UMLS:C0242379 - FACTA Search

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Query: UMLS:C0242379 (lung cancer)
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Erlotinib (CP-358774, OSI-774, Tarceva), a quinazoline derivative, is an orally active epidermal growth factor receptor tyrosine kinase inhibitor under development jointly by Genentech, OSI (formerly Oncogene Science) and Roche, both as monotherapy and combination therapy for the potential treatment of solid tumors, including non-small-cell lung cancer (NSCLC) and pancreatic, breast, head and neck cancers [203487]. Development of the compound is most advanced for NSCLC and pancreatic cancer; in July 2001, phase III combination trials were initiated for NSCLC [416835]. In October 2001, phase III monotherapy trials in NSCLC and phase III combination trials in pancreatic cancer were also initiated [426704]. In Japan, the compound was in phase I studies in January 2002 [439189].
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PMID:Erlotinib OSI/Roche/Genentech. 1249 17

Erlotinib [Tarceva, R 1415, CP 358774, OSI 774, NSC 718781] is a small molecular, once-a-day, orally active inhibitor of the epidermal growth factor receptor tyrosine kinase. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is one of a class of anticancer drugs that target the underlying molecular mechanism involving oncogenes and tumour suppressor genes, which play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is undergoing clinical development as an oral tablet by an alliance between OSI Pharmaceuticals, Genentech and Roche. OSI Pharmaceuticals, Genentech and Roche have entered an agreement for the global development and commercialisation of erlotinib. Under the terms of the agreement, Genentech and OSI will share costs and profit-taking for commercialising the product in the US. The overall costs of the development programme will be shared equally between the three companies. OSI will keep certain co-promotion rights in the US and Genentech will be responsible for commercialising the drug in the US should the FDA approve it. Roche will take the responsibility for obtaining regulatory approval and commercialisation in territories outside the US and pay royalties to OSI on net sales of the product in these markets. Initially, the alliance partners intend to pursue development of erlotinib in all the major tumour markets, particularly for non-small cell lung cancer (NSCLC) in which the group will focus on front-line combination approaches. Pfizer and OSI Pharmaceuticals in the US were developing erlotinib as a treatment for solid tumours. However, in June 2000, Pfizer merged with Warner-Lambert. The resulting company retained the Pfizer name, but in order to meet Federal Trade Commission requirements for the merger Pfizer granted all developmental and marketing rights for erlotinib to OSI Pharmaceuticals. This divestiture of the erlotinib portfolio, in effect, gave OSI a royalty-free, cashless license to the drug. In November 2001, OSI announced a partnership deal with HopeLink Corporation, a healthcare information technology company with an Internet-based Clinical Trial Service. The partnership will enable OSI to heighten awareness of its clinical trials and shorten patient accrual times. It will initially involve the presentation of the OSI phase III pancreatic and refractory NSCLC trials via Hopelink's Syndicated Network. In addition to this the two companies have also agreed to develop additional products and service together that will increase the efficiency of the clinical trial process, increase awareness of clinical trials, and enhance patient accrual techniques. OSI has also entered into an agreement with Therradex, a contract research organisation (CRO) to monitor phase II trials for erlotinib in NSCLC, ovarian and head and neck cancer. In addition, OSI entered into an agreement in 2001 with the US NCI. The NCI is conducting trials in a variety of different cancers. A phase III front-line NSCLC trial (TRIBUTE) of erlotinib in combination with carboplatin and paclitaxel was initiated in July 2001. The multicentre study is being conducted by Genentech in 1000 patients in the US, and will determine whether the addition of erlotinib to carboplatin chemotherapy is able to improve the duration of patient survival. Enrolment for this trial was completed in July 2002. An independent Data Monitoring Committee (DMC) has since reviewed the data from the trial and concluded that there are no safety or efficacy concerns that would warrant stopping the trial. However, the DMC did recommend stopping erlotinib at the time of disease progression or at the start of second-line therapy. A front-line phase III study of erlotinib in NSCLC (TALENT) in combination with gemcitabine and cisplatin chemotherapy was initiated by Roche in Europe in November 2001. Enrolment into this study was completed in September 2002, with approximately 1200 patients. Roche has confirmed that the study woulde has confirmed that the study would be included in the alliance's potential regulatory submission for front-line therapy in chemotherapy-naive patients in the US. Data from the trial is expected in the second half of 2003. OSI has opened two additional phase Ib studies to examine the potential of erlotinib in combination with carboplatin and paclitaxel in one study and gemcitabine and cisplatin in the other. A phase I study of erlotinib is also being conducted in patients with lung cancer in Japan. OSI received fast-track status from the US FDA in September 2002 for erlotinib as a second- or third-line treatment for patients with incurable stage IIIB/IV NSCLC who have failed to respond to standard therapy for advanced metastatic disease. Fast-track status was also granted to erlotinib in May 2002 for the treatment of chemotherapy-naive stage III/IV NSCLC. There are important differences between phase III studies of erlotinib and AstraZeneca's direct competitor drug gefitinib, which recently returned disappointing results in a frontline NSCLC trial with combination chemotherapy. In assessing the survival benefit of erlotinib with chemotherapy, the dose employed of 150 mg/day is the maximum tolerated dose (MTD), whereas the gefitinib trials were conducted at relatively lower doses than the MTD determined in earlier phase I studies. OSI is also investigating the survival benefit of erlotinib in a phase III study in refractory NSCLC patients, a key registration study. Patient size of the NSCLC trial was increased from 330 to 700 as OSI shifted emphasis from its pancreatic cancer trials. Phase II development for this indication was initiated based on data from a phase I trial, which had completed patient enrolment by April 2003. OSI and the US NCI signed a collaborative research agreement in 2001. The NCI is developing erlotinib through its CTEP programme for multiple tumour types including epithelial malignancies, gastrointestinal and genitourinary tracts, gynaecological malignancies and brain tumours. OSI supplies erlotinib for the trial, but the NCI provides the funding and manages the trials. A series of approximately ten phase Ib trials are already underway or were set to start in the US in 2001 to determine safety, tolerance and pharmacokinetic parameters of erlotinib in combination with a number of commonly used chemotherapeutic agents. The Wall Street Journal reported on 25 February 2002, that analysts at Robert Stephens, New York, USA, have forecast Tarceva to reach annual sales of >$US1 billion. Other analysts, at Merrill Lynch & Co., have predicted that products belonging to the same class as Tarceva could reach combined worldwide sales of $US6 billion to $US10 billion annually. In an earlier report by the Financial Times on 10 May 2001, it was stated that approximately 12 new anticancer agents are expected to be approved by the FDA through to the end of 2002. These agents, of which Tarceva is one, were said to have the potential to generate total sales of $US2.6 billion. Goldman Sachs have forecast Tarceva to reach peak sales of $US250 million for the indication of head and neck cancer alone. Previously in January 2001, the Financial Times claimed that OSI Pharmaceuticals, one of the development partners for Tarceva, stood to gain $US187 million pending regulatory approval. Genentech and Roche were each said to be buying $US35 million worth of OSI's stock and paying upfront fees. Tarceva is facing competition by two similar compounds, developed by AstraZeneca and ImClone, respectively.
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PMID:Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415. 1284 90

The epidermal growth factor receptor (EGFR) is a transmembrane receptor involved in the regulation of a complex array of essential biological processes such as cell proliferation and survival. Dysregulation of EGFR signaling network has been frequently reported in multiple human cancers and has been associated with the processes of tumor development, growth, proliferation, metastasis and angiogenesis. Inhibition of the EGFR was associated with antitumor effects in preclinical models. On the bases of these data, therapeutics targeting the EGFR were explore in clinical trials. Tarceva (OSI-774, OSI Pharmaceuticals, Uniondale, NY) is a small molecule selective inhibitor of the EGFR tyrosine kinase (TK). In preclinical studies, Tarceva inhibited the phosphorylation of the EGFR in a dose and concentration dependent manner resulting in cell cycle arrest and induction of apoptosis. In in vivo studies, the agent caused tumor growth inhibition and shoved synergistic effects when combined with conventional chemotherapy. Subsequent single agent phase I studies and phase I studies in combination with chemotherapy demonstrated that the agent has a good safety profile and induced tumor growth inhibition in a substantial number of patients with a variety of different solid tumor. Preliminary report from phase II studies confirmed the excellent tolerability of Tarceva as well as showed encouraging preliminary activity. Phase III studies have either been completed or are ongoing in several tumor types such as lung cancer and pancreatic cancer. In summary, Tarceva is a novel inhibitor of the EGFR TK which has shown promising activity in initial studies and is currently undergoing full development as an anticancer drug.
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PMID:Development of the epidermal growth factor receptor inhibitor Tarceva (OSI-774). 1290 62

Improved understanding of tumor biology has led to the identification of numerous growth factors that are involved in malignant transformation and tumor progression. Many of these factors induce cellular responses through receptors with intrinsic tyrosine kinase (TK) activity. Therefore, inhibiting the activity of TK receptors is one of the ways to effectively block the disordered proliferation of cancer that arises from these pathways. The human epidermal growth factor receptor (HER) family is overexpressed or dysfunctional in many human malignancies. Therefore, these receptors have been identified as targets for cancer therapy. Several agents have been developed that reversibly or irreversibly inhibit one, two, or all of the HER receptors. Iressa and Tarceva are HER1-specific TK inhibitors that are in advanced development. The large phase II study of Iressa (IDEAL1) in patients with non-small-cell lung cancer (NSCLC) in whom previous platinum-based therapy has failed, found that the median survival time (MST) was 7.6 months, which was no less than that with Docetaxel treatment. Other dual or pan-HER, reversible or irreversible, TK inhibitors are being investigated in phase I trials. Early data show that they are generally well tolerated and have provided evidence of against activity tumors. HER-TK inhibitors are likely to have a substantial impact on the treatment of cancer patients.
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PMID:Molecular target-based cancer therapy: tyrosine kinase inhibitors. 1295 75

The epidermal growth factor receptor (EGFR) has emerged in recent years as a key target of molecular therapy for solid tumors. The postembryonic role of EGFR is normally limited. In cancer, however, abnormal EGFR-tyrosine kinase (TK) activity plays a central role in many of the processes involved in tumor progression, such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Several different approaches have been taken to inhibit EGFR-mediated activity in tumor cells, including monoclonal antibodies directed at the ligand-binding portion of the EGFR and small-molecule agents that directly inhibit the intracellular TK domain of EGFR. Two of these TK inhibitors, gefitinib and erlotinib (OSI-774, Tarceva ), have shown antitumor activity and good tolerability across several tumor types in early dose-finding clinical trials, particularly for non-small-cell lung cancer (NSCLC). In heavily pretreated patients with advanced NSCLC, gefitinib showed clinically significant tumor responses and symptom relief with good tolerability. Based on these results, gefitinib has now been approved for the third-line treatment of advanced NSCLC. The use of gefitinib in standard treatment programs or combined with other molecular targeted agents may substantially improve the outlook for patients with NSCLC or other types of solid tumors
Clin Lung Cancer 2003 Sep
PMID:Biologically targeted treatment of non-small-cell lung cancer: focus on epidermal growth factor receptor. 1464 89

Non-small-cell lung cancer represents a growing global burden and remains a therapeutic challenge. Only small improvements in survival have been made with standard chemotherapeutic approaches to advanced disease in recent history. Novel biologic targeted therapies offer the potential of improving patient management and treatment outcomes in non-small-cell lung cancer. Prominent among these novel agents are the HER1/epithelial growth factor receptor (EGFR) inhibitors. One of these agents, gefitinib (Iressa), is already approved for use in advanced, refractory non-small-cell lung cancer. Erlotinib (Tarceva) is a promising HER1/EGFR inhibitor in phase III evaluation as first-line therapy combined with chemotherapy and as second-/third-line monotherapy in advanced non-small-cell lung cancer. In addition, erlotinib is being evaluated in combination with the angiogenesis inhibitor bevacizumab (Avastin), a strategy combining two new modalities in cancer treatment. Results of these trials will provide important information on optimal use of these new targeted therapies and may offer the promise of improving the treatment of non-small-cell lung cancer.
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PMID:Targeting the HER1/EGFR receptor to improve outcomes in non-small-cell lung cancer. 1468 17

Erlotinib (Tarceva) is an orally available selective small-molecule inhibitor of HER1/EGFR tyrosine kinase with a 50% inhibitory concentration of 2 nM for purified tyrosine kinase. This agent has been shown to produce stasis or regression of tumor growth in human cancer xenograft models, including non-small-cell lung cancer models. Ongoing preclinical investigations indicate that inhibition of the MAPK and Atk signaling pathways downstream of HER1/EGFR may be required for optimal antitumor effects. Erlotinib exhibits inhibition of MAPK and Atk kinases at concentrations higher than those required for HER1/EGFR tyrosine kinase inhibition; such findings suggest that maximal inhibition of HER1/EGFR, requiring high erlotinib doses, is necessary for optimum antitumor activity. These considerations are supported by tumor models, including non-small-cell lung cancer models, showing dose-related antitumor effects up to high doses of erlotinib. Erlotinib exhibits additive antitumor effects when combined with chemotherapeutic agents (cisplatin, doxorubicin, paclitaxel, gemcitabine [Gemzar], and capecitabine [Xeloda]), radiation therapy, and other targeted agents (e.g., bevacizumab [Avastin]). Recent studies indicate that erlotinib inhibits the EGFRvIII mutant at concentrations higher than those required for inhibition of wild-type receptor. Ongoing investigation will help to determine optimal dosing and dose frequency of erlotinib in various cancers in the clinical setting.
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PMID:Erlotinib: preclinical investigations. 1468 18

In phase I trials in healthy volunteers and patients with refractory cancers, erlotinib (Tarceva) was well tolerated and showed activity against non-small-cell lung cancer and other tumors. The dose identified for further clinical development was 150 mg/d; at this dose, erlotinib achieves high exposure, with maximum concentrations greater than 2,000 ng/mL and 24-hour area under the concentration-time cure greater than 35,000 ng.h/L. In a phase II trial in 57 patients with previously treated advanced non-small-cell lung cancer, erlotinib treatment produced an objective response rate of 12.3% and a stable disease rate of 38.6%, with median duration of response of 19.6 weeks; median overall survival was 8.4 months and 1-year survival was 40%, with 9 patients remaining alive over follow-up of greater than 18 months. No grade 4 toxicity was observed, and grade 3 toxicity was minimal. In an ongoing phase II trial in bronchioloalveolar carcinoma, erlotinib treatment has produced objective response in 26% of 50 evaluable patients, with median duration of response not yet having been reached. An ongoing phase II trial is examining the combination of erlotinib with the angiogenesis inhibitor bevacizumab (Avastin) in previously treated non-small-cell lung cancer; phase I evaluation revealed no dose-limiting toxicities at tested doses and provided evidence of antitumor activity. Two phase III trials are examining erlotinib in combination with carboplatin (Paraplatin)/paclitaxel (the TRIBUTE trial) or cisplatin/gemcitabine (Gemzar) (the TALENT trial) as first-line treatment in advanced non-small-cell lung cancer. The phase III BR.21 trial is assessing erlotinib monotherapy in advanced refractory non-small-cell lung cancer. Results of these phase II trials will soon be available.
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PMID:Clinical experience with the HER1/EGFR tyrosine kinase inhibitor erlotinib. 1468 19

Rash is a class effect of HER1/epidermal growth factor receptor (EGFR)-targeted agents, and has occurred with high frequency and in a dose-dependent manner in clinical trials of these agents in cancer patients. Analysis of phase II trials of erlotinib (Tarceva) in non-small-cell lung cancer, head and neck cancer, and ovarian cancer shows a significant association between rash severity and objective tumor response. Rash severity was highly significantly associated with survival in patients with non-small-cell lung cancer receiving erlotinib; median survival in patients with no rash was 46.5 days, compared with 257 days in those with grade 1 rash (P < .0001) and 597 days in those with grade 2/3 rash (P < .0001). Similarly, for the combined non-small-cell lung cancer, head and neck cancer, and ovarian cancer studies, median survival in patients with no rash was 103 days, compared with 191 days in those with grade 1 rash (P = .0001) and 266 days in those with grade 2/3/4 rash (P = .0001). Similar findings have been made with cetuximab (Erbitux) and in some settings with gefitinib (Iressa). The strong association of rash severity with response/survival suggests that rash may serve as a marker of response to erlotinib treatment and may be used to guide treatment to obtain optimal response. Dosing erlotinib at the maximum tolerated dose, which is associated with more frequent and more severe rash, may improve response rates and survival durations. Further study of the potentially important association between rash and outcome of treatment with EGFR-targeted agents is needed.
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PMID:Can rash associated with HER1/EGFR inhibition be used as a marker of treatment outcome? 1468 20

The identification of predictive or surrogate markers of response to HER1/epidermal growth factor receptor (EGFR) inhibitor treatment would permit selection of patients most likely to respond to such treatment. Markers could consist of tumor characteristics (e.g., characteristics of the receptor or downstream signaling molecules and determinants of resistance) or host characteristics (e.g., pharmacokinetic parameters and toxicities). The occurrence of rash may constitute a surrogate marker of response to erlotinib (Tarceva) treatment in patients with non-small-cell lung cancer and other cancers. The erlotinib marker identification program has been designed to identify and investigate other candidate markers by analysis of a large number of clinical samples from patients enrolled in erlotinib trials in non-small-cell lung cancer, including the phase III TALENT and TRIBUTE trials of erlotinib combined with chemotherapy and the phase III BR.21 trial of erlotinib monotherapy in advanced non-small-cell lung cancer. This program should both contribute to understanding of the molecular biology of HER1/EGFR inhibition and result in identification of potential markers that can be evaluated in the clinical setting.
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PMID:Identifying predictive and surrogate markers of erlotinib antitumor activity other than rash. 1468 21

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