Tal Zaks

Icahn School of Medicine at Mount Sinai, Manhattan, New York, United States

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Publications (14)108.98 Total impact

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    ABSTRACT: To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology. Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or uterine tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1,500 mg PO daily. The planned sample size was 250 patients with HER2 amplified tumors, with the goal of randomizing 100 patients with stable disease (SD) at week 12 to either lapatinib or placebo. Patients responding after 12 weeks continued on lapatinib; those who progressed were discontinued from study. The primary objectives were response rate after 12 weeks and the percentage of patients who remained progression free 12 weeks after randomization to placebo versus lapatinib. Secondary objectives were duration of response and determination of the incidence of HER2 amplification in multiple tumor types. A total of 141 patients were screened and 32 patients with HER2 amplified tumors were enrolled. At week 12, 1 (3%) patient had a complete response, 9 (28%) had stable disease, 20 (63%) had progressive disease, and 2 (6%) were unknown. Only 7 patients with SD underwent randomization. The low response rate coupled with slow screening and enrollment led to early study closure. Basing trial eligibility on the presence of a genetic target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy is associated with modest activity. The target-specific histology-independent randomized discontinuation design still merits consideration for targets clearly implicated in "oncogene addiction".
    Investigational New Drugs 04/2012; 30(2):695-701. · 3.50 Impact Factor
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    ABSTRACT: We conducted a phase II, open-label, multicenter study to evaluate the efficacy, safety, and tolerability of daily lapatinib plus weekly paclitaxel in treatment-naïve patients with inflammatory breast cancer (IBC). The primary end point was pathologic complete response (pCR). Secondary end points included combined clinical response rate (based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria and clinically evaluable skin disease criteria). Patients were assigned to either cohort A (human epidermal growth factor receptor 2 [HER2] 2+ or 3+ by immunohistochemistry [IHC] or fluorescent in situ hybridization [FISH] -amplified +/- epidermal growth factor receptor [EGFR] expression) or cohort B (HER2-negative/EGFR-positive). A subpopulation of cohort A considered HER2-positive by the current definition of overexpression (3+ by IHC or FISH-amplified) was also analyzed. Patients received lapatinib at 1,500 mg/d for 14 days, then lapatinib at 1,500 mg/d plus weekly paclitaxel (80 mg/m(2)) for 12 weeks, followed by surgical resection or additional chemotherapy. Forty-nine women were enrolled (cohort A, n = 42; cohort B, n = 7). Cohort B was terminated because of slow accrual and lack of efficacy observed in IBC patients with HER2-negative/EGFR-positive tumors enrolled onto the parallel study, EGF103009. pCR occurred in 18.2% (95% CI, 5.2% to 40.3%) of cohort A patients. Combined clinical response rate was 78.6% (95% CI, 63.2% to 89.7%) in all cohort A patients and 78.1% (95% CI, 60.0% to 90.7%) in the HER2-positive subset. Common adverse events included diarrhea, rash, alopecia, and nausea (> 50% of patients in both cohorts). The incidence of grade 3 diarrhea was 55%. Lapatinib monotherapy for 14 days followed by lapatinib plus paclitaxel for 12 weeks provided clinical benefit in IBC patients with HER2-overexpressing tumors without unexpected toxicity.
    Journal of Clinical Oncology 07/2010; 28(20):3248-55. · 18.04 Impact Factor
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    ABSTRACT: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non-small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history. Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications. Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of >or=24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of >or=24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens. Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC.
    Clinical Cancer Research 03/2010; 16(6):1938-49. · 7.84 Impact Factor
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    ABSTRACT: The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. Vascular endothelial growth factor (VEGF) receptors are expressed on the surface of vascular endothelial cells and cooperate with Met to induce tumor invasion and vascularization. EXEL-2880 (XL880, GSK1363089) is a small-molecule kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with additional inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor beta, and Tie-2. Binding of EXEL-2880 to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the Met kinase active site cleft. EXEL-2880 inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. In addition, EXEL-2880 prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis. Collectively, these data indicate that EXEL-2880 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors.
    Cancer Research 10/2009; 69(20):8009-16. · 9.28 Impact Factor
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    ABSTRACT: Inflammatory breast cancer is an aggressive and biologically distinct form with a higher frequency of HER2 overexpression than other breast cancers. For patients with resistance to conventional anthracycline or taxane and trastuzumab treatment, options are limited. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor tyrosine kinases, previously had a 50% response rate in a cohort of 30 patients with HER2-overexpressing (HER2+) recurrent or anthracycline-refractory inflammatory breast cancer. We aimed to assess efficacy of lapatinib in an expanded cohort of patients with relapsed or refractory HER2+ disease. From March, 2005, to September, 2007, 126 patients with relapsed or refractory HER2+ inflammatory breast cancer were treated with lapatinib 1500 mg once daily in a non-randomised, open-label, phase II study. Pretreatment tumour biopsies were done to verify pathological features of inflammatory breast cancer. Skin disease was assessed every 4 weeks, and response in sites of measurable locally advanced or metastatic disease were assessed by response evaluation in solid tumours (RECIST) criteria every 8 weeks. The primary aim was to assess combined objective response rate, by clinically evaluable skin disease criteria and RECIST, if applicable. Analyses were done by intention to treat; patients with missing data were treated as non-responders. This study is registered with ClinicalTrials.gov, number NCT00105950. Clinical presentation and biomarker analysis showed a tumour molecular profile consistent with inflammatory breast cancer. No patients had complete response. 49 patients (39%; 95% CI 30-48) had partial response. Median progression-free survival was 14.6 weeks (95% CI 12.1-16.0), with median duration of response of 20.9 weeks (12.7-32.1). Likelihood of response to lapatinib was not affected by previous treatment with trastuzumab. 130 (92%) of 141 patients had at least one adverse event; 45 (32%) had serious adverse events, the most common were dyspnoea (eight patients) and pleural effusion (six). Five patients had fatal adverse events that were possibly treatment related. Lapatinib monotherapy is a potentially effective treatment for relapsed or refractory HER2+ inflammatory breast cancer. GlaxoSmithKline.
    The Lancet Oncology 05/2009; 10(6):581-8. · 25.12 Impact Factor
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    ABSTRACT: To describe a phase II study design to evaluate the activity of novel anti-cancer agents that focuses on molecular pathogenesis rather than tumor histology. We propose an enrichment design that enrolls patients across histologies expressing target X and incorporates randomized discontinuation of drug Y after an initial treatment period to evaluate for potential cystostatic activity. We are currently evaluating the activity of lapatinib in patients with HER-2 amplified solid tumors using the target-specific, histology-independent, randomized discontinuation design. Patients receive treatment with lapatinib for an initial 12-week period. After restaging, patients with disease progression are removed from study, patients achieving an objective response continue treatment, and patients with stable disease are randomized to continue lapatinib versus initiate treatment with placebo. The primary endpoints are to evaluate the objective response rate during the initial treatment period and to evaluate the proportion of patients progression-free 12 weeks post-randomization. The target-specific, histology-independent, randomized discontinuation design is an attractive alternative to the traditional phase II design for the development of "targeted" therapeutics.
    Investigational New Drugs 04/2009; 28(2):194-8. · 3.50 Impact Factor
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    ABSTRACT: A majority of malignant melanomas harbor an oncogenic mutation in either BRAF or NRAS. If BRAF and NRAS transform melanoma cells by a similar mechanism, then additional genetic aberrations would be similar (or random). Alternatively, distinct mutation-associated changes would suggest the existence of unique cooperating requirements for each mutation group. We first analyzed a panel of 52 melanoma cell lines (n = 35, 11, 6 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively) by array-based comparative genomic hybridization for unique alterations that associate with each mutation subgroup. Subsequently, those DNA copy number changes that correlated with a mutation subgroup were used to predict the mutation status of an independent panel of 43 tumors (n = 17, 13, 13 for BRAF*, NRAS*, and BRAF/NRAS(wt/wt), respectively). BRAF mutant tumors were classified with a high rate of success (74.4%, P = 0.002), whereas NRAS mutants were not significantly distinguished from wild types (26/43, P = 0.12). Copy number gains of 7q32.1-36.3, 5p15.31, 8q21.11, and 8q24.11 were most strongly associated with BRAF* tumors and cell lines, as were losses of 11q24.2-24.3. BRAF* melanomas appear to be associated with a specific profile of DNA copy number aberrations that is distinct from those found in NRAS* and BRAF/NRAS(wt/wt) tumors. These findings suggest that although both BRAF and NRAS appear to function along the same signal transduction pathway, each may have different requirements for cooperating oncogenic events. The genetic loci that make up this profile may harbor therapeutic targets specific for tumors with BRAF mutations.
    Genes Chromosomes and Cancer 03/2009; 48(5):419-28. · 3.55 Impact Factor
  • Tal Zaks
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    ABSTRACT: The elucidation of the human genome sequence and the advent of genomic technologies have the potential to facilitate drug discovery and development as well as to define individual risks and benefits associated with specific therapeutic interventions. This chapter focuses on the application of this knowledge within the pharmaceutical industry, by providing current examples of the relevance of both germline and somatic genotypic variations to adverse event and efficacy profiles of recently developed anti-cancer drugs. These examples, discussed within the scientific, regulatory, and economic frameworks that shape the industry, highlight both the potential benefits and the emerging challenges to the application of post-genomic science to “real-life” drug development. Key WordsSingle nucleotide polymorphisms–CYP2C19–lapatinib–ADME–pharmacogenetics
    12/2008: pages 313-325;
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    ABSTRACT: A common aim of pharmacogenomic studies that use genome-wide assays on panels of cancers is the unbiased discovery of genomic alterations that are associated with clinical outcome and drug response. Previous studies of lapatinib, a selective dual-kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2 tyrosine kinases, have shown predictable relationships between the activity of these target genes and response. Under the hypothesis that additional genes may play a role in drug sensitivity, a predictive model for lapatinib response was constructed from genome-wide DNA copy number data from 24 cancer cell lines. An optimal predictive model which consists of aberrations at nine distinct genetic loci, includes gains of HER2, EGFR, and loss of CDKN2A. This model achieved an area under the receiver operating characteristic curve of approximately 0.85 (80% confidence interval, 0.70-0.98; P < 0.01), and correctly classified the sensitivity status of 8 of 10 head and neck cancer cell lines. This study shows that biomarkers predictive for lapatinib sensitivity, including the previously described copy number gains of EGFR and HER2, can be discovered using novel genomic assays in an unbiased manner. Furthermore, these results show the utility of DNA copy number profiles in pharmacogenomic studies.
    Molecular Cancer Therapeutics 05/2008; 7(4):935-43. · 5.60 Impact Factor
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    ABSTRACT: Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected. Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.
    Journal of Clinical Oncology 04/2008; 26(7):1066-72. · 18.04 Impact Factor
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    ABSTRACT: Tumor-derived cell lines are used as in vitro cancer models, but their ability to accurately reflect the phenotype and genotype of the parental histology remains questionable, given the prevalence of documented cell line-specific cytogenetic changes. We have addressed the issue of whether copy number alterations seen in tumor-derived cell lines reflect those observed in studies of fresh tissue by carrying out a meta-analysis of array-based comparative genomic hybridization data that considers both copy number alteration frequencies and the occurrence of cancer gene amplifications and homozygous deletions. Pairwise correlation comparisons between the data sets of seven diagnosis-specific matched tumor and cell line groups indicate that the trends in aberration frequencies are highly correlated between tumors and cell line sets of matched cancer histology relative to unmatched pairings. Despite their similarities, cell lines showed uniformly higher locus-specific alteration frequencies (P = 0.004) and several recurring cell line-specific alterations emerged. These include the previously documented losses of 13q and 9p and gains of 20q, as well as additional undescribed cell line-specific gains of 5p, 7p, and 17q and losses of 18q and 4q. These results indicate that, on average, cell lines preserve in vitro the genetic aberrations that are unique to the parent histology from which they were derived while acquiring additional locus-specific alterations. These data may enable a more predictive understanding of individual cell lines as in vitro models of cancer biology and therapy.
    Cancer Research 05/2007; 67(8):3594-600. · 8.65 Impact Factor
  • Oncogenomics, AACR, Phoenix, Arizona; 02/2007
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    ABSTRACT: Genomic aberrations in the form of subchromosomal DNA copy number changes are a hallmark of epithelial cancers, including breast cancer. The goal of the present study was to analyze such aberrations in breast cancer at high resolution. We employed high-resolution array comparative genomic hybridization with 4,134 bacterial artificial chromosomes that cover the genome at 0.9 megabase resolution to analyze 47 primary breast tumors and 18 breast cancer cell lines. Common amplicons included 8q24.3 (amplified in 79% of tumors, with 5/47 exhibiting high level amplification), 1q32.1 and 16p13.3 (amplified in 66% and 57% of tumors, respectively). Moreover, we found several positive correlations between specific amplicons from different chromosomes, suggesting the existence of cooperating genetic loci. Queried by gene, the most frequently amplified kinase was PTK2 (79% of tumors), whereas the most frequently lost kinase was PTK2B (hemizygous loss in 34% of tumors). Amplification of ERBB2 as measured by comparative genomic hybridization (CGH) correlated closely with ERBB2 DNA and RNA levels measured by quantitative PCR as well as with ERBB2 protein levels. The overall frequency of recurrent losses was lower, with no region lost in more than 50% of tumors; the most frequently lost tumor suppressor gene was RB1 (hemizygous loss in 26% of tumors). Finally, we find that specific copy number changes in cell lines closely mimicked those in primary tumors, with an overall Pearson correlation coefficient of 0.843 for gains and 0.734 for losses. High resolution CGH analysis of breast cancer reveals several regions where DNA copy number is commonly gained or lost, that non-random correlations between specific amplicons exist, and that specific genetic alterations are maintained in breast cancer cell lines despite repeat passage in tissue culture. These observations suggest that genes within these regions are critical to the malignant phenotype and may thus serve as future therapeutic targets.
    Breast cancer research: BCR 02/2005; 7(6):R1186-98. · 5.87 Impact Factor
  • European Journal of Medical Genetics - EUR J MED GENET. 01/2005; 48(4):492-493.