;DR: It is proposed that gefitinib induces EGFR dimmers, which alters the interaction characteristics with 125I-EGF, and this paper concludes that dimerization explains the varying affinity of EGF – EGFR in different cells.
Abstract: The tyrosine kinase inhibitor gefitinib inhibits growth in some tumor types by targeting the epidermal growth factor receptor (EGFR). Previous studies show that the affinity of the EGF-EGFR interaction varies between hosting cell line, and that gefitinib increases the affinity for some cell lines. In this paper, we investigate possible mechanisms behind these observations. Real-time interaction analysis in LigandTracer® Grey revealed that the HER2 dimerization preventing antibody pertuzumab clearly modified the binding of 125I-EGF to EGFR on HER2 overexpressing SKOV3 cells in the presence of gefitinib. Pertuzumab did not affect the binding on A431 cells, which express low levels of HER2. Cross-linking measurements showed that gefitinib increased the amount of EGFR dimers 3.0–3.8 times in A431 cells in the absence of EGF. In EGF stimulated SKOV3 cells the amount of EGFR dimers increased 1.8–2.2 times by gefitinib, but this effect was cancelled by pertuzumab. Gefitinib treatment did not alter the number of EGFR or HER2 expressed in tumor cell lines A431, U343, SKOV3 and SKBR3. Real-time binding traces were further analyzed in a novel tool, Interaction Map, which deciphered the different components of the measured interaction and supports EGF binding to multiple binding sites. EGFR and HER2 expression affect the levels of EGFR monomers, homodimers and heterodimers and EGF binds to the various monomeric/dimeric forms of EGFR with unique binding properties. Taken together, we conclude that dimerization explains the varying affinity of EGF – EGFR in different cells, and we propose that gefitinib induces EGFR dimmers, which alters the interaction characteristics with 125I-EGF.
85 citations
TL;DR: In this article, a time-resolved fluorescence resonance energy transfer (TR-FRET) method was proposed to quantify EGFR/HER2 heterodimers on cell surface to shed some light on the mechanism of such therapies.
77 citations
TL;DR: If validated, these findings will bring about a new direction in the design of antibodies whereby different epitopes on the same antibody may be targeted to lead to synergistic/cooperative inhibition and contribute to generate more potent therapeutics and to increase clinical efficacy.
Abstract: Human epidermal growth factor 2 (Her2), a receptor tyrosine kinase, is overexpressed in breast cancers. It has been successfully targeted by small molecule kinase inhibitors and by antibodies. Recent clinical data show a synergistic response in patients when two antibodies, trastuzumab and pertuzumab, are given in combination. This unexpected effect is rationalized through computer models and molecular dynamic simulations by hypothesizing that the two antibodies can co-localize on the same molecule of the Her2 extracellular domain. Simulations suggest that the clinical synergism observed for the two antibodies arises partly from enhanced affinity that originates in cooperative interactions between these two antibodies when they are co-localized on Her2 and "clamp" it; this may inhibit dimerization and possibly higher oligomerizations with neighboring receptors. In the presence of trastuzumab, the receptor becomes highly plastic, especially domains I to III, and this appears to promote increased association with pertuzumab. Further, the presence of pertuzumab evokes novel interactions between the receptor and trastuzumab. Indeed, splicing out of this region in silico results in a big reduction in the interactions of the antibody with the receptor. If validated, these findings will bring about a new direction in the design of antibodies whereby different epitopes on the same antibody may be targeted to lead to synergistic/cooperative inhibition and contribute to generate more potent therapeutics and to increase clinical efficacy.
65 citations
TL;DR: The NeoSphere study demonstrated significantly increased antitumor activity in the neoadjuvant setting for the combination of P and trastuzumab (H) plus docetaxel (T) compared with HT alone, consistent with the hypothesis of complementary mechanisms of action of P-H and H.
Abstract: Background: Pertuzumab (P) is a fully humanized investigational monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), preventing homo- and heterodimerization of HER2 and other HER family members and inducing antibody-dependent cell-mediated cytotoxicity. The NeoSphere study demonstrated significantly increased antitumor activity in the neoadjuvant setting for the combination of P and trastuzumab (H) plus docetaxel (T) compared with HT alone (Gianni et al . SABCS 2010), consistent with the hypothesis of complementary mechanisms of action of P and H. No increase in cardiac risk was observed with the addition of P to H and HT regimens. Anthracyclines have an important role in the treatment of breast cancer and may be especially efficacious in HER2−positive disease. In the TRYPHAENA study, P and H are being administered either sequentially or concurrently with an anthracycline-containing or concurrently with an anthracycline-free standard regimen in order to establish the tolerability profile of these regimens for testing in the adjuvant setting. Methods: Patients with centrally confirmed stage II or III (including locally advanced and inflammatory disease) HER2−positive breast cancer (defined as centrally confirmed HER2 IHC 3+ or FISH/CISH+) were randomized to receive: Study medication: P 840 mg loading dose and 420 mg maintenance; H 8 mg/kg loading dose and 6 mg/kg maintenance; T was given at 75 mg/m 2 with dose escalation to 100 mg/m 2 if the starting dose was well tolerated (no dose escalation in Arm C); FEC (5-fluorouracil 500 mg/m 2 , epirubicin 100 mg/m 2 , and cyclophosphamide 600 mg/m 2 ) and carboplatin AUC 6. All treatments were given intravenously q3w. The study is ongoing. All patients will receive H for 1 year. The primary endpoint is assessment of the safety and tolerability of neoadjuvant treatment. During neoadjuvant treatment, left ventricular ejection fraction is assessed at Cycles 2, 4, and 6 by echocardiogram or multiple-gated acquisition. Safety data are supervised by a data and safety monitoring board. The key secondary endpoint is the rate of pathological complete response (pCR) defined as absence of invasive disease in the breast at surgery. Tissue specimens at baseline and post-surgery were required for all patients. This study is registered at ClinicalTrials.gov: NCT00976989. Results: 225 patients have been recruited. No arm has required modification due to safety concerns or to excessive incidence of disease progression. Analysis of the study results is anticipated in Q3 2011. Safety/tolerability and efficacy (pCR) data will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-6.
TL;DR: Recent data from the randomized neo-adjuvant studies NeoALTTO and NeoSphere have shown that dual blockade of the HER2 receptor with anti-HER2 agents is significantly superior to using one agent alone.
TL;DR: Significant advances in the understanding of molecular biology of breast cancer have been made and should lead to an improvement in the outcome of MBC and more possibilities of cure can become an attainable goal in the near future.
Abstract: Current treatment of metastatic breast cancer (MBC) aims at achieving meaningful clinical responses, improved quality of life, long-term remissions, prolonged survival, and dares to hope for a cure in a small percentage of cases. This article will discuss both consensus and controversies in the management of MBC in the context of the new evolving breast cancer molecular classification. Hormonal therapy remains the mainstay of management of MBC Luminal A and B. Data is emerging on management of ErbB2-positive HR-positive MBC by combining hormonal manipulation and targeted anti-ErbB2 therapy and has recently received regulatory approval in Europe and USA. The optimal use and duration of single agent or combination chemotherapy is discussed. Data and controversies surrounding the use of newer agents such as nab-paclitaxel, ixabepilone, eribulin, and PARP inhibitors as well as trastuzumab is reviewed. Better understanding of pathophysiology has paved the way for the introduction of newer anti-ErbB2 agents such as lapatinib, pertuzumab, T-DM1 and neratinib. Controversies regarding bevacizumab and anti-angiogenesis are discussed. Bisphosphonates have significantly reduced skeletal related events and made significant improvements in the quality of life of patients with MBC. Newer anti-RANK Ligand antibodies show promising results. Significant advances in the understanding of molecular biology of breast cancer have been made and should lead to an improvement in the outcome of MBC. More possibilities of cure can become an attainable goal in the near future.
TL;DR: Combination treatment with HER-2 and VEGF peptide mimics provides greater efficacy than individual treatments, and to address the problem of degradability of l-amino acid peptides in vivo, the retro-inverso d-peptides that resulted in higher efficacy in treatment are synthesized.
TL;DR: Investigation of the antitumor effects of HER2-directed combination therapy in ovarian cancer xenograft models suggests that trastuzumab in combination with pertuzumAB could be an effective approach in high HER1-expressing ovarian cancers and could also enhance sensitivity to endocrine therapy in ERα-positive ovarian cancer.
Abstract: Purpose: The aim of this study was to investigate the antitumor effects of HER2-directed combination therapy in ovarian cancer xenograft models to evaluate their potential. The combinations of trastuzumab and pertuzumab, and trastuzumab and aromatase inhibitor therapy were investigated. Experimental Design: The effects of trastuzumab, pertuzumab, and letrozole on growth response, apoptosis, morphology, and gene and protein expression were evaluated in the SKOV3 ovarian cancer cell line xenograft and a panel of five human ovarian xenografts derived directly from clinical specimens. Results: The combination of HER2-directed antibodies showed enhanced antitumor activity compared with single antibody therapy in the SKOV3 xenograft model. Apoptosis, morphology, and estrogen-regulated gene expression were modulated by these antibodies in both spatial and temporal manners. A panel of ovarian cancer xenografts showed differential growth responses to the combination of trastuzumab and pertuzumab. High HER2 expression and increasing HER3 protein expression on treatment were associated with growth response. In trastuzumab-treated SKOV3 tumors, there was a change in tumor morphology, with a reduction in frequency of estrogen receptor alpha (ERα)-negative clear cell areas. Trastuzumab, but not pertuzumab, increased expression of ERα in SKOV3 xenografts when analyzed by quantitative immunofluorescence. ERα and downstream signaling targets were modulated by trastuzumab alone and in combination. Trastuzumab enhanced the responsiveness of SKOV3 xenografts to letrozole when given in combination. Conclusions: These data suggest that trastuzumab in combination with pertuzumab could be an effective approach in high HER2-expressing ovarian cancers and could also enhance sensitivity to endocrine therapy in ERα-positive ovarian cancer. Clin Cancer Res; 17(13); 4451–61. ©2011 AACR .
TL;DR: The major newly developed targeted agents in breast cancer treatment, including the novel anti-HER-2 monoclonal antibody pertuzumab or ertumaxomab, small molecular tyrosine inhibitor lapatinib, selective PARP1 inhibitor olaparib, mTOR inhibitor rapamycin analogues, and sheddase inhibitors are discussed.
Abstract: Summary Breast cancer is the most commonly diagnosed malignancy and one of the major causes of death among women. Breast cancer is also one of the most investigated diseases but whose biological features are still not well understood, several effective treating strategies having been explored in dealing with different types of advanced breast cancer, such as endocrine therapy and molecular targeted therapy. Trastuzumab is the first approved targeted anti-cancer agent to show an attractive response rate and outcomes in treating HER-2 positive metastatic breast cancer patients. However, primary or acquired trastuzumab resistance usually occurs some time into the use of trastuzumab and leads to treatment resistance or tumour progression. The promising results with trastuzumab targeted therapy encouraged further investigations in this area exploring several novel targeted agents aiming to overcome the resistance drawback of trastuzumab. In this review we discuss the major newly developed targeted agents in breast cancer treatment, including the novel anti-HER-2 monoclonal antibody pertuzumab or ertumaxomab, small molecular tyrosine inhibitor lapatinib, selective PARP1 inhibitor olaparib, mTOR inhibitor rapamycin analogues, and sheddase inhibitors. Many of these novel targeted drugs or molecules showed additional or complementary effects to trastuzumab therapy that need further and wider investigation.
TL;DR: The first phase III study to evaluate the combination of a targeted antibody and an ADC for first-line MBC has the potential to establish a new treatment paradigm by optimizing efficacy while minimizing toxicity.
Abstract: TPS102 Background: T-DM1 is a unique antibody-drug conjugate (ADC) composed of H, a stable thioether linker, and the highly potent cytotoxic agent DM1 (derivative of maytansine). In a randomized phase II trial, single-agent T-DM1 had comparable efficacy to H + docetaxel in the first-line treatment of HER2-positive locally advanced or MBC. P is the first HER2-directed dimerization inhibitor for the treatment of HER2-positive BC. T-DM1 and P bind to different epitopes on HER2, and have distinct mechanisms of action suggesting that the combination may result in more complete blockade of HER2. T-DM1 + P showed synergistic antitumor effects in preclinical models, and preliminary phase Ib/II trial results showed acceptable tolerability and promising efficacy in patients with MBC. Methods: MARIANNE BO22589 (trial registry #NCT01120184) is the first phase III study to evaluate the combination of a targeted antibody and an ADC for first-line MBC. This systemic chemotherapy-sparing combination has the potential to ...
TL;DR: Growth inhibition by anticancer drugs targeted to Her/ErbB receptors can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti‐EGFR/Her2 targeting.
Abstract: Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting Receptor- and, in turn, growth-stimulating effects, which potentially hamper antiproliferative cell treatment, have barely been investigated BT474 and SK-BR-3 breast cancer cell lines were treated with Trastuzumab, Pertuzumab, and Lapatinib alone using different combinations and concentrations Moreover, epidermal growth factor (EGF) or heregulin (HRG) was added to reveal potential growth factor-mediated compensatory effects Receptor and intracellular signaling were analyzed as a function of cell treatment Read-out parameters were cell proliferation and apoptosis BT474 cells were efficiently driven into quiescence by Trastuzumab, but not by Pertuzumab treatment Simultaneous EGF or HRG administration, however, restored the BT474 cell proliferation capacity In contrast, neither therapeutic antibody treatment caused a profound inhibition of SK-BR-3 cell-cycle progress Lapatinib turned out to be the most potent cell-cycle inhibitor in both cell lines even though its impact was significantly abrogated in the presence of EGF and HRG The compensatory effect of EGF on Lapatinib-induced cell-cycle inhibition was reversed by Trastuzumab as well as by Pertuzumab treatment Most importantly, HRG-caused compensation of Lapatinib-induced cell-cycle exit was reversed by Pertuzumab but not by Trastuzumab Apparently, multiple anti-EGFR/Her2 targeting by using Trastuzumab, Pertuzumab, and Lapatinib more efficiently affects receptor function (interaction and activation) and consequently enhances their antiproliferative capacity Growth inhibition by anticancer drugs targeted to Her/ErbB receptors, however, can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti-EGFR/Her2 targeting
TL;DR: There is already enough circumstantial evidence to justify anti-HER2 therapy alone in selected patients for whom chemotherapy is contraindicated, and trials and prospective studies are now warranted to investigate this issue further.
Patent•
07 Dec 2011TL;DR: In this paper, a combination therapy with paclitaxel, trastuzumab-MCC-DM1 and optionally, pertuzumabs was proposed. But the present invention relates to combination therapy only.
Abstract: The present invention relates to combination therapy with paclitaxel, trastuzumab-MCC-DM1 and optionally, pertuzumab.
TL;DR: No increase in overall toxicity and, in particular, no increase in cardiac events was observed with the addition of P to H and HT regimens and the primary endpoint was progression-free survival as determined by independent review.
Abstract: Background: Pertuzumab (P) is a fully humanized investigational monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), preventing dimerization of HER2 with other HER family members and inducing antibody-dependent cell-mediated cytotoxicity. Its mechanisms of action are complementary to those of the anti-HER2 antibody trastuzumab (H) and the two antibodies combined have superior activity compared with either antibody alone in preclinical and clinical studies. In patients with advanced disease, P in combination with H has been shown to be active in patients whose disease has progressed while on H therapy (Baselga et al. J Clin Oncol 2010). Furthermore, P has been shown to improve the activity of H and docetaxel (T) in a randomized neoadjuvant study (Gianni et al. SABCS 2010, S3-2). No increase in overall toxicity and, in particular, no increase in cardiac events was observed with the addition of P to H and HT regimens. Methods: In this double-blind Phase III study patients with centrally confirmed HER2−positive metastatic or locally recurrent, unresectable breast cancer were randomized to receive either placebo+H+T or P+H+T. Patients could have received one prior hormonal treatment for metastatic breast cancer and/or prior systemic neoadjuvant or adjuvant therapy including prior H and T. Patients had to have a baseline left ventricular ejection fraction ≥50% and no history of declines to Study medication was as follows: P 840 mg loading dose followed by 420 mg q3w; H 8 mg/kg loading dose followed by 6 mg/kg q3w; T 75 mg/m2 q3w (with subsequent dose escalation to 100 mg/m2 if 75 mg/m2 was well tolerated). Patients were recommended to receive at least 6 cycles of T. In the case of chemotherapy discontinuation due to cumulative toxicity, antibody therapy was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients were stratified according to region and prior treatment status (adjuvant therapy or de novo metastatic breast cancer). The primary endpoint for the study was progression-free survival (PFS) as determined by independent review. The primary analysis was planned to take place when approximately 381 independently confirmed PFS events had occurred. This would provide 80% power to detect a 33% improvement in PFS (HR=0.75) at the two-sided significance level of 5%. Secondary endpoints included overall survival, investigator-determined PFS, overall response rate, duration of response, safety, and quality of life. Patient safety was monitored throughout the study by an independent data monitoring committee and a cardiac review committee. This study is registered at ClinicalTrials.gov: NCT00567190. Results: 808 patients were recruited between February 2008 and July 2010. The required number of PFS events for analysis of the primary endpoint has been reached and independent assessment PFS is currently being performed. Results of the primary analysis of efficacy and safety will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-5.
TL;DR: A comprehensive HER2 blockade with two anti-HER2 monoclonal antibodies warrants further investigation in the adjuvant setting to compare invasive disease-free survival (IDFS) between both treatment arms.
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.
TL;DR: Several key questions need to be investigated further, such as the preferred combination chemotherapy and the optimal duration of trastuzumab in patients who achieve a pathologic complete response following preoperative chemotherapy with trastudumab.
Abstract: Approximately one quarter of patients with breast cancer demonstrate amplification of the human epidermal receptor type 2 (HER2) gene, the expression of which is associated with a relatively poor prognosis independent of other clinical and pathologic variables. Trastuzumab, a humanized recombinant monoclonal antibody specifically directed against the HER2 receptor, has been shown to be biologically active and of considerable clinical utility in HER2-positive breast cancer patients. Neoadjuvant chemotherapy has been used in breast cancer to downstage the tumor and increase the opportunity for breast-conserving surgery. Preoperative chemotherapy can also serve as an in vivo testing of chemotherapy sensitivity. Additionally, a pathologic complete response is usually a surrogate marker of disease-free survival. Following the successful use of trastuzumab in the metastatic and adjuvant settings, many clinical trials have recently reported the successful use of anti-HER2 therapy in combination with different chemotherapy regimens in the neoadjuvant setting with a significantly higher pathologic complete response. With the recent introduction of new anti-HER2 drugs, interest has shifted toward dual HER2 blockade. Two such studies were recently reported, both showing a significant advantage of dual anti-HER2 therapy using lapatinib or pertuzumab in addition to trastuzumab and chemotherapy. However, several key questions need to be investigated further, such as the preferred combination chemotherapy and the optimal duration of trastuzumab in patients who achieve a pathologic complete response following preoperative chemotherapy with trastuzumab. These issues and others are discussed in this review.
TL;DR: The PHEREXA study is designed to investigate the potential benefit of administering P and H combined with X in patients with HER2-positive MBC whose disease has progressed during or following H-based therapy for first-line MBC.
Abstract: TPS118 Background: Pertuzumab (P) is a promising new anti-HER2 antibody which has shown both activity and good tolerability when combined with trastuzumab (H) in patients with HER2-positive breast cancer. Capecitabine (X) in combination with H has been shown to be more efficacious than X alone as second-line treatment of patients with HER2-positive metastatic breast cancer (MBC). The PHEREXA study is designed to investigate the potential benefit of administering P and H combined with X in patients with HER2-positive MBC whose disease has progressed during or following H-based therapy for first-line MBC. Methods: In this multicenter, open-label, Phase II trial (NCT01026142), patients are randomized 1:1 to Arm A (H: 8 mg/kg loading dose followed by a 6 mg/kg maintenance dose; X: 1250 mg/m2 twice daily for 14d q3w) or Arm B (H: 8 mg/kg loading dose followed by a 6 mg/kg maintenance dose; X: 1000 mg/m2 twice daily for 14d; P: 840 mg loading dose and 420 mg thereafter q3w). Enrolment began in January 2010 and ...
TL;DR: Most of the studies using biological agents to hit multiple targets in HER2-positive breast cancer patients confirm that resistance to single-agent Her2-targeting can be overcome and it is possible that newer molecular predictive factors may allow a more rationale choice of the most appropriate targeting for each individual patient.
Abstract: Introduction: Pharmacological targeting of the tyrosine kinase receptor HER2 with the monoclonal antibody trastuzumab has dramatically changed the outlook of HER2-positive breast cancer patients. However, HER2 is part of a more complex biological network that, when deregulated, plays a central role in sustaining the cancer phenotype. These interactions account for primary or acquired resistance to drugs that hit a single biological target, like trastuzumab. Several preclinical models suggest that simultaneous targeting of crucial metabolic pathways has the potential to circumvent or delay the onset of resistance phenomena in HER2-positive breast cancer cells. Areas covered: This review describes the rationale and results of clinical trials using biologically targeted agents in HER2-positive breast cancer patients. Single drugs that hit multiple targets and cocktails of biologically targeted agents are considered, whereas combinations with chemotherapy are not addressed. Expert opinion: Most of the studies...
TL;DR: Neoadjuvant chemotherapy is established as a valid treatment option, as the breast conservation rate is increased, and the antibody trastuzumab is the first targeted agent established in neoadjuant regimens for the treatment of Her2-positive breast cancer, as it raised pCR rates up to 50%.
Abstract: Breast cancer is the most prevalent malignant disease in women worldwide. Traditionally, surgical tumour resection was the primary step within the treatment algorithm of early stage disease; systemic therapy in order to reduce the rate of systemic recurrences followed. National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-18 found that pre- and postoperative administration of chemotherapy was equally effective. This study therefore established neoadjuvant chemotherapy as a valid treatment option, as the breast conservation rate is increased. Modern neoadjuvant regimens encompassing anthracyclines and taxanes yield pathological complete response (pCR) rates of around 20%, with higher efficacy observed in triple-negative tumours. The antibody trastuzumab is the first targeted agent established in neoadjuvant regimens for the treatment of Her2-positive breast cancer, as it raised pCR rates up to 50%. Novel approaches are aiming to increase the efficacy of neoadjuvant therapy. Inclusion of capecitabine might further increase pCR rates in selected patients, although data are not unanimous throughout the respective clinical trials. In patients harbouring BRCA-1 germline mutations, platinum derivatives are apparently promising. Novel Her2-targeted agents such as lapatinib and pertuzumab are currently under investigation in several clinical trials, while the role of bevacizumab, a monoclonal antibody inhibiting angiogenesis, awaits future clarification.
18 Jul 2011
TL;DR: The results of the first randomized phase III trial of trastuzumab, a monoclonal antibody directed at the HER-2 receptor, in patients with metastatic gastric cancer were reported recently, and response rate, median progression-free survival, and median overall survival were all significantly improved.
Abstract: Correspondence: David Cunningham Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK Tel +44 208 661 3156 Fax +44 208 661 3890 email david.cunningham@rmh.nhs.uk Abstract: Gastric cancer is the fourth most common malignancy and second leading cause of cancer death world-wide, and is therefore a significant global health problem. Radical surgery with a D2 lymph node dissection is an accepted standard approach, and is a key component of multimodality therapy. Perioperative chemotherapy significantly improves 5-year overall survival compared with surgery alone. A significant improvement in overall survival has also been demonstrated with postoperative 5-fluorouracil-based chemoradiotherapy and adjuvant oral S-1 chemotherapy; approaches commonly used widely in North America and Japan, respectively. Approximately 10% to 20% of gastric cancers and 20% to 30% of esophago-gastric junction cancers are HER-2 positive. The effect of HER-2 overexpression and HER-2 gene amplification on gastric cancer prognosis remains unresolved. The results of the first randomized phase III trial of trastuzumab, a monoclonal antibody directed at the HER-2 receptor, in patients with metastatic gastric cancer were reported recently. Response rate, median progression-free survival, and median overall survival were all significantly improved with the addition of trastuzumab to a cisplatin/fluoropyrimidine doublet. Evaluation of trastuzumab in HER-2 positive operable esophago-gastric cancer is now underway. Lapatinib, a small-molecule inhibitor targeting EGFR and HER-2 is well established in the treatment of trastuzumab-refractory HER-2 positive breast cancer and phase III trials in advanced esophago-gastric cancers are ongoing. Novel, small molecule pan-HER inhibitors have entered early phase evaluation and the antibody-drug conjugate, trastuzumab-DM1, and pertuzumab, a monoclonal antibody which prevents HER-2/ HER-3 dimerization, are currently undergoing phase II/III evaluation in breast cancer. It is our hope that advances in the targeted treatment of HER-2 positive breast cancer will be replicated in HER-2 positive esophago-gastric cancers.
TL;DR: It is demonstrated that the novel antibody mixture Sym005 has a unique set of HER2 inhibitory mechanisms, which translates into superior anti-cancer activity in HER2-positive tumor xenografts and provides a clear rationale for evaluation of Sym005 in clinical trials on patients with HER2 positive tumors.
Abstract: Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL
Human epidermal growth factor receptor 2 (HER2) is involved in development and maintenance of malignant phenotypes of several human cancers and therefore represent an attractive therapeutic target. Trastuzumab is currently the only anti-HER2 antibody approved for treatment of human cancers and although succesful more efficacious treatments are warranted. Mixtures of recombinant monoclonal antibodies are promising candidates as the next generation of antibody therapeutics due to their multipotent activities.
The aim of the present study was to identify mixtures of anti-HER2 antibodies with superior activity to existing monoclonal antibodies. Anti-HER2 antibodies were raised in mice by immunizations with HER-2 in different antigen presenting formats. A large antibody repertoire consisting of approximately 150 unique anti-HER-2 antibodies was cloned from the mice using the mSymplex™ technology. Based on a thorough sequence and binding analysis, 40 antibodies were selected for functional evaluation. The 40 antibodies were tested as individual antibodies and in mixtures of two and three for the ability to inhibit the growth of four human cancer cell lines using a standard viability assay. In total, more than 1300 mixtures were evaluated for ability to inhibit growth of the four cell lines. The 20 mixtures with the highest levels of growth inhibition were further characterized with regard to potency (IC50) and ability to engage in ADCC and CDC. The results demonstrated that HER2 mixtures were superior to trastuzumab, pertuzumab and the mixture of the two at inhibiting the growth of seven of the 10 cell lines investigated. Interestingly, the mixtures also inhibited the growth of the trastuzumab resistant breast cancer cell line HCC202, reflecting the differentiated mechanisms of anti-HER2 antibody mixtures. In vivo, anti-HER2 mixtures had superior activity compared to the monoclonal anti-HER2 antibody trastuzumab in two models of human gastric cancer. Based on these results, a candidate mixture was selected and referred to as Sym005.
In conclusion, these data demonstrate that the novel antibody mixture Sym005 has a unique set of HER2 inhibitory mechanisms, which translates into superior anti-cancer activity in HER2-positive tumor xenografts. Furthermore, the results provide a clear rationale for evaluation of Sym005 in clinical trials on patients with HER2 positive tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4562. doi:10.1158/1538-7445.AM2011-4562