DOCSLIB.ORG

T-DM1 As a New Treatment Option for Patients with Metastatic HER2-Positive Breast Cancer in Clinical Practice

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
T-DM1 As a New Treatment Option for Patients with Metastatic HER2-Positive Breast Cancer in Clinical Practice ANTICANCER RESEARCH 35: 5085-5090 (2015) T-DM1 as a New Treatment Option for Patients with Metastatic HER2-positive Breast Cancer in Clinical Practice LAURA L. MICHEL1,2, JUSTO LORENZO BERMEJO3, ADAM GONDOS4, FREDERIK MARMÉ1,2 and ANDREAS SCHNEEWEISS1,2 1National Center for Tumor Diseases and 2Department of Obstetrics and Gynecology, University Hospital, Heidelberg, Germany; 3Institute of Medical Biometry and Informatics, University of Heidelberg, Germany; 4Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany Abstract. Aim: To compare results of trastuzumab- targeted approach (1, 2). Within the last few years, additional emtansine (T-DM1) treatment in our clinical practice with HER2-directed agents such as the monoclonal antibody data from phase III clinical trials. Patients and Methods: A pertuzumab and the dual epidermal growth factor receptor retrospective chart review of all 23 patients with metastatic (EGFR)/HER2 tyrosine kinase inhibitor, lapatinib, were human epidermal growth factor receptor 2 (HER2)-positive developed to overcome resistance to trastuzumab and provide breast cancer who were started on T-DM1 until April 2014 additional treatment options for these patients (3, 4). was performed. Results: Four patients (17.4%) received The newest agent, which was approved by the Food and T-DM1 as first-line, three (13.0%) as second-line, six Drug Administration (FDA) in February 2013 for HER2- (26.0%) as third-line, and 10 (43.5%) as fifth- or further-line positive metastatic breast cancer is trastuzumab-emtansine therapy. Overall, the response rate (ORR) was 26.0%, (T-DM1, Roche, Basel). T-DM1 represents a new generation disease control rate 78.3% and median progression-free of cytotoxic drugs. It is an antibody–drug conjugate survival (PFS) 8.4 months. The only toxicities of grade 3 or consisting of the monoclonal antibody trastuzumab linked to more were fatigue (21.7%), thrombocytopenia (4.3%) and the cytotoxic agent emtansine (DM1), a microtubule elevation of liver enzymes (8.7%). ORR and PFS were polymerization inhibitor (5-7). T-DM1, therefore, combines similar to the TH3RESA and EMILIA trials. Compared to the the tumor selectivity of antibodies with the cytotoxic EMILIA study, we recorded higher rates of newly-diagnosed potential of chemotherapeutics. cerebral metastasis and cerebral progression in patients with T-DM1 binds to the HER2 receptor, is internalized and stable peripheral metastases. Conclusion: T-DM1 is effective undergoes lysosomal degradation. The active cytotoxic DM1 and well-tolerated even in intensively pre-treated patients. moiety is released inside HER2-expressing cells. This reduces systemic exposure. Additionally to inhibiting tubulin Over the past decade, the management of human epidermal polymerization similarly to the vinca alkaloids, T-DM1 also growth factor receptor 2 (HER2)-positive breast cancer has acts by trastuzumab-mediated HER2-targeting antitumor improved dramatically. The monoclonal antibody trastuzumab properties: it inhibits HER2 extracellular domain shedding, as was the first HER2-directed agent for the treatment of HER2- well as the phosphatidylinositol-3-kinase signaling pathway positive breast cancer. It was approved in 2000 in the EU. Its and induces antibody-dependent cellular cytotoxicity (7). introduction into clinical therapy represented a paradigm shift Results from multiple phase III studies have confirmed the in oncology from non-specific chemotherapy to a molecularly- efficacy and safety of T-DM1 in patients with metastatic breast cancer. The EMILIA (TDM4370) study is an international, randomized phase III study that compares the efficacy and safety of T-DM1 to capecitabine plus lapatinib. A total of 991 Correspondence to: Laura L. Michel, MD, National Center for Tumor women with metastatic HER2-positive breast cancer whose Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 460, disease progressed on or within 6 months after receiving D-69120 Heidelberg, Germany. Tel: +49 62215638795, e-mail: trastuzumab and who had received taxane chemotherapy were [email protected] included (8). Patients received T-DM1 at a dose of 3.6 mg/kg Key Words: HER2-positive metastatic breast cancer, T-DM1, once every 21 days or oral lapatinib plus capecitabine. The chemotherapy. primary end-points were progression-free survival (PFS) and 0250-7005/2015 $2.00+.40 5085 ANTICANCER RESEARCH 35: 5085-5090 (2015) overall survival (OS). Patients had previously received a mg/kg. In cases of toxicities of grade 3 or more, the dose was reduced median of three systemic agents for metastatic disease. 12.0% by ~20%, corresponding to 3.0 mg/kg (level −1) and 2.4 mg/kg (level of the patients received T-DM1 as a first -line treatment. The −2). T-DM1 was given every three weeks. Echocardiography was performed every 12 weeks to rule out cardiotoxicity. median PFS was 9.6 months in the T-DM1 group vs. 6.4 For follow-up, patients were seen on a regular basis at least months in the lapatinib-plus-capecitabine group. The hazard quarterly at our Outpatient Clinic. According to our center's ratio (HR) for PFS was 0.65 with T-DM1 vs. capecitabine- guidelines, response was evaluated every third cycle by magnetic plus-lapatinib. The median survival was 30.9 months in the T- resonance imaging or computed tomographic scans and evaluation DM1-treated group vs. 25.1 months in the group treated with of tumor markers. lapatinib plus capecitabine (8). The TH3RESA study investigated the use of T-DM1 in Statistical analysis. Descriptive statistics were used to summarize patient and tumor characteristics. The overall response rate (ORR) comparison to the treatment of the physician's choice in was defined as complete and partial response (CR+PR) according to patients with HER2-positive breast cancer who had received the Response Evaluation Criteria in Solid Tumors (RECIST) version at least two prior regimens of HER2-directed therapy. The 1.1 (11). Disease control rate (DCR) was defined as CR plus PR plus primary end-points were PFS and OS. The median PFS was stable disease (SD) according to RECIST criteria. PFS was defined 6.2 months in the T-DM1-treated group vs. 3.3 months in the as the interval between the first dose of T-DM1 and the time of physician's choice group. Interim OS analysis showed a trend disease progression or death. OS was defined as the time interval favoring T-DM1 (stratified HR=0.552; 95% confidence between the first dose of T-DM1 and death. OS and PFS were examined using the Kaplan–Meier method. The follow-up of patients interval (CI)=0.369-0.826; p=0.0034) without crossing the without documented events at the last follow-up was censored. stopping boundary (9). Analysis of adverse events (AEs), combining available data Results from all single-agent T-DM1 studies to date including 884 T- DM1-exposed patients, revealed that the most commonly Patients' characteristics. Patient and tumor characteristics are reported all-grade AEs were fatigue (46.4%), nausea (43.0%), summarized in Table I and reflected the typical population thrombocytopenia (32.2%), headache (29.4%), and of patients with MBC seen in our clinical practice. Overall, constipation (26.5%). The most common grade 3 to 4 AEs 23 patients with MBC were treated with T-DM1 between observed were thrombocytopenia (11.9%) and increased serum November 2010 to April 2014. The median follow-up was aspertate transaminase (AST) concentration (4.3%). There 285 (range=21-1016) days. At the cut-off date (October, 8th, were 12 AE-related deaths. AEs resulted in dose reductions in 2014), nine patients were still under therapy with T-DM1. 17.2% of patients and drug discontinuations in 7.0% (10). The median age was 54 (range=32-79) years. Overall 91.3% It is common belief that controlled clinical trials provide the of patients had visceral metastases. A total of 73.9% patients highest level of evidence. Yet it is also undisputed that clinical had received prior (neo-) adjuvant cytotoxic therapy; 91.3% trials are prone to selection bias and do not always reflect received prior anti-HER2 treatment either in the (neo-) clinical reality. After the introduction of T-DM1 in the EU at adjuvant (47.8%) or palliative (82.6%) setting, or both. Most the beginning of 2014, use of T-DM1 is still not common in patients (91.3%) had received prior antibody therapy with German clinical practice. At our Institution, T-DM1 has been trastuzumab for a median of 32 (range=5-120) months. integrated into routine treatment of HER2-positive metastatic Fourteen patients (60.9%) had been treated with lapatinib breast cancer (MBC). In this retrospective study, we report our and eight (34.8%) had received pertuzumab before. first experiences with T-DM1 in routine clinical practice and aim to determine how our treatment results compare to the Treatment. Details of T-DM1 treatment are outlined in Table data generated in controlled clinical trials. II. Four patients (17.4%) received T-DM1 as first-line treatment, 10 patients (43.5%) had received more than four Patients and Methods prior lines of systemic treatment for metastatic disease. All patients started with T-DM1 at 3.6 mg/kg. The median Patients. We performed a retrospective chart review of all 29 number of cycles administered was 10 (range=1-42). Dose patients who started treatment with T-DM1 at our Department from delay was required for 10 patients (43.5%) and dose November 2010 to April 2014. Six patients were excluded from our reduction was necessary for three patients (13.0%). patient cohort: two of them received T-DM1 in a post-neoadjuvant setting; in four other patients, therapy with T-DM1 was initiated at Efficacy. Efficacy data are summarized in Table III. No CR our Clinic and was continued after the first two cycles at other was observed.
Load more

Recommended publications
  • TYKERB  Decreases in Left Ventricular Ejection Fraction (LVEF) Have Been Reported
    HIGHLIGHTS OF PRESCRIBING INFORMATION ---------------------------WARNINGS AND PRECAUTIONS------------------- These highlights do not include all the information needed to use TYKERB Decreases in left ventricular ejection fraction (LVEF) have been reported. safely and effectively. See full prescribing information for TYKERB. Confirm normal LVEF before starting TYKERB and continue evaluations TYKERB® (lapatinib) tablets, for oral use during treatment. (5.1) Initial U.S. Approval: 2007 TYKERB has been associated with hepatotoxicity. Monitor liver function tests before initiation of treatment, every 4 to 6 weeks during treatment, and as WARNING: HEPATOTOXICITY clinically indicated. Discontinue and do not restart TYKERB if patients See full prescribing information for complete boxed warning. experience severe changes in liver function tests. (5.2) Hepatotoxicity has been observed in clinical trials and postmarketing Dose reduction in patients with severe hepatic impairment should be experience. The hepatotoxicity may be severe and deaths have been considered. (2.2, 5.3, 8.7) reported. Causality of the deaths is uncertain. (5.2) Diarrhea, including severe diarrhea, has been reported during treatment. Manage with antidiarrheal agents, and replace fluids and electrolytes if --------------------------------INDICATIONS AND USAGE--------------------------- severe. (5.4) TYKERB is a kinase inhibitor indicated in combination with: (1) TYKERB has been associated with interstitial lung disease and pneumonitis. capecitabine for the treatment of patients with advanced or metastatic breast Discontinue TYKERB if patients experience severe pulmonary symptoms. cancer whose tumors overexpress human epidermal growth factor receptor 2 (5.5) (HER2) and who have received prior therapy, including an anthracycline, a TYKERB may prolong the QT interval in some patients. Consider taxane, and trastuzumab. electrocardiogram (ECG) and electrolyte monitoring.
    [Show full text]
  • Combining Paclitaxel and Lapatinib As Second-Line Treatment for Patients with Metastatic Transitional Cell Carcinoma: a Case Series
    ANTICANCER RESEARCH 32: 3949-3952 (2012) Combining Paclitaxel and Lapatinib as Second-line Treatment for Patients with Metastatic Transitional Cell Carcinoma: A Case Series STÉPHANE CULINE, ZINEB SELLAM, LINDA BOUAITA, ELIAS ASSAF, CATHERINE DELBALDO, MURIEL VERLINDE-CARVALHO and DAMIEN POUESSEL Department of Medical Oncology, Henri Mondor Hospital, Créteil, France Abstract. Background: Current first-line cisplatin-based trial comparing vinflunine with best supportive care (BSC) combination chemotherapy regimens provide interesting to BSC alone, an estimated difference in overall survival response rates but limited impact on survival for patients with (OS) of 2 months was reached in the intent-to-treat metastatic transitional cell carcinoma of the urothelium. Such population. However, a significant difference in OS was only results leave a significant patient population in need of salvage seen after removing patients who had major protocol therapy. Patients and Methods: As the epidermal growth factor violations (2). Therefore therapy for patients who fail first- receptors 1 and 2 (EGFR and HER2) are frequently line cisplatin-based chemotherapy remains a highly unmet overexpressed in urothelial carcinoma, we explored the medical need. feasibility of a combination of paclitaxel (80 mg/m2/week) and In a phase II study led by the French Genito-Urinary lapatinib (1,500 mg orally daily) for six patients who were Tumor group (GETUG), the activity of weekly paclitaxel as treated after failure of first-line platinum-based chemotherapy. second-line chemotherapy was assessed in 45 patients with Results: Only one out of six patients was able to receive the MTCCU. A low objective response rate (9%) along with a full doses during the first six weeks of treatment, while grade high rate of stabilization (38%) suggested limited impact as 2 or 3 diarrhea events required lapatinib dose reduction (one a single agent (3).
    [Show full text]
  • HER2-Positive Male Breast Cancer: an Update
    Breast Cancer: Targets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW HER2-positive male breast cancer: an update Laura Ottini1 Abstract: Although rare, male breast cancer (MBC) remains a substantial cause for morbidity Carlo Capalbo2 and mortality in men. Based on age frequency distribution, age-specific incidence rate pattern, Piera Rizzolo1 and prognostic factor profiles, MBC is considered similar to postmenopausal breast cancer Valentina Silvestri1 (BC). Compared with female BC (FBC), MBC cases are more often hormonal receptor Giuseppe Bronte3 (estrogen receptor/progesterone receptor [ER/PR]) positive and human epidermal growth factor Sergio Rizzo3 receptor 2 (HER2) negative. Treatment of MBC patients follows the same indications as female postmenopausal with surgery, systemic therapy, and radiotherapy. To date, ER/PR and HER2 Antonio Russo3 status provides baseline predictive information used in selecting optimal adjuvant/neoadjuvant 1 Department of Experimental therapy and in the selection of therapy for recurrent or metastatic disease. HER2 represents Medicine, “Sapienza” University of ® Rome, Rome, Italy; 2Medical Oncology, a very interesting molecular target and a number of compounds (trastuzumab [Herceptin ; IDI-IRCCS, Rome, Italy; 3Department F. Hoffmann-La Roche, Basel, Switzerland] and lapatinib [Tykerb®, GlaxoSmithKline, London, of Surgical and Oncological Sciences, UK]) are currently under clinical evaluation. Particularly, trastuzumab, a monoclonal antibody Section of Medical Oncology, University of Palermo, Palermo, Italy which selectively binds the extracellular domain of HER2, has become an important therapeutic agent for women with HER2-positive (HER2+) BC. Currently, data regarding the use of trastuzumab in MBC patients is limited and only few case reports exist.
    [Show full text]
  • Lapatinib Has Been Associated with Hepatotoxicity
    HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------- WARNINGS AND PRECAUTIONS ---------------- These highlights do not include all the information needed to use • Decreases in left ventricular ejection fraction have been reported. TYKERB safely and effectively. See full prescribing information for Confirm normal LVEF before starting TYKERB and continue evaluations TYKERB. during treatment. (5.1) • Lapatinib has been associated with hepatotoxicity. Monitor liver function TYKERB (lapatinib) tablets tests before initiation of treatment, every 4 to 6 weeks during treatment, Initial U.S. Approval: 2007 and as clinically indicated. Discontinue and do not restart TYKERB if patients experience severe changes in liver function tests. (5.2) WARNING: HEPATOTOXICITY • Dose reduction in patients with severe hepatic impairment should be See full prescribing information for complete boxed warning. considered. (2.2, 5.3, 8.7) Hepatotoxicity has been observed in clinical trials and postmarketing • Diarrhea, including severe diarrhea, has been reported during treatment. experience. The hepatotoxicity may be severe and deaths have been Manage with anti-diarrheal agents, and replace fluids and electrolytes if reported. Causality of the deaths is uncertain. [See Warnings and severe. (5.4) Precautions (5.2).] • Lapatinib has been associated with interstitial lung disease and pneumonitis. Discontinue TYKERB if patients experience severe pulmonary symptoms. (5.5) ---------------------------RECENT MAJOR CHANGES -------------------- Boxed Warning. Month YEAR • Lapatinib prolongs the QT interval in some patients. Consider ECG and Hepatotoxicity. (5.2, 17.6) Month YEAR electrolyte monitoring. (5.6) Interstitial lung disease and pneumonitis. (5.5) August 2007 • Fetal harm can occur when administered to a pregnant woman. Women should be advised not to become pregnant when taking TYKERB.
    [Show full text]
  • Fasting Potentiates the Anticancer Activity of Tyrosine Kinase Inhibitors by Strengthening MAPK Signaling Inhibition
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 6, No. 14 Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition Irene Caffa1, Vito D’Agostino2, Patrizia Damonte1, Debora Soncini1, Michele Cea1, Fiammetta Monacelli1, Patrizio Odetti1,3, Alberto Ballestrero1,3, Alessandro Provenzani2, Valter D. Longo4,5 and Alessio Nencioni1,3 1 Department of Internal Medicine, University of Genoa, Genoa, Italy 2 Laboratory of Genomic Screening, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy 3 IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy 4 Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA 5 IFOM, FIRC Institute of Molecular Oncology, Milan, Italy Correspondence to: Valter D. Longo, email: [email protected] Correspondence to: Alessio Nencioni, email: [email protected] Keywords: tyrosine kinase inhibitors, fasting, MAPK pathway, E2F transcription factors, cell cycle regulation Received: March 04, 2015 Accepted: March 11, 2015 Published: March 18, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Tyrosine kinase inhibitors (TKIs) are now the mainstay of treatment in many types of cancer. However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies. Cycles of fasting enhance the activity of chemo-radiotherapy in preclinical cancer models and dietary approaches based on fasting are currently explored in clinical trials. Whether combining fasting with TKIs is going to be potentially beneficial remains unknown.
    [Show full text]
  • Identification of Candidate Repurposable Drugs to Combat COVID-19 Using a Signature-Based Approach
    www.nature.com/scientificreports OPEN Identifcation of candidate repurposable drugs to combat COVID‑19 using a signature‑based approach Sinead M. O’Donovan1,10, Ali Imami1,10, Hunter Eby1, Nicholas D. Henkel1, Justin Fortune Creeden1, Sophie Asah1, Xiaolu Zhang1, Xiaojun Wu1, Rawan Alnafsah1, R. Travis Taylor2, James Reigle3,4, Alexander Thorman6, Behrouz Shamsaei4, Jarek Meller4,5,6,7,8 & Robert E. McCullumsmith1,9* The COVID‑19 pandemic caused by the novel SARS‑CoV‑2 is more contagious than other coronaviruses and has higher rates of mortality than infuenza. Identifcation of efective therapeutics is a crucial tool to treat those infected with SARS‑CoV‑2 and limit the spread of this novel disease globally. We deployed a bioinformatics workfow to identify candidate drugs for the treatment of COVID‑19. Using an “omics” repository, the Library of Integrated Network‑Based Cellular Signatures (LINCS), we simultaneously probed transcriptomic signatures of putative COVID‑19 drugs and publicly available SARS‑CoV‑2 infected cell lines to identify novel therapeutics. We identifed a shortlist of 20 candidate drugs: 8 are already under trial for the treatment of COVID‑19, the remaining 12 have antiviral properties and 6 have antiviral efcacy against coronaviruses specifcally, in vitro. All candidate drugs are either FDA approved or are under investigation. Our candidate drug fndings are discordant with (i.e., reverse) SARS‑CoV‑2 transcriptome signatures generated in vitro, and a subset are also identifed in transcriptome signatures generated from COVID‑19 patient samples, like the MEK inhibitor selumetinib. Overall, our fndings provide additional support for drugs that are already being explored as therapeutic agents for the treatment of COVID‑19 and identify promising novel targets that are worthy of further investigation.
    [Show full text]
  • Votrient, INN-Pazopanib
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT Votrient 200 mg film-coated tablets Votrient 400 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Votrient 200 mg film-coated tablets Each film-coated tablet contains 200 mg pazopanib (as hydrochloride). Votrient 400 mg film-coated tablets Each film-coated tablet contains 400 mg pazopanib (as hydrochloride). For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet. Votrient 200 mg film-coated tablets Capsule-shaped, pink, film-coated tablet with GS JT debossed on one side. Votrient 400 mg film-coated tablets Capsule-shaped, white, film-coated tablet with GS UHL debossed on one side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Renal cell carcinoma (RCC) Votrient is indicated in adults for the first-line treatment of advanced renal cell carcinoma (RCC) and for patients who have received prior cytokine therapy for advanced disease. Soft-tissue sarcoma (STS) Votrient is indicated for the treatment of adult patients with selective subtypes of advanced soft-tissue sarcoma (STS) who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo) adjuvant therapy. Efficacy and safety has only been established in certain STS histological tumour subtypes (see section 5.1). 4.2 Posology and method of administration Votrient treatment should only be initiated by a physician experienced in the administration of anti-cancer medicinal products. 2 Posology Adults The recommended dose of pazopanib for the treatment of RCC or STS is 800 mg once daily. Dose modifications Dose modification (decrease or increase) should be in 200 mg decrements or increments in a stepwise fashion based on individual tolerability in order to manage adverse reactions.
    [Show full text]
  • BC Cancer Benefit Drug List September 2021
    Page 1 of 65 BC Cancer Benefit Drug List September 2021 DEFINITIONS Class I Reimbursed for active cancer or approved treatment or approved indication only. Reimbursed for approved indications only. Completion of the BC Cancer Compassionate Access Program Application (formerly Undesignated Indication Form) is necessary to Restricted Funding (R) provide the appropriate clinical information for each patient. NOTES 1. BC Cancer will reimburse, to the Communities Oncology Network hospital pharmacy, the actual acquisition cost of a Benefit Drug, up to the maximum price as determined by BC Cancer, based on the current brand and contract price. Please contact the OSCAR Hotline at 1-888-355-0355 if more information is required. 2. Not Otherwise Specified (NOS) code only applicable to Class I drugs where indicated. 3. Intrahepatic use of chemotherapy drugs is not reimbursable unless specified. 4. For queries regarding other indications not specified, please contact the BC Cancer Compassionate Access Program Office at 604.877.6000 x 6277 or [email protected] DOSAGE TUMOUR PROTOCOL DRUG APPROVED INDICATIONS CLASS NOTES FORM SITE CODES Therapy for Metastatic Castration-Sensitive Prostate Cancer using abiraterone tablet Genitourinary UGUMCSPABI* R Abiraterone and Prednisone Palliative Therapy for Metastatic Castration Resistant Prostate Cancer abiraterone tablet Genitourinary UGUPABI R Using Abiraterone and prednisone acitretin capsule Lymphoma reversal of early dysplastic and neoplastic stem changes LYNOS I first-line treatment of epidermal
    [Show full text]
  • Genome-Wide DNA Copy Number Predictors of Lapatinib Sensitivity in Tumor-Derived Cell Lines
    935 Genome-wide DNA copy number predictors of lapatinib sensitivity in tumor-derived cell lines Joel Greshock,1 Jie Cheng,2 David Rusnak,1 either EGFR or HER2, lapatinib treatment results in growth Anne Marie Martin,3 Richard Wooster,1 arrest and cell death (1), suggesting that it may be possible Tona Gilmer,1 Kwan Lee,2 Barbara L. Weber,1 to predict clinical response based on a tumor’s genetic in vitro and Tal Zaks3 profile. Although larger screens confirm strong associations between EGFR and HER2amplification with 1Translational Medicine Oncology, GlaxoSmithKline, King of lapatinib responsiveness, some tumor models seem to Prussia, Pennsylvania and 2Department of Biostatistics and Data 3 respond in the absence of these markers (2, 3). This Management and Medicines Development Center, Oncology, observation indicates that additional proteins may cooper- GlaxoSmithKline, Collegeville, Pennsylvania ate with HER2in promoting lapatinib responsiveness, thereby forming the basis of a more inclusive means of Abstract predicting clinical response. Such proteins may include the A common aim of pharmacogenomic studies that use linear cascades that constitute the mitogen-activated genome-wide assays on panels of cancers is the unbiased cascade, the stress-activated protein kinase cascade, protein discovery of genomic alterations that are associated with kinase C, and the Akt pathway (4). clinical outcome and drug response. Previous studies of Altered DNA copy number is a hallmark feature of the lapatinib, a selective dual-kinase inhibitor of epidermal cancer genome. A number of tumor suppressor genes have growth factor receptor (EGFR) and HER2 tyrosine kinases, been mapped to homozygous deletions, including RB1 and have shown predictable relationships between the activity SMAD4/DPC4 (5, 6).
    [Show full text]
  • Activity of Lapatinib Is Independent of EGFR Expression Level in HER2-Overexpressing Breast Cancer Cells
    1846 Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing breast cancer cells Dongwei Zhang,1,2 Ashutosh Pal,3 overexpressed (i.e., HER2-positive) in 20% to 30% of breast William G. Bornmann,3 Fumiyuki Yamasaki,1,2 cancers (4, 5). EGFR and HER2 are known to drive tumor Francisco J. Esteva,1,4 Gabriel N. Hortobagyi,4 growth and progression and have emerged as promising Chandra Bartholomeusz,1,2 and Naoto T. Ueno1,2,4 targets for cancer therapy. A number of small molecules that target individual or 1Breast Cancer Translational Research Laboratory, dual ErbB receptors have been developed and tested in Departments of 2Stem Cell Transplantation and Cellular 3 4 clinical trials. Lapatinib, a dual inhibitor of EGFR and Therapy, Experimental Diagnostic Imaging, and Breast HER2 tyrosine kinases, has already been approved by the Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas US Food and Drug Administration as a treatment for HER2-positive metastatic breast cancer (6, 7). Lapatinib as a single agent or in combination with trastuzumab or Abstract capecitabine exhibited activity against HER2-positive ad- Epidermal growth factor receptor (EGFR/ErbB1) and HER2 vanced or metastatic breast cancer that has progressed after (ErbB2/neu), members of the ErbB receptor tyrosine kinase trastuzumab therapy (8–10). The activity of lapatinib in family, are frequently overexpressed in breast cancer and inflammatory breast cancer was evaluated in an interna- are known to drive tumor growth and progression, making tional Phase II trial (11). Although lapatinib showed them promisingtargetsfor cancer therapy.
    [Show full text]
  • Changing the Destiny of HER2 Expressing Solid Tumors
    International Journal of Molecular Sciences Review Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors Alice Indini 1 , Erika Rijavec 1 and Francesco Grossi 2,* 1 Medical Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; [email protected] (A.I.); [email protected] (E.R.) 2 Medical Oncology Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy * Correspondence: [email protected] or [email protected] Abstract: HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer.
    [Show full text]
  • 5Th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 5)5
    SPECIAL ARTICLE 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5)5 F. Cardoso1*, S. Paluch-Shimon2, E. Senkus3, G. Curigliano4, M. S. Aapro5, F. André6, C. H. Barrios7, J. Bergh8, G. S. Bhattacharyya9, L. Biganzoli10, F. Boyle11, M.-J. Cardoso1,12, L. A. Carey13, J. Cortés14,15, N. S. El Saghir16, M. Elzayat17, A. Eniu18, L. Fallowfield19, P. A. Francis20, K. Gelmon21, J. Gligorov22, R. Haidinger23, N. Harbeck24,X.Hu25, B. Kaufman26, R. Kaur27, B. E. Kiely28, S.-B. Kim29, N. U. Lin30, S. A. Mertz31, S. Neciosup32, B. V. Offersen33, S. Ohno34, O. Pagani35, A. Prat36,37,38, F. Penault-Llorca39,40, H. S. Rugo41, G. W. Sledge42, C. Thomssen43, D. A. Vorobiof44, T. Wiseman45,B.Xu46, L. Norton47, A. Costa48,49 & E. P. Winer30 1Breast Unit, Champalimaud Clinical Centre/Champalimaud Foundation, Lisbon, Portugal; 2Sharett Division of Oncology, Hadassah University Hospital, Jerusalem, Israel; 3Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; 4Department of Oncology and Hemato-Oncology, European Institute of Oncology, IRCCS, Division of Early Drug Development, University of Milan, Milan, Italy; 5Breast Center, Clinique de Genolier, Genolier, Switzerland; 6Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; 7Latin American Cooperative Oncology Group (LACOG), Grupo Oncoclínicas, Porto Alegre, Brazil; 8Department of Oncology-Pathology, Karolinska Institute & University Hospital, Stockholm, Sweden; 9Department of Medical Oncology, Salt Lake City Medical Centre,
    [Show full text]