Showing papers on "Lapatinib published in 2005"

Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

Abstract: Background We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. Methods The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclit...

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer

Abstract: background Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. methods This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. results Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. conclusions One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (clinicaltrials.gov number, NCT 00045032.)

Role of Tyrosine Kinase Inhibitors in Cancer Therapy

Abstract: Cancer chemotherapy has been one of the major medical advances in the last few decades. However, the drugs used for this therapy have a narrow therapeutic index, and often the responses produced are only just palliative as well as unpredictable. In contrast, targeted therapy that has been introduced in recent years is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. Tyrosine kinases are an especially important target because they play an important role in the modulation of growth factor signaling. This review focuses on small molecule inhibitors of tyrosine kinase. They compete with the ATP binding site of the catalytic domain of several oncogenic tyrosine kinases. They are orally active, small molecules that have a favorable safety profile and can be easily combined with other forms of chemotherapy or radiation therapy. Several tyrosine kinase inhibitors (TKIs) have been found to have effective antitumor activity and have been approved or are in clinical trials. The inhibitors discussed in this manuscript are imatinib mesylate (STI571; Gleevec), gefitinib (Iressa), erlotinib (OSI-1774; Tarceva), lapatinib (GW-572016), canertinib (CI-1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), sutent (SU11248), and leflunomide (SU101). TKIs are thus an important new class of targeted therapy that interfere with specific cell signaling pathways and thus allow target-specific therapy for selected malignancies. The pharmacological properties and anticancer activities of these inhibitors are discussed in this review. Use of these targeted therapies is not without limitations such as the development of resistance and the lack of tumor response in the general population. The availability of newer inhibitors and improved patient selection will help overcome these problems in the future.

Phase I Safety, Pharmacokinetics, and Clinical Activity Study of Lapatinib (GW572016), a Reversible Dual Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinases, in Heavily Pretreated Patients With Metastatic Carcinomas

Abstract: Purpose This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors.

Study of the Biologic Effects of Lapatinib, a Reversible Inhibitor of ErbB1 and ErbB2 Tyrosine Kinases, on Tumor Growth and Survival Pathways in Patients With Advanced Malignancies

Abstract: Purpose This was a pilot study to assess the biologic effects of lapatinib on various tumor growth/survival pathways in patients with advanced ErbB1 and/or ErbB2-overexpressing solid malignancies. Patients and Methods Heavily pretreated patients with metastatic cancers overexpressing ErbB2 and/or expressing ErbB1 were randomly assigned to one of five dose cohorts of lapatinib (GW572016) administered orally once daily continuously. The biologic effects of lapatinib on tumor growth and survival pathways were assessed in tumor biopsies obtained before and after 21 days of therapy. Clinical response was determined at 8 weeks. Results Sequential tumor biopsies from 33 patients were examined. Partial responses occurred in four patients with breast cancer, and disease stabilization occurred in 11 others with various malignancies.Respondersexhibitedvariablelevelsof inhibitionof p-ErbB1, p-ErbB2, p-Erk1/2, p-Akt, cyclin D1, and transforming growth factor alpha. Even some nonresponders demonstrated varying degrees of biomarker inhibition. Increased tumor cell apoptosis (TUNEL) occurred in patients with evidence of tumor regression but not in nonresponders (progressive disease). Clinical response was associated with a pretreatment TUNEL score 0 and increased pretreatment expression of ErbB2, p-ErbB2, Erk1/2, p-Erk1/2, insulin-like growth factorreceptor-1,p70S6kinase,andtransforminggrowthfactoralphacomparedwithnonresponders. Conclusion Lapatinib exhibited preliminary evidence of biologic and clinical activity in ErbB1 and/or ErbB2overexpressing tumors. However, the limited sample size of this study and the variability of the biologic endpoints suggest that further work is needed to prioritize biomarkers for disease-directed studies, and underscores the need for improved trial design strategies in early clinical studies of targeted agents.

Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells

Abstract: Antibodies and small molecule tyrosine kinase inhibitors targeting ErbB2 exhibit distinct, noncross resistant mechanisms of action. Here, apoptosis of ErbB2-overexpressing breast cancer cells was enhanced by combining lapatinib, an inhibitor of ErbB1 and ErbB2 tyrosine kinases, with anti-ErbB2 antibodies, including (i) trastuzumab, a humanized monoclonal antibody, and (ii) pAb, rabbit polyclonal antisera generated by vaccination with a human ErbB2 fusion protein. Treating ErbB2-overexpressing breast cancer cell lines with a relatively low concentration of lapatinib alone resulted in a minimal increase in tumor cell apoptosis with an associated decrease in steady-state protein levels of p-ErbB2, p-Akt, p-Erk1/2, and notably survivin, compared to baseline. Exposure to pAb alone reduced total ErbB2 protein, disrupting ErbB3 transactivation, leading to a marked inhibition of p-Akt; however, survivin protein levels remained unchanged and apoptosis only increased slightly. Treatment with trastuzumab alone had relatively little effect on survivin and apoptosis was unaffected. Combining lapatinib with either pAb or trastuzumab markedly downregulated survivin protein and enhanced tumor cell apoptosis. The association between the inhibition of survivin and enhanced apoptosis following the combination of ErbB2-targeted therapies provides a biological effect in order to identify therapeutic strategies that promote tumor cell apoptosis and might improve clinical response.

The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer

Abstract: cis-Diaminedichloroplatinum (II) (cisplatin) is routinely used to treat various types of cancers; however, a significant number develop resistance. One of the underlying factors that contribute to cisplatin resistance is the elevated level of BCL-2 and/or BCL-XL, which promotes cell survival. A potential method of overcoming such resistance is to use a potentiator that is capable of neutralizing the antiapoptotic effects of BCL-2/BCL-XL, such as Siva-1. We previously cloned the proapoptotic protein Siva-1 and showed a possible role for it in both extrinsic and intrinsic apoptosis. Using an adenovirus-based expression system, we now show that Siva-1 can synergize with cisplatin in inducing apoptosis in MCF7 and MDA-MB-231 breast cancer cells. In an anchorage-independent clonogenicity assay, MCF7/caspase-3 cells stably expressing Siva-1, but not the control cells, showed a dramatic decrease in the number of colonies formed on one-time cisplatin treatment. Further, we show that the unique putative amphipathic helical region (SAH) in Siva-1 (amino acid residues 36-55) is necessary and sufficient for the observed enhancement in cisplatin-induced apoptosis by Siva-1. Although cisplatin treatment results in significant elevation in the expression of Fas ligand and intracellular p21 levels, expression of Siva-1 has no additional benefit. Instead, the enhancement in apoptosis seems to be due to activation of intrinsic pathway that involves caspase-9 activation. Moreover, Siva-1 augments cisplatin-mediated cell death in MCF7 cells stably expressing BCL-2. We therefore propose that Siva-1 or its SAH region can be used as a potentiator of cisplatin-based chemotherapy.

Inhibition of HER-2/neu Kinase Impairs Androgen Receptor Recruitment to the Androgen Responsive Enhancer

Abstract: Advanced prostate cancer invariably recurs despite androgen deprivation therapy. The androgen receptor (AR) likely plays a key role in this progression and in the continued survival and proliferation of prostate cancer cells in the low androgen environment. Cross-talk with growth factor receptors, such as epidermal growth factor receptor (EGFR) family, has been postulated as a potential mechanism to activate AR in recurrent prostate cancer. We have investigated the role of HER-2/neu (ErbB-2) tyrosine kinase in AR function by characterizing the effect of inhibiting endogenous HER-2 activity in LNCaP cells. We used two independent methods, expression of intracellular single-chain antibody against HER-2 and treatment with a novel dual EGFR/HER-2 kinase inhibitor GW572016 (lapatinib). Expression of intracellular HER-2 antibody scFv-5R and treatment with GW572016 inhibited HER-2 signaling. This HER-2 inhibition led to impairment of AR-mediated functions, such as androgen-stimulated growth and the induction of endogenous prostate-specific antigen (PSA) mRNA and protein. Androgen-stimulated recruitment of AR and histone acetylation at the androgen responsive enhancer of the PSA gene, detected by chromatin immunoprecipitation analysis, were impaired by HER-2 inhibition. GW572016 was more potent in its ability to inhibit PSA expression and AR recruitment and histone acetylation than the EGFR-selective kinase inhibitor ZD1839 (gefitinib), consistent with the HER-2 kinase playing the major role in AR regulation. These results show that HER-2 signaling is required for optimal transcriptional activity of AR in prostate cancer cells and suggest that HER-2 inhibition may provide a novel strategy to disrupt AR function in prostate cancer.

A phase II, randomized trial using the small molecule tyrosine kinase inhibitor lapatinib as a first-line treatment in patients with FISH positive advanced or metastatic breast cancer

Abstract: 3046 Background: Phase I and II studies of lapatinib, an oral small molecule inhibitor of both ErbB1 (EGFR) and ErbB2 (Her-2/neu) kinase activity, suggested activity in metastatic breast cancer in ...

Small molecules with EGFR-TK inhibitor activity.

Abstract: Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic. In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.

Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab refractory metastatic breast cancer

Abstract: 3004 Background: Lapatinib is an oral tyrosine kinase inhibitor that potently inhibits both ErbB1 and ErbB2 tyrosine kinase activity. Results of two Phase II trials in metastatic breast cancer (MBC) suggest activity of lapatinib in trastuzumab (T) pretreated patients. The main objective of this report was a combined biomarker analysis from these two large studies to evaluate correlations between clinical parameters, tissue/serum biomarker expression and response to lapatinib. Methods: Eligible patients had MBC with disease progression following T-containing regimens in the 1st phase II study and were anthracycline, taxane, capecitabine and T exposed in the 2nd phase II study. Tumor tissues were obtained on each patient from the time of most recent biopsy. Using standard IHC techniques, tumors were stained for: ErbB1-4, IGF1R, truncated ErbB2 (p95), heregulin and p-Erk 1/2. Sequential quanitation of extra-cellular domain (ECD) for both ErbB1 and ErbB2 were obtained. Results: Investigator reported efficacy ...

A single arm, multicenter, open label, phase II study of lapatinib as 2L treatment of pts with locally advanced/metastatic transitional cell carcinoma (TCC) of the urothelial tract

Abstract: 4594 Background: Lapatinib is an oral reversible inhibitor of ErbB1 (EGFR) and ErbB2 (HER-2/neu) receptor tyrosine kinases. Methods: The primary endpoint was RECIST response rate. Key eligibility criteria included stage IIIB/IV TCC of the bladder, progression following a first-line platinum regimen, expression of ErbB1 and or ErbB2 (1, 2 or 3+ by IHC) and KPS ≥ 70. Lapatinib (1250 mg, qd) was administered until disease progression or unacceptable toxicity. Tumor and safety assessments were performed every 8 and 4 wks, respectively. Cardiac function was monitored at baseline and every 8 wks. Tumor tissue was analyzed for biomarkers (TUNEL, p53, pAkt, Her3, pHer3, pErk, IGF-1R, Rb, pS6). Results: Fifty-nine pts were enrolled. Investigators reported 2 (3%) PRs and 12 (20%) SD; independent radiologic review (IRR) reported 1 (2%) PR and 18 (31%) SD. Based upon investigator and IRR, six and three pts had durable SD lasting 4 and 6 mos, respectively. At wk 8, 10 pts had some degree of cytoreduction; however, mos...

A phase I, open-label study of lapatinib (GW572016) plus trastuzumab; a clinically active regimen

Abstract: 559 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases leading to cell growth arrest and/or apoptosis in ErbB1 and ErbB2 dependent tumor cell lines and xenografts. Combining two ErbB2-targeted therapies, e.g., anti-ErbB2 antibody with small molecule tyrosine kinase inhibitor, that act at different sites of the receptor with distinct mechanisms of action, may enhance the efficacy of both drugs. Methods: Patients (pts) with metastatic breast cancer that overexpress the ErbB2 protein 2+ or 3+ were enrolled at escalating dose levels of lapatinib (750 - 1500 mg/d) in combination with weekly, standard dosing of trastuzumab (4 mg/kg loading dose followed by weekly 2 mg/kg infusions). Three pts were treated at each dose level, with expansion to 6 in the event of dose-limiting toxicity (DLT). Gr 1 - 3 diarrhea, anorexia, fatigue and rash were the common toxicities. Assessments of clinical response per RECIST criteria were performed every 8 weeks. ...

An open-label multicenter phase II study of oral lapatinib (GW572016) as single agent, second-line therapy in patients with metastatic colorectal cancer

Abstract: 3583 Background: Lapatinib is an orally active, reversible inhibitor of the tyrosine kinase activity of ErbB1 (EGFR) and ErbB2 (HER-2/neu). This multicenter, open-label, phase II study was designed to evaluate the safety and efficacy of single-agent lapatinib in patients with metastatic colorectal carcinoma, whose tumors progressed on first-line therapy with 5-fluorouracil in combination with irinotecan or oxaliplatin. Methods: Eighty-six (86) patients received 1250mg of oral lapatinib daily until disease progression or unacceptable toxicity. Safety and efficacy assessments were performed at 4-week and 8-week intervals respectively. Tumor response was determined by an independent review committee using RECIST guidelines. Results: The median age was 60 years (22–83) and median KPS was 90 (70–100). Patients were not selected based on ErbB expression; however, 54.2% and 44.1% of the patients had positive expression (+1, +2, +3) for ErbB1 and ErbB2, respectively. The most commonly encountered adverse events w...

Clinical trials of intracellular signal transductions inhibitors for breast cancer--a strategy to overcome endocrine resistance.

Abstract: Clinical trials of intracellular signal transductions inhibitors for breast cancer - a strategy to overcome endocrine resistance Acquired resistance to endocrine therapy in breast cancer is associated with an increase in peptide growth factor signaling that results in cross-talk activation of the estrogen receptor (ER). Small molecule signal transduction inhibitors (STIs) can target components of these intracellular pathways, and may prove effective in anticancer therapy. However, early phase II clinical trials with various STIs as monotherapy in advanced breast cancer have shown only a modest level of efficacy for these intracellular inhibitors. Preclinical data suggest that combinations of tamoxifen with STIs may provide significantly greater growth inhibition than either therapy alone, and, furthermore, may delay the emergence of endocrine resistance. There are now several trials assessing the efficacy of combinations of small molecule tyrosine kinase inhibitors (TKIs), such as gefitinib and lapatinib, with either tamoxifen or aromatase inhibitors both in the second-line, endocrine-resistant and first-line, hormone-sensitive setting. Similar trials continue with both farnesyltransferase inhibitors (FTIs) and mTOR antagonists, where there are strong preclinical data to suggest additive or synergistic effects for either of these agents in combination with endocrine therapies. Biomarker studies in the presurgical setting are also being utilized as an alternative approach to investigate whether combined endocrine/STI therapy is an effective clinical strategy. This article reviews some of the preclinical evidence supporting this strategy, together with the current status of clinical trials in this area.

A phase I, open-label study of the safety, tolerability and pharmacokinetics of lapatinib (GW572016) in combination with letrozole in cancer patients

Abstract: 3001 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases leading to cell growth arrest and/or apoptosis in ErbB1 and ErbB2 dependent tumor cell lines and xenografts. Co-expression of ErbB2 and ER is associated with a reduced response rate to hormone therapy in breast cancer. A rational approach to treatment may be to block simultaneously both ER and ErbB2 pathways. Methods: Patients (pts) with advanced breast cancer, ER or PR +, or other tumors (e.g., ovarian, endometrial) that would be likely to respond to the combination therapy were enrolled. Escalating doses of lapatinib (1250–1500 mg/d) were administered in combination with letrozole (2.5 mg/d). Three pts were treated at each dose level, with expansion to 6 in the event of dose-limiting toxicity (DLT). Once the optimally tolerated regimen (OTR) was determined, an additional 8 - 16 pts were to be enrolled to establish the pharmacokinetic profiles of lapatinib and letrozole when adminis...

Preliminary safety results of a phase II trial comparing two schedules of lapatinib (GW572016) as first line therapy for advanced or metastatic non-small cell lung cancer

Abstract: 7099 Background: Lapatinib (GW572016) is an oral reversible, dual tyrosine kinase inhibitor of ErbB1 and ErbB2. Sixty three pts (as of July 6, 2004) with advanced or metastatic NSCLC, including a s...

Therapeutic targeting of multiple signaling pathways in malignant pleural mesothelioma.

Abstract: The majority of malignant pleural mesotheliomas (MPMs) aberrantly express the epidermal growth factor receptor (ErbB1). We examined the efficacy of GW572016 (lapatinib), a dual inhibitor of ErbB1/ErbB2 with a panel of 10 MPM cell lines. Two of the 10 MPM cell lines, H2373 and H2452, underwent G1/S cell cycle arrest and growth inhibition with an IC(50) of 1 muM and 0.8 muM, respectively. There was no relationship between the presence or the amount of ErbB1, phospho-ErbB1, phospho-ErbB2, ErbB3, ErbB4, phospho-Akt, and Akt or the ability of lapatinib to inhibit phospho-ErbB1 in these cell lines compared to those that did not respond to lapatinib. The sensitive cell lines had a time-dependent decrease in phospho-Akt and/or ERK1/2, and an increase in p27 and when treated with lapatinib. The combination of lapatinib with U0126, LY294002 or rapamycin caused greater growth inhibition than either drug alone in the sensitive cell lines while this did not occur in the resistant cell lines. Our findings suggest that ErbB1 alone is a therapeutic target for the minority of mesotheliomas and that combining ErbB1 inhibitors with signal transduction inhibitors in mesothelioma will enhance their effectiveness. Furthermore, combinations of growth factor and signal transduction inhibitors may be needed to inhibit the growth of the majority of MPM cell lines, and therefore patients with MPM.

Tyrosine kinase inhibitors in endometrial cancer: 0020

Abstract: Introduction: The EGFR family and relationship to carcinogenesis The epidermal growth factor family is comprised of EGFR (ErbB1), HER-2/neu (ErbB2), HER-3 (ErbB3), and HER-4 (ErbB4). All are present in reproductive tissues. Growth factors and their receptors are known to play critical roles in cell growth and differentiation(1). Growth factors such as EGF are potent mitogens for several human epithelial cell types including the endometrium(2,3) and have been implicated in cancer development(4). EGFR has been shown to be highly expressed in normal endometrium and overexpressed in endometrial cancer specimens(5), where it has been associated with a poor prognosis(6–8). Increased expression of EGF related protein and EGFR may contribute to a drug resistant phenotype(9). Inhibition of EGFR with monoclonal antibodies leads to growth arrest(10), and a similar, and potentially synergistic effect is anticipated with inhibition of EGFR tyrosine kinase activity(11–14). New therapeutic molecules which block EGFR are under study in tumors from many sites, now including the endometrium. Agents in phase II clinical trials include Iressa (ZD1839), Herceptin, and Lapatinib (GW572016). The studies and discussion that follow outline the biologic rationale and suggest potential clinical applications for these agents in endometrial cancer. Methods and study results: EGFR signaling in endometrial cancer cells EGFR has intrinsic tyrosine kinase activity which is activated upon ligand binding. Downstream serine/threonine kinase cascades are then induced, leading to cell proliferation and the inhibition of apoptosis(15,16). We have now identified multiple downstream targets of the EGFR pathway in Hec50co poorly differentiated and Ishikawa well differentiated endometrial cancer cells. Phosphoproteomic profiling of downstream targets of EGFR was carried out using Kinetworks Phospho-Site Screen 1.3 (Kinexus, Victoria, BC) multilane immunoblotting that determines the phosphorylation state of 31 downstream signaling molecules. These experiments demonstrate that EGFR activation upregulates and tyrosine kinase inhibitors prevent the phosphorylation of MAP kinase Erk1/2, MAP kinase kinase MEK1/2, cyclin dependent kinase 1, protein kinase B (Akt), oncogene Raf 1, retinoblastoma 1, and signal transducer and activator of transcription 3. These findings define the principal EGFR signaling pathways activated in two representative endometrial cancer cell lines. Potential EGFR cross-talk with steroid hormone receptors: implications in type I and type II endometrial tumors The EGF/EGFR pathway is induced by estrogen and is arguably the principal growth promoting mechanism in the endometrium(2,3). Estrogen and progesterone are the most important steroid hormones that modulate endometrial cell proliferation and differentiation, respectively, and their receptors (ER and PR) are expressed in many endometrial tumors. However, ER and PR are frequently down-regulated in advanced endometrial cancers. Type I endometrial tumors are those that arise in a hormone-dependent manner and express normally-functioning and regulated ER, PR, and EGFR. Type II endometrial tumors are not responsive to hormones and may not express ER and PR(17). Type II tumors are proposed to exhibit constitutive activation of alternative growth pathways such as those controlled by EGFR. We propose that the loss of ER and PR and the constitutive activation of EGFR may be functionally linked. Indeed, ER and PR are downstream phosphorylation targets of EGFR. Following work in breast cancer cells(18–21), we have now shown in endometrial cancer cells that in the presence of progesterone, phosphorylation of PR occurs via this pathway, leading to receptor ubiquitination and the targeting of PR to the proteasome for destruction. Clinical trials The tyrosine kinase inhibitor ZD1839 (Iressa™) has been studied as a single agent in a phase II clinical trial (GOG 229C) of women with advanced endometrial cancer. Preliminary data analysis indicates that of 29 patients enrolled, 1 patient experienced a complete response and several others had stable disease at 6 months. These findings await official confirmation and are presented at this time for illustrative purposes only. Another GOG study is now underway, GOG 229D, which will evaluate the effectiveness of the dual tyrosine kinase inhibitor, GW572016 (Lapatinib™), as a single agent in a similar cohort of patients. As in other organ sites, it is possible that tyrosine kinase inhibitors will show activity in only a small subset of patients, if at all. It remains to be determined whether response will be linked to mutations in the ATP binding pocket of EGFR, as has been demonstrated in lung cancer patients(22,23). However, based upon the studies below, we propose that tyrosine kinase inhibitors are likely to provide the most benefit for the general population of patients with endometrial tumors when used in conjunction with other traditional therapies. Effects of Iressa alone and in combination with chemotherapy in experimental models Using in vitro cell lines Hec50co, KLE, and Ishikawa, we have evaluated the concentration of Iressa, Taxol, and Iressa + Taxol that kills 50% of the cells after 24 hours of treatment (the IC50). The IC50 for Iressa as a single agent is 11 μM in well differentiated Ishikawa cells, 63 μM in poorly differentiated Hec50co cells, and 100 μM in poorly differentiated KLE cells. In Hec50co and KLE cells, Taxol alone exhibits an IC50 of 14.7 nM. However, the addition of 10 μM Iressa to Taxol substantially reduces the IC50 of Taxol by 10-fold, and results in a synergistic inhibition of cell survival. These studies are meant to serve as preliminary data upon which to base the choice of combination regimens in future clinical trials. The synergistic action of Iressa added to Taxol was seen at all doses, with maximal activity at 10 μM. As Iressa is concentrated within cells, it is likely that this drug concentration is achievable even when circulating levels of Iressa are much lower, in the range of 1 μM (personal communication, AstraZeneca Pharmaceuticals, Inc.), making it feasible that levels of Iressa can be reached in patients that could potentiate Taxol's effects. In addition, our laboratory has used two xenografted animal models, the athymic mouse and the nude rat, for confirmatory preclinical studies. These further demonstrate the effectiveness of combining a biologic agent with chemotherapy. We conclude that combinatorial strategies should be further evaluated in the laboratory and incorporated into future clinical trials if the preclinical findings are encouraging. Acknowledgments: Funding for these studies was provided by NIH CAR01 99908-01 (KL), The University of New Mexico Cancer Research and Treatment Center (SD, KL), the Gynecologic Oncology Group Core Laboratory for Receptors (KL), The Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine (JB, LL, LA, AH, TN), The Barbara Beach Family Fund for Endometrial Cancer Research (KL, SD, DD), Dean and Alice Irvin, and Shirley Leslie.

Phase I study of GW572016 (lapatinib), a dual kinase inhibitor, in combination with irinotecan (IR), 5-fluorouracil (FU) and leucovorin (LV)

Abstract: 3086 Background: Lapatinib is an orally active reversible inhibitor of ErbB1/ErbB2 tyrosine kinases. This study evaluated the safety, tolerability and pharmacokinetics (PK) of daily lapatinib in combination with IR/FU/LV (FOLFIRI) q14d. Methods: Cohorts of 3 patients (pts) each (25 total) with solid tumours received lapatinib (1000 or 1250mg daily) and FOLFIRI (80% or 60% of the standard doses) to determine the optimally tolerated regimen (OTR). Additional pts were enrolled at the OTR to evaluate the PK of lapatinib and FOLFIRI alone and in combination. Results: The standard FOLFIRI doses were reduced to 80% and 60% due to DLTs of diarrhea and/or myelosuppression at the starting doses. Toxicity required the lapatinib dose to be interrupted or reduced at these doses. The OTR was defined as lapatinib 1250mg with IR 120mg/m2, FU 240mg/m2 bolus and 360mg/m2 infusion, plus LV 200mg/m2on days 1 and 2, every 14 days. At the OTR, common non-hematological adverse events were grade 1 or 2 diarrhea, nausea/vomiting,...

Lapatanib : Oncolytic dual EGFR and erbB-2 inhibitor

Abstract: Human epidermal growth factor receptor (EGFR) and erbB-2 are subclass I receptor tyrosine kinases that have been linked with a number of cancers, thereby making inhibitors of these proteins attractive targets for drug development. Several signaling cascades are associated with EGFR, which plays a role in mitogenesis, apoptosis, cell migration, differentiation and angiogenesis, all important processes in tumorigenesis. EGFR and its ligands are overexpressed in a number of solid tumors, including pancreatic, lung, ovarian, renal, gastric, hepatic and breast cancer. ErbB-2 overexpression has been found in a wide variety of cancers, including breast, bladder, colorectal, gastric, ovarian, prostate, renal and uterine cancers. Agents that target EGFR and erbB-2 are therefore under development or currently available for a number of cancer indications. One such agent is lapatinib, a potent and reversible dual EGFR and erbB-2 inhibitor that has shown promising pharmacological activity and pharmacokinetics. Lapatinib has been investigated as an anticancer monotherapy, as well as in combination with trastuzumab, capecitabine, letrozole, paclitaxel and FOLFIRI (irinotecan, 5-fluorouracil and leucovorin), in a number of clinical trials. It is currently in phase III testing for the oral treatment of metastatic breast, head and neck, lung, gastric, renal and bladder cancer. Additional trials of lapatinib in patients with brain, gallbladder, prostate, ovarian, endometrial and hepatobiliary cancers are also under way.

Optimizing outcomes in HER2-positive breast cancer: the molecular rationale.

Abstract: The epidermal growth factor (EGF) receptor HER2 is a transmembrane receptor tyrosine kinase that plays a crucial role in the regulation of cell proliferation and survival. The overexpression of HER2 correlates strongly with prognosis in breast cancer. The targeted blockade of HER2 activity with monoclonal antibodies (e.g., trastuzumab [Herceptin]) and small-molecule tyrosine kinase inhibitors (e.g., lapatinib) results in the inhibition of tumor growth in HER2-positive cancers. Anti-HER2 therapies have also shown efficacy in combination with chemotherapy in clinical trials in patients with HER2-positive breast cancer. Their efficacy may, however, be limited by molecular mechanisms that compensate for HER2 suppression (e.g., activity of EGF receptor) or mechanisms of resistance (e.g., loss of PTEN). HER2 continues, however, to be overexpressed by the cancer cells, and the continued suppression of HER2 may be required for maximum antitumor effect. It should be noted that in the absence of definitive data from randomized trials showing an absence or presence of benefit, the use of anti-HER2 agents such as trastuzumab in multiple sequential regimens has become the standard of care. Combining HER2 blockers with agents that overcome the compensatory or resistance mechanisms may increase the efficacy of anti-HER2 therapies. In addition, anti-HER2 therapies can have synergy with common chemotherapy regimens and remain effective through multiple lines of therapy. Optimizing the use of therapies that target HER2 signaling will lead to further advances in the treatment of breast cancer.

Combining lapatinib (GW572016) with anti-erbB2 antibodies elicits synergistic apoptotic effects in erbB2 overexpressing breast cancer cells

Abstract: 557 Background: Combining non-cross resistant agents is the mainstay of cancer treatment. The question is whether evaluate combining a small molecule ErbB1/ErbB2 kinase inhibitor with anti-ErbB2 an...

Lapatinib: the evidence for its therapeutic value in metastatic breast cancer

Abstract: Introduction Breast cancer is the most common cancer affecting women. Many patients ultimately progress to metastatic disease and optimal management of this disease remains a significant therapeutic challenge. Lapatinib, a dual tyrosine kinase inhibitor, is in clinical development for treatment of this disease. Aims The objective of this article is to review the published evidence for the treatment of metastatic breast cancer with lapatinib, and assess its therapeutic potential. Evidence review Most evidence has appeared in meeting abstract reports of phase I and II studies in healthy volunteers and cancer patients. Four studies have included patients with exclusively breast cancer. Complete and partial responses and stable disease has been reported in some patients. Emerging evidence indicates that complete and partial responses can be achieved in some patients with metastatic breast cancer. Lapatinib appears to be well tolerated in cancer patients and the maximum tolerated dose is in the region of 1800 mg/day. In addition, it has been used in combination with other cancer treatments. Five ongoing or planned phase II monotherapy and three phase III combination-therapy studies with lapatinib have been identified. Outcomes summary The phase I and II studies reported to date have provided safety data and preliminary indications regarding efficacy. There is preliminary evidence that lapatinib can achieve objective response rates of 10-38% in patients with metastatic breast cancer. Patients with tumors overexpressing ErbB1 and/or ErbB2 are likely to benefit from lapatinib treatment.