Showing papers on "Pertuzumab published in 2013"
TL;DR: The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD, and the tolerability of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer was assessed.
849 citations
TL;DR: A significant improvement in overall survival is shown with pertuzumab, trastuzumAB, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo,trastuzuab, anddocetaxe and this regimen represents a substantial improvement on the standard of care.
Abstract: Summary Background CLEOPATRA is a phase 3 study to compare the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer. The results of the primary analysis showed significantly longer median progression-free survival in the pertuzumab group than in the placebo group. Interim analysis of overall survival favoured the pertuzumab group but was not significant. Here, we report results for overall survival after an additional year of follow-up. Methods The study was a double-blind randomised trial undertaken at 204 centres in 25 countries. Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab, and docetaxel (n=402) or the same regimen with a matching placebo replacing pertuzumab (n=406). Randomisation was in a 1:1 ratio, stratified by geographical region and previous treatment status. The primary endpoint was progression-free survival (assessed independently), which has been reported previously; no follow-up data were gathered for the primary endpoint. Secondary endpoints included overall survival, progression-free survival (assessed by investigator), objective response rate, and safety. Median follow-up was 30 months in both groups. Efficacy endpoints were analysed in the intention-to-treat population and safety was analysed by treatment received. The study is completed but safety and survival data continue to be followed up. This trial is registered with ClinicalTrials.gov, number NCT00567190. Findings In the intention-to-treat population, 267 patients died by data cutoff (May 14, 2012), 154 (38%) of 406 in the placebo group and 113 (28%) of 402 in the pertuzumab group. Median overall survival was 37·6 months (95% CI 34·3–NE [not estimable]) in the placebo group but had not been reached (95% CI 42·4–NE) in the pertuzumab group (hazard ratio 0·66, 95% CI 0·52–0·84; p=0·0008). Investigator-assessed median progression-free survival was 12·4 months (95% CI 10·4–13·5) in the placebo group and 18·7 months (16·6–21·6) in the pertuzumab group (hazard ratio 0·69, 95% CI 0·58–0·81). Serious adverse events were reported in 115 (29%) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36%) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhoea, pneumonia, and cellulitis. Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity. Interpretation Our analysis shows a significant improvement in overall survival with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel. Since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients. Funding F Hoffmann-La Roche, Genentech.
826 citations
TL;DR: PIK3CAH1047R accelerates Her2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies.
Abstract: Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2+), PIK3CAH1047R-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2+/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2+/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2+/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CAH1047R accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies.
165 citations
TL;DR: Novel agents that inhibit mTOR, PI3K, the insulin-like growth factor, heat shock protein 90, and histone deacetylase have shown promise in phase I-III trials and offer exciting new possibilities for the treatment of this often fatal disease.
Abstract: For many years, the medical treatment of breast cancer was reliant solely on cytotoxic chemotherapy. However, over the past twenty years, treatment has evolved to a more target-directed approach. We now employ tailored therapy based on the presence or absence of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER2). We expect this trend to continue, as agents that use novel approaches to target HER2, as well as targeting different portions of the HER signaling pathway, are in various stages of development. Notably, pertuzumab, a humanized monoclonal antibody that binds to a different domain of the extracellular portion of the HER2 receptor than trastuzumab, was recently approved for use, as was lapatinib, a small-molecule tyrosine kinase inhibitor. Patients with triple negative breast cancer, particularly those with the BRCA mutation, have more limited treatment options and carry a worse prognosis than those who are hormone receptor positive. However, recent data has shown that PARP inhibitors may have significant anti-tumor effect in those with this subtype of breast cancer. Novel agents that inhibit mTOR, PI3K, the insulin-like growth factor, heat shock protein 90, and histone deacetylase have shown promise in phase I-III trials and offer exciting new possibilities for the treatment of this often fatal disease. As we are presented with an ever increasing number of treatment options, the timing and combinations of therapeutic agents used becomes ever more complex in the age of personalized care, but we are hopeful that ultimately this will lead to improved patient outcomes.
151 citations
TL;DR: The combination of pertuzumab plus trastuzumAB plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC, and the majority of heart adverse events were reversible.
Abstract: INTRODUCTION We report cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel observed in the phase III study CLEOPATRA in patients with HER2-positive first-line metastatic breast cancer (MBC). PATIENTS AND METHODS Left ventricular ejection fraction (LVEF) ≥ 50% and ECOG performance status of 0 or 1 were required for study entry. During the study, LVEF assessments took place every 9 weeks. Pertuzumab/placebo was given at 840 mg, then 420 mg q3w; trastuzumab was administered at 8 mg/kg, then 6 mg/kg q3w, and docetaxel was initiated at 75 mg/m(2) q3w. RESULTS The incidence of cardiac adverse events (all grades) was 16.4% in the placebo arm and 14.5% in the pertuzumab arm, with left ventricular systolic dysfunction (LVSD, all grades) being the most frequently reported event (8.3% versus 4.4% in the placebo and pertuzumab arm). Declines in LVEF by ≥ 10% points from baseline and to <50% were reported in 6.6% and 3.8% of patients in the placebo and pertuzumab arm, respectively. Seventy-two percent (placebo arm) and 86.7% (pertuzumab arm) of those patients recovered to a value ≥ 50%. The incidence of symptomatic LVSD was low, occurring in 1.8% (n = 7) versus 1.0% (n = 4) of patients in the placebo and pertuzumab arm. In 8/11 patients, the symptomatic LVSD had resolved at data cutoff. CONCLUSION The combination of pertuzumab plus trastuzumab plus docetaxel did not increase the incidence of cardiac adverse events, including LVSD, compared with the control arm in HER2-positive MBC. The majority of cardiac adverse events were reversible.
138 citations
TL;DR: The pertuzumab and trastuzumsumab anti-HER2 dual blockade is likely to represent a substantial advance for patients with HER2-positive BCs and a new milestone on the way to personalized medicine.
137 citations
TL;DR: A novel HER3 monoclonal antibody that can neutralize multiple modes of HER3 activation is described, making it a superior candidate for clinical translation as a therapeutic candidate and establishing that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.
Abstract: HER2/HER3 dimerization resulting from overexpression of HER2 or neuregulin (NRG1) in cancer leads to HER3-mediated oncogenic activation of phosphoinositide 3-kinase (PI3K) signaling. Although ligand-blocking HER3 antibodies inhibit NRG1-driven tumor growth, they are ineffective against HER2-driven tumor growth because HER2 activates HER3 in a ligand-independent manner. In this study, we describe a novel HER3 monoclonal antibody (LJM716) that can neutralize multiple modes of HER3 activation, making it a superior candidate for clinical translation as a therapeutic candidate. LJM716 was a potent inhibitor of HER3/AKT phosphorylation and proliferation in HER2-amplified and NRG1-expressing cancer cells, and it displayed single-agent efficacy in tumor xenograft models. Combining LJM716 with agents that target HER2 or EGFR produced synergistic antitumor activity in vitro and in vivo. In particular, combining LJM716 with trastuzumab produced a more potent inhibition of signaling and cell proliferation than trastuzumab/pertuzumab combinations with similar activity in vivo. To elucidate its mechanism of action, we solved the structure of LJM716 bound to HER3, finding that LJM716 bound to an epitope, within domains 2 and 4, that traps HER3 in an inactive conformation. Taken together, our findings establish that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.
118 citations
TL;DR: The efficacy of HER2-directed therapies, focussing on monoclonal antibodies and tyrosine kinase inhibitors targeting HER2 that have been tested in phase II-III studies in MBC, is reviewed.
101 citations
TL;DR: Results of the pivotal phase III study CLEOPATRA in patients with HER2-positive metastatic breast cancer demonstrated that the addition of pertuzumab to first-line combination therapy with docetaxel and trastuzumAB significantly prolonged progression-free and overall survival without increasing cardiac toxicity.
Abstract: g Praxis fur Interdisziplinare Onkologie und Hamatologie, Freiburg i.Br., h Westdeutsche Studiengruppe GmbH, Brustzentrum Niederrhein, Evangelisches Krankenhaus Bethesda, Monchengladbach, i Gynakologisch-Onkologische Schwerpunktpraxis, Hannover, j Gynakologisch-Onkologische Schwerpunktpraxis, Furstenwalde, k Summary The humanized monoclonal antibody pertuzumab prevents the dimerization of HER2 with other HER receptors, in par- ticular the pairing of the most potent signaling heterodimer HER2/HER3, thus providing a potent strategy for dual HER2 inhibition. It binds to the extracellular domain of HER2 at a different epitope than trastuzumab. Pertuzumab and trastu- zumab act in a complementary fashion and provide a more complete blockade of HER2-mediated signal transduction than either agent alone. Phase II studies demonstrated that pertuzumab was generally well tolerated as a single agent or in combination with trastuzumab and/or cytotoxic agents, and implied an improved clinical efficacy of the combina- tion of pertuzumab and trastuzumab in early and advanced HER2-positive breast cancer. Results of the pivotal phase III study CLEOPATRA in patients with HER2-positive metastatic breast cancer demonstrated that the addition of pertuzumab to first-line combination therapy with docetaxel and trastu- zumab significantly prolonged progression-free and overall survival without increasing cardiac toxicity. Currently, the combination of both antibodies is being explored in the palliative setting as well as in the treatment of early HER2- positive breast cancer. Dual HER2 inhibition with the HER2 dimerization inhibitor pertuzumab and trastuzumab may change clinical practice in HER2-positive first-line metastatic breast cancer treatment.
101 citations
TL;DR: On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns and limited its approval to lots not affected by manufacturing problems.
Abstract: On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P 30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues.
98 citations
TL;DR: The combination of strong signaling inhibition and enhanced ADCC capability rendered RG7116 a highly potent HER3-targeting agent suitable for clinical development.
Abstract: The EGF receptor (EGFR) HER3 is emerging as an attractive cancer therapeutic target due to its central position in the HER receptor signaling network. HER3 amplifies phosphoinositide 3-kinase (PI3K)-driven tumorigenesis and its upregulation in response to other anti-HER therapies has been implicated in resistance to them. Here, we report the development and characterization of RG7116, a novel anti-HER3 monoclonal antibody (mAb) designed to block HER3 activation, downregulate HER3, and mediate enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via glycoengineering of the Fc moiety. Biochemical studies and X-ray crystallography revealed that RG7116 bound potently and selectively to domain 1 of human HER3. Heregulin binding was prevented by RG7116 at concentrations more than 1 nmol/L as was nearly complete inhibition of HER3 heterodimerization and phosphorylation, thereby preventing downstream AKT phosphorylation. In vivo RG7116 treatment inhibited xenograft tumor growth up to 90% relative to controls in a manner accompanied by downregulation of cell surface HER3. RG7116 efficacy was further enhanced in combination with anti-EGFR (RG7160) or anti-HER2 (pertuzumab) mAbs. Furthermore, the ADCC potency of RG7116 was enhanced compared with the nonglycoengineered parental antibody, both in vitro and in orthotopic tumor xenograft models, where an increased median survival was documented. ADCC degree achieved in vitro correlated with HER3 expression levels on tumor cells. In summary, the combination of strong signaling inhibition and enhanced ADCC capability rendered RG7116 a highly potent HER3-targeting agent suitable for clinical development.
TL;DR: The clinical outcome of some of these new therapies, including bevacizumab and olaparib, which have been designated as promising targeted therapies for ovarian cancer, are discussed.
TL;DR: Therapeutic inhibitors of HER3 should be considered as part of multidrug combinations aimed at completely and rapidly disabling the HER2 network in HER2-overexpressing breast cancers.
Abstract: Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or with pertuzumab is a superior treatment approach compared with single-agent HER2 inhibitors. However, many HER2-overexpressing breast cancers still escape from this combinatorial approach. Inhibition of HER2 and downstream phosphoinositide 3-kinase (PI3K)/AKT causes a transcriptional and posttranslational upregulation of HER3 which, in turn, counteracts the antitumor action of the HER2-directed therapies. We hypothesized that suppression of HER3 would synergize with dual blockade of HER2 in breast cancer cells sensitive and refractory to HER2 antagonists. Experimental Design: Inhibition of HER2/HER3 in HER2 + breast cancer cell lines was evaluated by Western blotting. We analyzed drug-induced apoptosis and two- and three-dimensional growth in vitro . Growth inhibition of PI3K was examined in vivo in xenografts treated with combinations of trastuzumab, lapatinib, and the HER3-neutralizing monoclonal antibody U3-1287. Results: Treatment with U3-1287 blocked the upregulation of total and phosphorylated HER3 that followed treatment with lapatinib and trastuzumab and, in turn, enhanced the antitumor action of the combination against trastuzumab-sensitive and -resistant cells. Mice bearing HER2 + xenografts treated with lapatinib, trastuzumab, and U3-1287 exhibited fewer recurrences and better survival than mice treated with lapatinib and trastuzumab. Conclusions: Dual blockade of HER2 with trastuzumab and lapatinib does not eliminate the compensatory upregulation of HER3. Therapeutic inhibitors of HER3 should be considered as part of multidrug combinations aimed at completely and rapidly disabling the HER2 network in HER2-overexpressing breast cancers. Clin Cancer Res; 19(3); 610–9. ©2012 AACR .
TL;DR: Neoadjuvant clinical trial data in HER2-positive breast cancer is systematically reviewed and key unanswered clinical questions are discussed, including which, if any, chemotherapy backbone should be used, and which patients need dual HER2 blockade.
TL;DR: Cardiac dysfunction rate of the novel HER2-targeted therapies is significantly lower than the trastuzumab and combination of these agents with trastzumab did not significantly increase the cardiac adverse events.
Abstract: Background:Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab.Scope:Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; ‘trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and ...
TL;DR: Pertuzumab is a novel anti‐HER2 monoclonal antibody, which blocks HER2 dimerization with other ligand‐activated HER family members, which exerts only minor complement‐mediated cytotoxicity (CDC).
TL;DR: The addition of pertuzumab to carboplatin-based chemotherapy did not substantially prolong PFS in unselected patients with platinum-sensitive, recurrent advanced ovarian cancer.
TL;DR: In the years to come, the authors anticipate an increase in the number of neoadjuvant trials testing novel therapies that hopefully will open a new path in bringing efficacious new therapies to patients with breast cancer.
Abstract: The traditional drug development process in breast cancer based on large phase III studies has serious limitations and needs a major overhaul. Searching for new approaches, the testing of novel agents in the preoperative (neoadjuvant) setting approach offers a potentially rapid and efficient strategy for drug development utilizing pathologic complete response (path CR), a surrogate marker for survival, as the primary endpoint. In addition, neoadjuvant studies allow the assessment of drug effects on the target (pharmacodynamic response) and the development of predictive biomarkers of response. Molecular profiling of the residual tumor in the surgical specimen may also provide insights into actionable mechanisms of resistance. Recognizing the potential of neoadjuvant trials for drug development, the U.S. Food and Drug Administration (FDA) recently announced consideration of neoadjuvant trials for accelerated drug approval in early breast cancer, particularly for tumors with high risk of recurrence and unfavorable prognosis, and provided accelerated approval to neoadjuvant pertuzumab in September 2013. The FDA has emphasized that while improvement in path CR could be utilized for "accelerated" approval, improvement in survival will still need to be demonstrated for "regular" approval. Key considerations in conduct of such neoadjuvant drug development trials include (i) study design such as utilization of biomarker stratified design to evaluate a biomarker that could enrich response, (ii) definition of path CR, (iii) distribution of factors that influence path CR between the treatment arms, (iv) prespecified plan for follow-up to obtain data on survival, and (v) safety as it involves a patient population with curable disease. In the years to come, we anticipate an increase in the number of neoadjuvant trials testing novel therapies that hopefully will open a new path in bringing efficacious new therapies to patients with breast cancer.
TL;DR: Neoadjuvant trials offer the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials, and the issue of acquired resistance and pretreatments, which may distort treatment efficacy, can be avoided.
Abstract: Traditionally, neoadjuvant treatment for breast cancer was preserved for locally advanced and inflammatory disease, converting an inoperable to a surgical resectable cancer. In recent years, neoadjuvant therapy has become an accepted treatment option also for lower tumor stages in order to increase the rate of breast conserving therapy and to reduce the extent of surgery. Furthermore, treatment response can be monitored, and therefore, patient compliance may be increased. Neoadjuvant trials, additionally, offer the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials. Compared to the metastatic setting, the issue of acquired resistance and pretreatments, which may distort treatment efficacy, can be avoided. New trial designs like window-of-opportunity trials or postneoadjuvant trials provide the chance to identify tumor sensitivity or to overcome tumor resistance in early tumor stages. In particular, in HER2-positive breast cancer, the neoadjuvant approach yielded great successes. The dual HER2 blockade with trastuzumab and pertuzumab recently showed the highest pCR rates ever reported. Many new drugs are in clinical testing with the aim to further increase pCR rates. Whether this endpoint really represents a surrogate for long-term outcome is not answered yet and will be discussed in this review.
TL;DR: The development of a bispecific anti-ErbB2 antibody that retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule warrants its consideration as a promising treatment in the clinic.
Abstract: The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic.
TL;DR: Pertuzumab is a recombinant humanized monoclonal antibody that binds to the extracellular dimerization domain II of HER2 and inhibits heterodimerization of Her2 with other HER family members, including EGF receptor (EGFR), HER3, and HER4.
Abstract: Pertuzumab has been approved by the U.S. Food and Drug Administration for use in combination with trastuzumab and docetaxel for the first-line treatment of patients with advanced HER2-positive (HER2(+)) breast cancer. Pertuzumab is a recombinant humanized monoclonal antibody that binds to the extracellular dimerization domain II of HER2 and inhibits heterodimerization of HER2 with other HER family members, including EGF receptor (EGFR), HER3, and HER4. The HER2-HER3 heterodimer is a robust activator of phosphoinositide 3-kinase (PI3K) pathway signaling and functions as the most transforming and mitogenic of the receptor complexes formed by the HER family of proteins; thus, blockade of HER2-HER3 likely represents the most relevant action of pertuzumab. In the seminal phase III study, patients with HER2(+) metastatic breast cancer were randomized to receive trastuzumab and docetaxel, with or without pertuzumab: Addition of pertuzumab significantly prolonged progression-free survival with an increase of 6.1 months (12.4 vs. 18.5 months, respectively). In a subsequent analysis with 30 months of median follow-up, pertuzumab conferred a 34% reduction in the risk of mortality. Here, we review the mechanism of action of pertuzumab, the rationale for combining it with trastuzumab/pertuzumab, clinical data, and future directions for this work.
TL;DR: Combining pertuzumAB with trastuzumab and docetaxel had no adverse impact on HRQoL and may prolong time to worsening of breast cancer-specific symptoms.
TL;DR: New families of targeted drugs, including tyrosine kinase inhibitors (TKIs) such as lapatinib and PF-00299804, mammalian target of rapamycin (mTOR) pathway inhibitors such as everolimus, and antibody-chemotherapy conjugates such as trastuzumab-emtansine (T-DM1), could offer alternative second-line treatments whentrastuzuab-based first-line therapy fails.
Abstract: The prognostic value of human epidermal growth factor receptor 2 (HER2) in gastric cancer is controversial. Consensus guidelines have standardized the testing of HER2 status in gastric cancer. Overexpression of this receptor occurs in approximately 20% of gastric and gastro-esophageal junction adenocarcinomas, predominantly those of the intestinal type. Recently, trastuzumab has emerged as the first targeted drug to improve overall survival when combined with chemotherapy in advanced HER2-positive gastric cancer. Primary and secondary resistance to trastuzumab has become a major problem and new strategies to overcome this resistance are needed. A high percentage of advanced HER2-positive gastric cancer patients who progress on trastuzumab therapy are candidates for second-line therapy. New families of targeted drugs, including tyrosine kinase inhibitors (TKIs) such as lapatinib and PF-00299804, mammalian target of rapamycin (mTOR) pathway inhibitors such as everolimus, heat-shock protein 90 (HSP90) inhibitors such as AUY922, HER dimerization inhibitors such as pertuzumab, and antibody-chemotherapy conjugates such as trastuzumab-emtansine (T-DM1), could offer alternative second-line treatments when trastuzumab-based first-line therapy fails.
Journal Article•
TL;DR: Clinical data informing the effective management of Her2-positive MBC is reviewed, including identification of the optimal sequence of HER2-targeted agents and the best drug combinations to use, as well as the recognition of primary and acquired drug resistance.
Abstract: Human epidermal growth factor receptor 2 (HER2) overexpression drives the biology of 20% of breast cancers, and predicts a poor prognosis for patients. HER2-targeted therapies significantly improve outcomes for HER2-positive patients with both early and metastatic breast cancer. Currently three HER2-targeted agents, trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta), are available for the treatment of HER2-positive metastatic breast cancer (MBC). Numerous studies have attempted to optimize their use by combining them with each other, or with endocrine and cytotoxic therapies. Most recently, the FDA approved the combination of trastuzumab, pertuzumab, and docetaxel as first-line treatment for MBC, and in late February 2013 approved a fourth HER2-targeted agent, trastuzumab emtansine (T-DM1, Kadcyla), for accelerated approval. These advances create a number of clinical dilemmas, including identification of the optimal sequence of HER2-targeted agents and the best drug combinations to use, as well as the recognition of primary and acquired drug resistance. In this article, we review clinical data informing the effective management of HER2-positive MBC.
TL;DR: Results from pre-defined subgroup analyses conducted by age group from a randomized, double-blind, placebo-controlled phase III trial in patients with HER2-positive metastatic breast cancer suggest that the combined use of pertuzumab, trastuzumAB, and docetaxel should not be limited by patient age.
Abstract: Although the incidence of cancer increases with age, older patients are under-represented in cancer treatment trials, resulting in limited data availability in this patient population. Here we present results from pre-defined subgroup analyses conducted by age group (<65 vs ≥65 years) from a randomized, double-blind, placebo-controlled phase III trial in patients with HER2-positive metastatic breast cancer. Patients who had not received previous chemotherapy or biological therapy for HER2-positive locally recurrent, unresectable or metastatic breast cancer were randomly assigned to treatment with placebo, trastuzumab, and docetaxel or with pertuzumab, trastuzumab, and docetaxel. Primary endpoint was independently assessed progression-free survival. We performed pre-specified subgroup analyses of progression-free survival according to age. The study is registered with ClinicalTrials.gov, NCT00567190. 808 patients were enrolled. Of those, 127 patients were 65 years of age or older (placebo arm: 67, pertuzumab arm: 60). Patients in both age groups experienced progression-free survival benefit with treatment in the pertuzumab arm (<65 years: HR: 0.65; 95 % CI 0.53–0.80; ≥65 years: HR: 0.52; 95 % CI 0.31–0.86). Diarrhoea, fatigue, asthenia, decreased appetite, vomiting, and dysgeusia were reported more frequently in patients 65 years of age or older compared with younger patients. Neutropenia and febrile neutropenia were reported less frequently in the older age group. The efficacy and safety data reported in CLEOPATRA suggest that the combined use of pertuzumab, trastuzumab, and docetaxel should not be limited by patient age.
TL;DR: Petzumab and trastuzumab admixture in a single i.v. bag is physically and chemically stable for up to 24 h at 5°C or 30°C and can be used for clinical administration.
TL;DR: A number of investigational agents that target HER2 and other members of that receptor family are in clinical development for patients with HER2-positive MBC whose disease has progressed on trastuzumab.
TL;DR: Although the war on cancer has not yet been won, neither has it been lost, with continued basic and clinical research, cancer is being transformed into a chronic disease in which patients have increased survival rates and better quality of life.
Abstract: Of all the diseases affecting humankind, cancer is one of the most difficult to treat and cure. One of the main reasons for this difficulty relates to the fact that cancer is not a single disease but consists of hundreds of different types. Furthermore, cancers exhibit considerable genetic complexity with more than 400 different genes implicated in their development. In addition, cancers display major inter- and intratumor heterogeneity. Despite these complexities, several successes have been achieved in recent years. Most of these successes relate to the specific targeting of driver genes involved in cancer development. These successes include imatinib for the treatment of chronic myeloid leukemia, anti-HER2 therapies (trastuzumab, pertuzumab, and lapatinib) to treat breast cancer, anti-EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) to treat non-small cell lung cancer, and anti-BRAF agents (vemurafenib and dabrafenib) to treat melanoma. Although the war on cancer has not yet been won, neither has it been lost. With continued basic and clinical research, cancer is being transformed into a chronic disease in which patients have increased survival rates and better quality of life.
TL;DR: A meta‐analysis of randomized trials provides evidence supporting comparable cardiac toxicity between anti‐HER2 combination therapy and anti‐ HER2 monotherapy.
Abstract: Although dual HER2 blockade shows promising results in patients with HER2-positive breast cancer it is unclear whether this treatment strategy increases the risk for cardiac adverse events. We conducted a meta-analysis of randomized trials to investigate the risk of cardiac adverse events when a combination of anti-HER2 therapies compared to anti-HER2 monotherapy. We searched Medline, the Cochrane library, as well as the electronic abstract databases of the major international congresses' proceedings to identify randomized trials that evaluated the administration of anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) versus anti-HER2 combination (pertuzumab plus trastuzumab or trastuzumab plus lapatinib) therapy in breast cancer. The trials were considered eligible if the only systematic difference between the study arms was the type of anti-HER2 therapy used. Study outcomes were the congestive heart failure (CHF) grade ≥3 and left ventricular ejection fraction (LVEF) decline <50% or more than 10% from baseline. Six trials were considered eligible. Overall incidence results for CHF in the combined anti-HER2 therapy and the anti-HER2 monotherapy were 0.88% (95% CI: 0.47-1.64%) and 1.49% (95% CI: 0.98-2.23%). The incidence of LVEF decline was 3.1% (95% CI: 2.2-4.4%) and 2.9% (95% CI: 2.1-4.1%), respectively. The OR of CHF between anti-HER2 combination and monotherapy was 0.58 (95% CI: 0.26-1.27, p-value= 0.17) while the OR of LVEF decline was 0.88 (95% CI: 0.53-1.48, p-value= 0.64). This meta-analysis provides evidence supporting comparable cardiac toxicity between anti-HER2 combination therapy and anti-HER2 monotherapy.
TL;DR: A mini-review of the role of human epidermal growth factor receptor 2 (HER2) in clinical management of advanced gastric cancer providing higher survival and quality of life and some issues are discussed.
Abstract: Gastric cancer usually is diagnosed in advanced stages and thus current medical practice affords limited therapeutic options. However, recent studies established the role of human epidermal growth factor receptor 2 (HER2) in clinical management. Trastuzumab, an anti-HER2 monoclonal antibody, acquired a main role in advanced gastric cancer harboring HER2 overexpression and/or amplification improving survival to 17.1 mo according to trastuzumab for gastric cancer phase III trial results. Also, new promising drugs, such as c-Met inhibitors, are in development and assessment for this setting. Certainly, novel drugs will emerge in the next feel years for help oncologists improve clinical management of advanced gastric cancer providing higher survival and quality of life. In this mini-review we will discuss some issues in this regard and provide an actual overview of this setting.