Lapatinib for advanced or metastatic breast cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Opdam FL
PROVIDER: S-EPMC3336826 | biostudies-other | 2012
REPOSITORIES: biostudies-other
Publications
Lapatinib for advanced or metastatic breast cancer.
Opdam Frans L FL Guchelaar Henk-Jan HJ Beijnen Jos H JH Schellens Jan H M JH
The oncologist 20120403 4
Lapatinib is a potent reversible and selective inhibitor of the tyrosine kinase domains of epidermal growth factor receptor and human epidermal growth factor receptor (HER)-2 that exerts its action by competitive binding to the intracellular ATP-binding site of the receptor. It is registered for the treatment of advanced or metastatic HER-2+ breast cancer in combination with capecitabine and for hormone receptor-positive breast cancer in combination with an aromatase inhibitor. Lapatinib adminis ...[more]
Similar Datasets
Project description:To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab.In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m(-2)) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated.Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3' (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3-4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3-4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30-40% compared with DL1.The MTD LPT 1000 mg/VNR 22.5 mg?m(-2) (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance.
| S-EPMC3322949 | biostudies-literature
Project description:Heparanase (HPSE) is the dominant mammalian endoglycosidase and important tumorigenic, angiogenic, and pro-metastatic molecule. Highest levels of HPSE activity have been consistently detected in cells possessing highest propensities to colonize the brain, emphasizing the therapeutic potential for targeting HPSE in brain metastatic breast cancer (BMBC). Lapatinib (Tykerb) is a small-molecule and dual inhibitor of human epidermal growth factor receptor1 and 2 (EGFR and HER2, respectively) which are both high-risk predictors of BMBC. It was approved by the US Food and Drug Administration for treatment of patients with advanced or metastatic breast cancer. However, its role is limited in BMBC whose response rates to lapatinib are significantly lower than those for extracranial metastasis. Because HPSE can affect EGFR phosphorylation, we examined Roneparstat, a non-anticoagulant heparin with potent anti-HPSE activity, to inhibit EGFR signaling pathways and BMBC onset using lapatinib-resistant clones generated from HER2-transfected, EGFR-expressing MDA-MB-231BR cells. Cell growth, EGFR pathways, and HPSE targets were assessed among selected clones in the absence or presence of Roneparstat and/or lapatinib. Roneparstat overcame lapatinib resistance by inhibiting pathways associated with EGFR tyrosine residues that are not targeted by lapatinib. Roneparstat inhibited the growth and BMBC abilities of lapatinib-resistant clones. A molecular mechanism was identified by which HPSE mediates an alternative survival pathway in lapatinib-resistant clones and is modulated by Roneparstat. These results demonstrate that the inhibition of HPSE-mediated signaling plays important roles in lapatinib resistance, and provide mechanistic insights to validate the use of Roneparstat for novel BMBC therapeutic strategies.
| S-EPMC4309682 | biostudies-literature
Project description:Molecular mechanisms of lapatinib resistance in breast cancer are not well understood. The aim of this study was to correlate expression of selected proteins involved in ErbB family signaling pathways with clinical efficacy of lapatinib. Study group included 270 HER2-positive advanced breast cancer patients treated with lapatinib and capecitabine. Immunohistochemical expression of phosphorylated adenosine monophosphate-activated protein (p-AMPK), mitogen-activated protein kinase (p-MAPK), phospho (p)-p70S6K, cyclin E, phosphatase and tensin homolog were analyzed in primary breast cancer samples. The best discriminative value for progression-free survival (PFS) was established for each biomarker and subjected to multivariate analysis. At least one biomarker was determined in 199 patients. Expression of p-p70S6K was independently associated with longer (HR 0.45; 95% CI: 0.25-0.81; p = 0.009), and cyclin E with shorter PFS (HR 1.83; 95% CI: 1.06-3.14; p = 0.029). Expression of p-MAPK (HR 1.61; 95% CI 1.13-2.29; p = 0.009) and cyclin E (HR 2.99; 95% CI: 1.29-6.94; p = 0.011) was correlated with shorter, and expression of estrogen receptor (HR 0.65; 95% CI 0.43-0.98; p = 0.041) with longer overall survival. Expression of p-AMPK negatively impacted response to treatment (HR 3.31; 95% CI 1.48-7.44; p = 0.004) and disease control (HR 3.07; 95% CI 1.25-7.58; p = 0.015).the efficacy of lapatinib seems to be associated with the activity of downstream signaling pathways - AMPK/mTOR and Ras/Raf/MAPK. Further research is warranted to assess the clinical utility of these data and to determine a potential role of combining lapatinib with MAPK pathway inhibitors.
| S-EPMC4808017 | biostudies-literature
Project description:BackgroundHER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies.MethodsIn studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab.ResultsFor HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8-28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9-34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib.ConclusionLapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.
| S-EPMC2778543 | biostudies-literature
Project description:BackgroundTo evaluate the efficacy of lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, in therapy-resistant HER2-positive CTCs in metastatic breast cancer (MBC).Patients and methodsPatients with MBC and HER2-positive CTCs despite disease stabilization or response to prior therapy, received lapatinib 1500 mg daily in monthly cycles, till disease progression or CTC increase. CTC monitoring was performed by immunofluorescent microscopy using cytospins of peripheral blood mononuclear cells (PBMCs) double stained for HER2 or EGFR and cytokeratin.ResultsA total of 120 cycles were administered in 22 patients; median age was 62.5 years, 15 (68.2%) patients were post-menopausal and 20 (90.1%) had HER2-negative primary tumors. At the end of the second course, HER2-positive CTC counts decreased in 76.2% of patients; the median number of HER2-positive CTCs/patient also declined significantly (p = 0.013), however the decrease was significant only among patients presenting disease stabilization (p = 0.018) but not among those with disease progression during lapatinib treatment. No objective responses were observed. All CTC-positive patients harbored EGFR-positive CTCs on progression compared to 62.5% at baseline (p = 0.054). The ratio of EGFR-positive CTCs/total CTCs detected in all patients increased from 17.1% at baseline to 37.6% on progression, whereas the mean percentage of HER2-negative CTCs/patient increased from 2.4% to 30.6% (p = 0.03).ConclusionsThe above results indicate that lapatinib is effective in decreasing HER2-positive CTCs in patients with MBC irrespectively of the HER2 status of the primary tumor and imply the feasibility of monitoring the molecular changes on CTCs during treatment with targeted agents.Trial registrationClinical trial.gov NCT00694252.
| S-EPMC4471111 | biostudies-literature
Project description:The addition of lapatinib (Tykerb/Tyverb) to capecitabine (Xeloda) delays disease progression more effectively than capecitabine monotherapy in women with previously treated HER2+ metastatic breast cancer (MBC). The quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) method was used to compare treatments. The area under survival curves was partitioned into health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse period until death or end of follow-up (REL). Average times spent in each state, weighted by utility, were derived and comparisons of Q-TWiST between groups performed with varying combinations of the utility weights. Utility weights of 0.5 for both TOX and REL, that is, counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favouring combination therapy (P=0.0013). The Q-TWiST difference is clinically meaningful and was statistically significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses. An analysis with utilities based on EQ-5D scores was consistent with the above findings. Combination therapy of lapatinib with capecitabine resulted in greater quality-adjusted survival than capecitabine monotherapy in trastuzumab-refractory MBC patients.
| S-EPMC2528149 | biostudies-other
Project description:PurposeThis phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways.MethodsEligibility for this dose-escalation study included unresectable and locally recurrent or chemotherapy-refractory and locally advanced breast cancer, and adequate organ function. Patients underwent three serial biopsies: at baseline, after 1 week of lapatinib alone, and after 1 week of lapatinib and radiation. Endpoints included determination of toxicity, maximum tolerated dose, and analysis of the effect of lapatinib with or without radiation on EGFR and HER2 signaling pathways by immunohistochemistry.ResultsDoses of lapatinib up to 1,500 mg/day were well tolerated. Toxicity of grade 3 or more was limited to radiation dermatitis and pain. Out of 19 patients treated, in field responses per response evaluation criteria in solid tumors criteria were complete in four patients and partial in six patients. Serial biopsies were obtained in 16 patients with no complications. Total Her2 was relatively unchanged while phospho-Her2, phospho-Akt, and phospho-ERK showed variable responses to both lapatinib alone and dual therapy with lapatinib and radiation.ConclusionsThe combination of lapatinib and radiation was well tolerated in this patient cohort. Overall local response rates were comparable to those reported in other studies in this patient population. Biopsies were safely performed at all time points. Inhibition of HER2 and downstream signaling pathways was identified, although no strong correlation with response was seen.
| S-EPMC3528381 | biostudies-literature
Project description:Preclinical data have demonstrated that the combination of antihuman epidermal growth factor receptor-2 (anti-HER2) and antivascular endothelial growth factor (anti-VEGF)--targeted agents has antitumor activity; these data indicate certain patients with HER2-overexpressing breast cancer may derive clinical benefit from this combination. The purpose of this single-arm phase II study was to determine the efficacy and safety of the dual-targeting combination of lapatinib and bevacizumab. Women with HER2-overexpressing advanced breast cancer received 1,500 mg oral lapatinib daily plus 10 mg/kg IV bevacizumab every 2 weeks. The primary endpoint was progression-free survival (PFS) at week 12; secondary endpoints included overall tumor response rate (ORR), clinical benefit rate (CBR), duration of response, time-to-response, PFS, and safety. Circulating tumor cells (CTC) and circulating endothelial cells (CEC) were measured at baseline and during study treatment as potential response markers. Fifty-two patients with stage IV disease were enrolled. The 12-week investigator-assessed PFS rate was 69.2% (95% confidence interval [CI]: 54.9, 81.3). Median PFS was 24.7 weeks (95% CI: 20.4, 35.1), and the CBR was 30.8% (95% CI: 18.7, 45.1). Of 45 patients with measurable disease, 6 were determined to have a partial response per Response Evaluation Criteria in Solid Tumors (ORR: 13.3%; 95% CI: 5.1, 26.8). The most common adverse events (AEs) included diarrhea, rash, and fatigue; most of these were either grade 1 or 2. Clinical responses were correlated with decreases in CTC and CEC. Lapatinib plus bevacizumab was active in patients with HER2-overexpressing breast cancer. The AE profile of the combination was consistent with the known profiles for these agents.
| S-EPMC3397213 | biostudies-other
Project description:The cost-effectiveness of first-line treatment with lapatinib plus letrozole for postmenopausal women with hormone receptor-positive (hr+), human epidermal growth factor receptor 2-positive (her2+) metastatic breast cancer (mbc) has not been assessed from the Canadian health care system and societal perspectives.A partitioned survival analysis model with 3 health states (alive, pre-progression; alive, post-progression; dead) was developed to estimate direct and indirect costs and quality-adjusted life years (qalys) with lapatinib-letrozole, letrozole, anastrozole, or trastuzumab-anastrozole as first-line treatment. Clinical inputs for lapatinib-letrozole and letrozole were taken from the EGF30008 trial (NCT00073528). Clinical inputs for anastrozole and trastuzumab-anastrozole were taken from a network meta-analysis of published studies. Drug costs were obtained from the manufacturer's price list, the Quebec list of medications, and imsBrogan. Other costs were taken from the Ontario Health Insurance Plan's Schedule of Benefits and Fees and published studies. A 10-year time horizon was used. Costs and qalys were discounted at 5% annually. Deterministic and probabilistic sensitivity analyses were performed to assess the effects of changes in model parameters.Quality-adjusted life years gained with lapatinib-letrozole were 0.236 compared with trastuzumab-anastrozole, 0.440 compared with letrozole, and 0.568 compared with anastrozole. Assuming a health care system perspective, incremental costs were $5,805, $67,029, and $67,472 respectively. Given a cost per qaly threshold of $100,000, the probability that lapatinib-letrozole is preferred was 21% compared with letrozole, 36% compared with anastrozole, and 68% compared with trastuzumab-anastrozole. Results from the societal perspective were similar.In postmenopausal women with hr+/her2+ mbc receiving first-line treatment, lapatinib-letrozole may not be cost-effective compared with letrozole or anastrozole, but may be cost-effective compared with trastuzumab-anastrozole.
| S-EPMC3805407 | biostudies-literature
Project description:BackgroundPoly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC.MethodsA first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded.ResultsTwenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0-2). Fifty percent of patients were Caucasian, 45% African-American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug-drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders.ConclusionsLapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed.Trial registrationClinicalTrials.gov , NCT02158507 . Registered on 12 September 2014.
| S-EPMC7934554 | biostudies-literature