Showing papers on "Lapatinib published in 2007"
TL;DR: Breast tumors that express p95HER2 are resistant to trastuzumab and may require alternative or additional anti-HER2-targeting strategies, and women with HER2-overexpressing breast cancers that express this receptor should be responsive to these agents.
Abstract: Background Women with HER2-overexpressing breast cancers have poor prognosis, and many are resistant to the HER2 monoclonal antibody trastuzumab. A subgroup of HER2-overexpressing tumors also express p95HER2, an amino terminally truncated receptor that has kinase activity. Because p95HER2 cannot bind to trastuzumab but should be responsive to the HER2 tyrosine kinase inhibitor lapatinib, we compared the sensitivity of tumors expressing p95HER2 and tumors expressing the full-length HER2 receptor to these agents. Methods MCF-7 and T47D breast cancer cells were stably transfected with either full-length HER2 or p95HER2. We studied the effects of trastuzumab and lapatinib on receptor signaling, cell proliferation, and the growth of xenograft tumors. A paraffin-based immunofluorescence assay was developed to study the association between p95HER2 expression and sensitivity to trastuzumab in patients with advanced breast cancer. All statistical tests were two-sided. Results Treatment of p95HER2-expressing cells with lapatinib inhibited p95HER2 phosphorylation, reduced downstream phosphorylation of Akt and mitogen-activated protein kinases, inhibited cell growth (MCF-7p95HER2 clones, lapatinib versus control, mean growth inhibition = 57.6% versus 22.6%, difference = 35%, 95% confidence interval [Cl] = 22.5% to 47.3%; P<.001; T47Dp95HER2 clones, lapatinib versus control, mean growth inhibition = 36.8% versus 20%, difference = 16.8%, 95% Cl = 11.3% to 22.3%, P<.001), and inhibited growth of MCF-7p95HER2 xenograft tumors (lapatinib versus control, mean = 288.8 versus 435 mm 3 , difference = 146.2 mm 3 , Cl = 73.8 to 218.5 mm 3 , P =.002). By contrast, treatment with trastuzumab had no effect on any of these parameters. Of 46 patients with metastatic breast cancer who were treated with trastuzumab, only one of nine patients (11.1%) expressing p95HER2 responded to trastuzumab (with a partial response), whereas 19 of the 37 patients (51.4%) with tumors expressing full-length HER2 achieved either a complete (five patients) or a partial (14 patients) response (P=.029). Conclusions Breast tumors that express p95HER2 are resistant to trastuzumab and may require alternative or additional anti-HER2-targeting strategies.
792 citations
TL;DR: What is known about the cardiotoxicity of cancer drugs that target tyrosine kinases is summarized and basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death are highlighted.
Abstract: Cancer therapy has progressed remarkably in recent years. In no area has this been more apparent than in the development of "targeted therapies", particularly those using drugs that inhibit the activity of certain tyrosine kinases, activating mutations or amplifications of which are causal, or strongly contributory, to tumorigenesis. However, some of these therapies have been associated with toxicity to the heart. Here we summarize what is known about the cardiotoxicity of cancer drugs that target tyrosine kinases. We focus on basic mechanisms through which interruption of specific signalling pathways leads to cardiomyocyte dysfunction and/or death, and contrast this with therapeutic responses in cancer cells.
744 citations
TL;DR: The current knowledge on the preclinical and clinical evidence about the mechanism of action of trastuzumab and on the mechanisms underlying the development of resistance are summarized and their possible clinical implications are discussed.
561 citations
TL;DR: The results are consistent with the inability of trastuzumab to block the heterodimerization of HER2 and suggest that amplification of ligand-induced activation of ErbB receptors is a plausible mechanism of acquired resistance to trastzumab that should be investigated in primary mammary cancers.
Abstract: Purpose: We have investigated mechanisms of acquired resistance to the HER2 antibody trastuzumab in BT-474 human breast cancer cells. Experimental Design: BT-474 xenografts established in athymic nude mice were eliminated by trastuzumab. Continuous cell lines (HR for Herceptin resistant) were generated from tumors that recurred in the presence of continuous antibody therapy. Results: The isolated cells behaved resistant to trastuzumab in culture as well as when reinjected into nude mice. They retained HER2 gene amplification and trastuzumab binding and were exquisitely sensitive to peripheral blood mononuclear cells ex vivo in the presence of the antibody. The HR cells exhibited higher levels of phosphorylated epidermal growth factor receptor (EGFR) and EGFR/HER2 heterodimers. Phosphorylation of HER2 in HR cells was inhibited by the EGFR tyrosine kinase inhibitors erlotinib and gefitinib. Gefitinib also inhibited the basal association of p85 with phosphorylated HER3 in HR cells. Both inhibitors as well as the dual EGFR/HER2 inhibitor, lapatinib, induced apoptosis of the HR cells in culture. Growth of established HR5 xenografts was inhibited by erlotinib in vivo . In addition, the HR cells overexpressed EGFR, transforming growth factor α, heparin-binding EGF, and heregulin RNAs compared with the parental trastuzumab-sensitive cells. Conclusions: These results are consistent with the inability of trastuzumab to block the heterodimerization of HER2 and suggest that amplification of ligand-induced activation of ErbB receptors is a plausible mechanism of acquired resistance to trastuzumab that should be investigated in primary mammary cancers.
491 citations
TL;DR: 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, and pertuzumab, a humanised monoclonal antibody directed against heterodimerisation of HER2 and HER3 has entered phase II and III clinical trials.
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.
265 citations
TL;DR: Although no responses were observed, lapatinib was well tolerated, with prolonged tumor stabilization of > or = 6 months in 36% (95% CI, 21% to 54%) of assessable patients.
Abstract: Purpose Expression of erbB2 and/or epidermal growth factor receptor (EGFR) is associated with biologic aggressiveness and poor prognosis in malignant salivary gland tumors (MSGTs). This phase II study was conducted to determine the antitumor activity of lapatinib, a dual inhibitor of EGFR and erbB2 tyrosine kinase activity, in MSGTs.
225 citations
TL;DR: Through improved understanding of EGFR biology in human cancers, there is anticipation that more tumor-selective therapy approaches with diminished collateral normal tissue toxicity can be advanced, and many questions remain to be answered.
Abstract: Epidermal growth factor receptor (EGFR) signaling inhibition represents a highly promising arena for the application of molecularly targeted cancer therapies. Evolving from several decades of systematic research in cancer cell biology, a series of EGFR inhibitors from both the monoclonal antibody (mAb) and tyrosine kinase inhibitor (TKI) class have been developed and promoted into clinical application. Several EGFR inhibitors have recently gained US Food and Drug Administration approval for cancer therapy in the United States (and many other countries), including the mAbs cetuximab and panitumumab, and the small molecule TKIs gefitinib, erlotinib, and lapatinib. The rapidly expanding preclinical and clinical data contributing to these US Food and Drug Administration drug registrations validates a central role of the EGFR as an important molecular target in epithelial malignancies. In this review, we focus primarily on the biology of EGFR interactions. Through improved understanding of EGFR biology in human cancers, there is anticipation that more tumor-selective therapy approaches with diminished collateral normal tissue toxicity can be advanced. Many questions remain to be answered, particularly with regard to how best combine EGFR inhibitors with conventional cancer therapies, and how to select those patients (tumors) most likely to benefit from EGFR inhibition strategies.
214 citations
TL;DR: The data strongly support further study of lapatinib as a potential therapeutic in breast cancers that have progressed on trastuzumab and show that the dual epidermal growth factor receptor (EGFR)/human EGFR-2 (HER2) kinase inhibitor Lapatinib induces apoptosis in trastizumab-resistant cells derived from the HER2-overexpressing SKBR3 breast cancer line.
Abstract: The majority of breast cancer patients who achieve an initial therapeutic response to the HER2-targeted antibody trastuzumab will show disease progression within 1 year. Thus, the identification of novel agents that effectively inhibit survival of cancer cells that have progressed on trastuzumab is critical. In the current study, we show that the dual epidermal growth factor receptor (EGFR)/human EGFR-2 (HER2) kinase inhibitor lapatinib induces apoptosis in trastuzumab-resistant cells derived from the HER2-overexpressing SKBR3 breast cancer line. Lapatinib inhibited EGFR and HER2 signaling in resistant cells, blocking activation of downstream Akt, mitogen-activated protein kinase [corrected] Importantly, lapatinib also inhibited insulin-like growth factor I (IGF-I) signaling and growth-promoting effects in parental and resistant cells, and the cytotoxic effects of lapatinib were further enhanced by the IGF-I receptor-blocking antibody alphaIR3. As increased IGF-I receptor signaling has been implicated in trastuzumab resistance, our data strongly support further study of lapatinib as a potential therapeutic in breast cancers that have progressed on trastuzumab.
210 citations
TL;DR: The results suggest that simultaneous consideration of EGFR and HER2 expression, as well as tissue type yields the best determinant of lapatinib selectivity in cultured cells.
Abstract: . Objective: Lapatinib (Tykerb®, GW572016), a potent inhibitor of the catalytic activities of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) (ErbB2), inhibits population growth of selected EGFR and HER2 overexpressing cell lines. Previous studies with a small number of cell lines suggest a correlation between overexpression of EGFR and/or HER2 and sensitivity to growth inhibition by lapatinib; however, the precise determinants of lapatinib selectivity for tumour and/or other cells remain unclear. Materials and methods: To clarify the determinants of its selectivity in cultured cells, lapatinib-induced cell population growth inhibition and relative EGFR and HER2 protein expression were quantified in 61 different human tumour cell lines from 12 tumour types, two oncogene transformed human cell lines and two normal human cell cultures. Using statistical tools to analyse the data, a model describing the relationship between lapatinib IC50 (the response variable) and EGFR and HER2 expression and tissue type (explanatory variables) was derived. Conclusion: The results suggest that simultaneous consideration of EGFR and HER2 expression, as well as tissue type yields the best determinant of lapatinib selectivity in cultured cells.
172 citations
TL;DR: Targeting of epidermal growth factor receptor (EGFR) and HER2 is a proven anti-cancer strategy, however, heterodimerisation, compensatory 'crosstalk' and redundancy exist in the ErbB network, and there is a sound scientific rationale for dual inhibition of EGFR and Her2.
162 citations
TL;DR: L lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner, and the importance of assessing PTEN status in tumors when selecting Erb B2-targeted therapies in patients with breast cancer is emphasized.
Abstract: Trastuzumab antitumor activity in ErbB2-overexpressing breast cancers seems to be dependent upon the presence of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphatase that dampens phosphatidylinositol 3-kinase-Akt signaling. Consequently, PTEN deficiency, which occurs in 50% of breast cancers, predicts for resistance to trastuzumab monotherapy. Here, we show that lapatinib, a small-molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, exerts its antitumor activity in a PTEN-independent manner. Steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels were inhibited within 30 min following lapatinib but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of lapatinib). Whereas trastuzumab reportedly inhibits SRC phosphorylation (Y416), which in turn reduced SRC-ErbB2 protein interactions, lapatinib had no effect on either variable. To assess the potential functional role that PTEN might play in lapatinib antitumor activity, we selectively knocked down PTEN in BT474 and Au565 cells using small interfering RNA transfection. Loss of PTEN did not affect induction of tumor cell apoptosis by lapatinib in either cell line. In addition, lapatinib inhibited Akt phosphorylation in MDA-MB-468 cells, an ErbB1-expressing/ErbB2 non-overexpressing breast cancer line, despite their PTEN-null status. Moreover, patients with ErbB2-overexpressing inflammatory breast cancers responded to lapatinib monotherapy regardless of PTEN status. Thus, lapatinib seems to exert its antitumor activity in ErbB2-overexpressing breast cancers in a PTEN-independent manner. These data emphasize the importance of assessing PTEN status in tumors when selecting ErbB2-targeted therapies in patients with breast cancer.
TL;DR: The tyrosine kinase inhibitors that are currently registered for use or in an advanced stage of development are given, and the future role of TKIs in the treatment of solid tumors is discussed.
Abstract: Small molecule tyrosine kinase inhibitors (TKIs) are developed to block intracellular signaling pathways in tumor cells, leading to deregulation of key cell functions such as proliferation and differentiation. Over 25 years ago, tyrosine kinases were found to function as oncogenes in animal carcinogenesis; however, only recently TKIs were introduced as anti cancer drugs in human cancer treatment. Tyrosine kinase inhibitors have numerous good qualities. First, in many tumor types they tend to stabilize tumor progression and may create a chronic disease state which is no longer immediately life threatening. Second, side effects are minimal when compared to conventional chemotherapeutic agents. Third, synergistic effects are seen in vitro when TKIs are combined with radiotherapy and/or conventional chemotherapeutic agents. In this article, we will give an update of the tyrosine kinase inhibitors that are currently registered for use or in an advanced stage of development, and we will discuss the future role of TKIs in the treatment of solid tumors. The following TKIs are reviewed: Imatinib (Gleevec/Glivec), Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva), Lapatinib (GW-572016, Tykerb), Canertinib (CI-1033), Sunitinib (SU 11248, Sutent), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava).
TL;DR: Several targeted therapies with anti-tumour activity in human cancer cell lines and xenograft models have now been shown to produce objective responses, delay disease progression and, in some cases, improve survival of patients with advanced malignancies.
Abstract: Targeted therapies are rationally designed to interfere with specific molecular events that are important in tumour growth, progression or survival. Several targeted therapies with anti-tumour activity in human cancer cell lines and xenograft models have now been shown to produce objective responses, delay disease progression and, in some cases, improve survival of patients with advanced malignancies. These targeted therapies include cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody; gefitinib and erlotinib, EGFR-specific tyrosine kinase inhibitors; trastuzumab, an anti-human EGFR type 2 (HER2)-related monoclonal antibody; lapatinib, a dual inhibitor of both EGFR- and HER2-associated tyrosine kinases; and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody. On the basis of preclinical and clinical evidence, EGFR, HER2 and VEGF represent validated targets for cancer therapy and remain the subject of intensive investigation. Both EGFR and HER2 are targets found on cancer cells, whereas VEGF is a target that acts in the tumour microenvironment. Clinical studies are focusing on how to best incorporate targeted therapy into current treatment regimens and other studies are exploring whether different strategies for inhibiting these targets will offer greater benefit. It is clear that optimal use of targeted therapy will depend on understanding how these drugs work mechanistically, and recognising that their activities may differ across patient populations, tumour types and disease stages, as well as when and how they are used in cancer treatment. The results achieved with targeted therapies to date are promising, although they illustrate the need for additional preclinical and clinical study.
TL;DR: Within the past 2 years, four separate groups have reported marked improvement in relapse-free survival when trastuzumab was added to adjuvant chemotherapy in patients with HER2-overexpressing breast cancer, adding further credence to the relevance of this receptor as a tumor target.
Abstract: Within the past 2 years, four separate groups have reported marked improvement in relapse-free survival when trastuzumab was added to adjuvant chemotherapy in patients with HER2-overexpressing breast cancer. These results add further credence to the relevance of this receptor as a tumor target. Despite the significant benefits observed in early and advanced HER2-positive breast cancer, overexpression of the receptor is still associated with a poorer prognosis and an increased risk of disease relapse, even in patients with primary operable disease. Besides cytotoxic chemotherapy, and possibly hormonal therapy, patients whose tumors exhibit resistance to trastuzumab have few molecular-targeted options available. Recently, lapatinib, a small molecule dual inhibitor of both HER2 and EGF receptors, has been developed to expand the options for treating HER-positive breast cancer.
TL;DR: This paper reviews lapatinib-associated toxicities and provides practical management recommendations based on available data that are effective in patients with metastatic breast cancer, with inflammatory Breast cancer, and possibly, with brain metastases.
Abstract: Lapatinib is an oral receptor tyrosine kinase inhibitor, inhibiting both the ErbB-1 and ErbB-2 receptors. Lapatinib has been shown to have activity in ErbB-2-overexpressing breast cancer in several phase II and III clinical trials. Specifically, lapatinib is effective in patients with metastatic breast cancer, with inflammatory breast cancer, and possibly, with brain metastases. An ongoing clinical trial and another anticipated clinical trial will investigate lapatinib as adjuvant treatment in early-stage disease. Lapatinib has specific toxicities, the most common being diarrhea and rash. Cardiac toxicity is rarely seen with lapatinib. This paper reviews lapatinib-associated toxicities and provides practical management recommendations based on available data.
TL;DR: Targeted pathway studies of phosphorylation and gene expression changes in human breast cancer cell lines in the presence or absence of lapatinib provide insight into the mechanism of action of Lapatinib in breast cancer cells.
Abstract: Lapatinib (GW572016) is a small-molecule dual inhibitor of epidermal growth factor receptor (ErbB1) and ErbB2 receptor kinase activities currently in phase III clinical trials. We used phosphoprotein and microarray analyses to carry out targeted pathway studies of phosphorylation and gene expression changes in human breast cancer cell lines in the presence or absence of lapatinib. Studies were done in four breast cancer cell lines, two of which were responsive and two of which were nonresponsive to lapatinib. Responsive cell lines, BT474 and SKBr3, constitutively overexpress ErbB2 and show an IC(50) of 25 or 32 nmol/L for lapatinib, respectively. In contrast, nonresponsive MDA-MB-468 and T47D cells expressed a low basal level of ErbB2 and showed IC(50) values in the micromolar range. Cells responsive to lapatinib exhibited strong differential effects on multiple genes in the AKT pathway. After 12 h of exposure to 1.0 micromol/L of lapatinib, AKT1, MAPK9, HSPCA, IRAK1, and CCND1 transcripts were down-regulated 7- to 25-fold in responsive BT474 and SKBr3 cells. In contrast, lapatinib weakly down-regulated the AKT pathway in nonresponsive breast cancer cell lines (<5-fold down-regulation of most genes in the pathway). Furthermore, the proapoptotic gene FOXO3A, which is negatively regulated by AKT, was up-regulated 7- and 25-fold in lapatinib-responsive SKBr3 and BT474 cells, respectively. Phosphorylated Akt and Akt-mediated phosphorylation of FOXO3A also decreased in responsive breast cancer cell lines exposed to lapatinib. Gene expression profiling also revealed that lapatinib stimulated the expression of estrogen and progesterone receptors and modulated the expression of genes involved in cell cycle control, glycolysis, and fatty acid metabolism. In BT474 and T47D cells, which expressed moderate basal levels of the estrogen and progesterone receptors, 1.0 micromol/L of lapatinib induced expression by 7- to 11-fold. These data provide insight into the mechanism of action of lapatinib in breast cancer cells.
TL;DR: It is shown that lapatinib has meaningful clinical activity in the setting of HER2-positive advanced breast cancer patients, but its activity in epidermal growth factor receptor-dominated cancers, such as colorectal cancer or squamous cell carcinoma of the head and neck, is modest.
Abstract: Lapatinib (GW 572016) is an oral inhibitor of the tyrosine kinase activity of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2), which are both frequently altered in human malignant tumors Being a multitargeting agent, it has the theoretical ability to provide more efficient antitumor activity and delay the onset of tumor resistance Based on promising preclinical results, lapatinib is being extensively studied in cancer patients In Phase I clinical trials, the side effect profile of lapatinib results are favorable, with a few patients experiencing serious toxicity Phase II studies showed that lapatinib has meaningful clinical activity in the setting of HER2-positive advanced breast cancer patients Unfortunately, its activity in epidermal growth factor receptor-dominated cancers, such as colorectal cancer or squamous cell carcinoma of the head and neck, is modest An extensive program is now ongoing in breast cancer patients to establish the correct role of lapatinib in this clinical setting Studies in breast cancer, as well as in other solid tumors are also collecting a large amount of biological data Correlative studies will hopefully clarify predictive factors of lapatinib efficacy that can be applied in clinical practice in order to select patients for treatment
TL;DR: It is found that the bioavailability of lapatinib is greatly increased by food, especially a high-fat meal, and the officially recommended dose must match the dose used in the pivotal trial, which was five 250-mg tablets taken fasting.
Abstract: Drug labels (ie, package inserts) must be approved by national regulatory agencies (eg, US Food and Drug Administration), and are the product of a negotiation between the drug’s sponsor and the regulators. Labels are intended to provide important information for prescribers, pharmacists, and patients regarding the drug’s indication(s) and toxicities, but also include information regarding the drug’s pharmacokinetics, which may not be of interest to most prescribers. However, the label for lapatinib (approved by the US Food and Drug Administration on March 13, 2007) includes a number of pharmacokinetic details of high interest to both prescribers and patients. A most notable finding—also presented at the 2007 meeting of the American Society for Clinical Pharmacology and Therapeutics—is that the bioavailability of lapatinib is greatly increased by food, especially a high-fat meal. A randomized, crossover, food-effect study demonstrated that both peak concentration and area under the concentration–time curve were increased markedly when a single 1,500-mg dose of lapatinib was taken with food as opposed to when fasting, and was increased further by a high-fat meal. The (geometric) mean increase for the area under the concentration–time curve was 167% for low-fat meals and 325% for high-fat meals. These results are not surprising, given that food often increases a drug’s bioavailability. So why does the lapatinib package insert, including the patient information, indicate, “TYKERB should be taken at least one hour before, or at least one hour after, food”? The answer is fairly straightforward: this is how the sponsor conducted its pivotal phase III trial—the sponsor apparently did not know the result of the food effect study. Thus, the officially recommended dose must match the dose used in the pivotal trial, which was five 250-mg tablets taken fasting. The recommendation for 1,250 mg fasting is even more problematic in light of the required colabeling with capecitabine, which is administered bid (approximately 12 hours apart) with food and has its own independent dosing issues. Obviously, it would be much easier for patients to take all of their pills at one time with food, as opposed to having to deal with the complexity of taking one set of pills fasting and one set of pills with food. The economic implications of this food effect study are particularly remarkable. At the current price of $2,900 per month, a cost savings of 60% or $1,740 per month would be realized if the drug were taken with food. If one were so inclined, there are also opportunities for additional cost savings through dietary modification. The package insert notes that strong CYP3A inhibitors, including grapefruit juice, “may also increase plasma concentrations.” Thus, it is possible that one 250-mg lapatinib pill, accompanied by food and washed down with a glass of grapefruit juice, may yield plasma concentrations comparable to five 250-mg pills on an empty stomach, which would result in a total cost savings of 80% (minus the cost of the food and juice). As a separate issue, the lapatinib label also notes that dividing the daily dose results in a doubling of drug exposure, which would be another approach that may allow a reduction in the number of daily pills (and costs). There would also be potential clinical benefit to using a lower dose of lapatinib with food. Diarrhea is a major toxicity of lapatinib, and it is suggested that this effect is due to unabsorbed drug, given that its frequency is better correlated with dose than with plasma concentration. Thus, using a lower dose with food would markedly reduce the amount of unabsorbed drug, and therefore theoretically also reduce the frequency and/or severity of diarrhea. The use of a lower dose with food would also mitigate the potential risk of standard doses of lapatinib with food, which could increase the risk of toxicity. In recent years, there has been an increased enthusiasm for development of oral agents, which is based on both clinical and economic motivations. This includes both completely new agents and analogs of existing parenteral agents, such as capecitabine. The development of oral agents requires a much greater knowledge of a drug’s clinical pharmacology than with parenteral development, because of the multitude of factors that can affect bioavailability (eg, food, dose, and concomitant oral medications). Furthermore, the rapidly escalating price of medications (especially for cancer and other life-threatening diseases) has provided incentives to explore pharmacologic approaches to lower the costs of drugs. Thus, ketoconazole has been combined with cyclosporine, tacrolimus, and sirolimus to decrease the cost of transplant rejection prophylaxis. Grapefruit juice also has the potential to be used to lower drug costs by increasing oral bioavailability, due to the effects of furanocoumarins. In fact, we currently are conducting a prospective phase I trial of the combination of oral sirolimus (rapamycin) and grapefruit juice, with the intention of developing the least expensive approach possible to inhibit the mammalian target of rapamycin. Therefore, as we enter an era of targeted anticancer agents with a monthly cost measured in thousands of dollars, we should JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 25 NUMBER 23 AUGUST 1
TL;DR: Improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes are allowing us to bring patient-specific novel therapies such as lapatinib to the clinic.
TL;DR: This study was designed to characterize further the activity reported with lapatinib in an initial phase II trial in women with HER2+ disease metastatic to brain, and to define CNS response as defined by a = 50% volumetric reduction of CNS lesions in the absence of: new lesions, need for increased dose of steroids, progressive neurological signs/symptoms (NSS), or progressive extra-CNS disease.
Abstract: 1012 Background: CNS disease is a major problem among pts treated with H for stage IV HER2+ breast cancer with a reported incidence of 28–43%. This study was designed to characterize further the ac...
TL;DR: In BC, T2A amplification appears to be a good predictor of response to anthracyclines, but these data are still in the process of validation, and the significance of T1A deletions is currently under investigation.
TL;DR: This study suggests that simultaneously blocking the ErbB family of receptor tyrosine kinases and Bcl-2 family of proteins may be a benefit to breast cancer patients.
Abstract: The epidermal growth factor receptor (EGFR) (ErbB1) and HER-2/neu (ErbB2) are members of the ErbB family of receptor tyrosine kinases. These receptors are overexpressed in a variety of human tumors and overexpression generally correlates with poor prognosis and decreased survival. Lapatinib, a reversible inhibitor of both EGFR and HER-2/neu, has shown some success in achieving clinical responses in heavily pretreated advanced cancer patients. GW2974 is a reversible dual inhibitor similar to lapatinib, but GW2974 was not progressed to clinical trials due to pharmacokinetic issues. Bcl-2, an anti-apoptotic protein, is also overexpressed in a number of human tumors. Bcl-2 inhibitors induce apoptosis and sensitize cancer cells to other therapies. The purpose of this study was to assess the effects of combining ErbB and Bcl-2 inhibitors on the growth of human breast cancer cell lines. EGFR/HER-2/neu tyrosine kinase inhibitors (lapatinib and GW2974) were combined with Bcl-2 inhibitors (HA14-1 or GX15-070) and the anti-proliferative effects were determined by the MTT tetrazolium dye assay. Combinations were tested in MCF-7 human breast cancer cells, a HER-2/neu transfected MCF-7 cell line (MCF/18), and a tamoxifen-resistant MCF-7 cell line (MTR-3). A synergistic inhibitory effect was observed with the combination of inhibitors of EGFR-HER-2/neu (lapatinib or GW2974) and Bcl-2 (GX15-070 or HA14-1) on the growth of the MCF-7, MCF/18, and MTR-3 human breast cancer cell lines. This study suggests that simultaneously blocking the ErbB family of receptor tyrosine kinases and Bcl-2 family of proteins may be a benefit to breast cancer patients.
TL;DR: Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed, and clinical activity was observed in patients with previously treated, advanced solid malignancies.
Abstract: Purpose This phase I trial (EGF10005) assessed the safety, optimally tolerated regimen (OTR), and pharmacokinetics of lapatinib and capecitabine in combination in patients with advanced solid malignancies. Patients and Methods Patients with previously treated, advanced solid malignancies were eligible. Cohorts of at least three patients each received once-daily oral lapatinib (continuous) and capecitabine (twice daily for 14 days every 21 days). Doses of lapatinib and capecitabine were escalated based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. Additional patients were treated at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. Results Forty-five patients were treated in the study. The OTR was determined to be lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m2/d. The majority of drug-related adverse events were grade 1 to grade 2 in severity, with few grade 3 and no grade 4 toxicities. The most common drug-related toxicities (> 15% of ...
TL;DR: The determination of the molecular abnormalities underlying the different subtypes of salivary gland cancers might lead to more active targeted therapies and new pathways, such as vascular endothelial growth factor, might be worth targeting and clinical trials with anti-angiogenic agents are ongoing.
TL;DR: The rationale for these strategies, and the lessons that need to be learnt if they are to successfully integrate these new drugs with aromatase inhibitors in the clinic are reviewed.
TL;DR: The increasing role of molecular targeted therapies in BC is reviewed, with a particular focus on those drugs currently being tested in early BC, as well as, on future perspectives.
TL;DR: In conclusion, trastuzumab remains the gold standard in HER-2-positive breast cancer therapy, however, in trastzumab-resistant disease, new strategies and compounds are currently under evaluation.
Abstract: Therapeutic antibodies have shown great promise as targeted agents in the treatment of patients with cancer. Trastuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor-2 (HER-2), is of special importance in breast cancers overexpressing HER-2. Such rationally designed substances bind to cancer cells expressing the targeted antigen and, by various mechanisms, lead to tumor cell degradation. Only one-third of patients, however, initially respond to trastuzumab monotherapy and the majority of initial responders demonstrate disease progression within 1 year of treatment initiation. Therefore, alternative compounds targeting the HER-2 receptor or downstream signaling pathways are of great importance. Lapatinib is a tyrosine kinase inhibitor, blocking tryosine kinase domains of both epidermal growth factor receptor and HER-2. This substance holds promise for the treatment of cancer after trastuzumab failure, and might be active in cerebral metastases. Other strategies in trastuzumab-resistant disease include bispecific antibodies (which bind to HER-2 and Fc receptors, thereby directing immune cells towards the tumor), the combination of antibodies, or targeting tumor vessel growth by blocking vascular endothelial growth factor (VEGF) or VEGF receptors. Heat shock protein 90, a chaperone protein that controls the folding of HER-2, also represents a potential target. Multi-targeted kinase inhibitors such as sunitinib or sortenib are already established in renal cell cancer. These compounds are currently being evaluated in breast cancer and might represent interesting options both in HER-2-positive and -negative disease. In conclusion, trastuzumab remains the gold standard in HER-2-positive breast cancer therapy. However, in trastuzumab-resistant disease, new strategies and compounds are currently under evaluation.
TL;DR: This study assessed the response rate, time to treatment failure (TTF), overall survival (OS), toxicities and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome in patients treated with GW572016.
Abstract: 4621 Background: GW572016 is a dual tyrosine kinase inhibitor of EGFR and HER2/ErbB2. Overexpression of EGFR and ErbB2 has been described in 15 to 45% of gastric cancer, making this a potential target in advanced/metastatic tumors. Methods: The primary objective of this study was to assess the response rate (confirmed complete (CR) and partial responses (PR)). Secondary objectives included time to treatment failure (TTF), overall survival (OS), toxicities and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome in patients treated with GW572016. A two-stage design was used to detect a difference in the null hypothesis of 5% response probability and the alternative 20% response probability. If at least one response occurred after the first 20 pts, another 20 were to be accrued. GW572016 was administered to chemonaiive metastatic gastric cancer patients at a dose of 1,500 mg orally daily. A cycle was defined as 28 days of therapy, and patients were staged after 2 cycles of trea...
TL;DR: The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan.
TL;DR: Evidence is presented that lapatinib cooperates with clinically relevant cytotoxic agents and may have therapeutic utility in the management of chemotherapy-naive metastatic bladder cancer and enable reduced-dose chemotherapy, a potential toxicity-sparing strategy.