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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular targeting strategies for cancer therapy are distinct from conventional chemotherapy and radiotherapy in their potential to provide increased tumor specificity. One particular molecular target of high promise in oncology is the epidermal growth factor receptor (EGFR). The EGFR is overexpressed, dysregulated or mutated in many epithelial malignancies, and EGFR activation appears important in tumor growth and progression. Advances in signal transduction biology continue to sharpen our understanding regarding specific contributions of EGFR signaling networks to cancer behavior. Two predominant classes of EGFR inhibitors have been developed including monoclonal antibodies (mAbs) that target the extracellular domain of EGFR, such as cetuximab (Erbitux), and small molecule tyrosine kinase inhibitors (TKIs) that target the receptor catalytic domain of EGFR, such as gefitinib (Iressa) and erlotinib (Tarceva). Mechanisms of action for EGFR inhibitors have been investigated in preclinical model systems. Safety, activity, pharmacokinetics and pharmacodynamics have been assessed in clinical trials. The anti-EGFR mAbs and TKIs have partially overlapping toxicity profiles, but distinct routes of administration, serum half-lives and therefore dosing schedules. Both classes of agents show clear antitumor activity, and cetuximab and gefitinib have been recently FDA approved for colorectal and lung cancer indications respectively. However, the absence of survival benefit for EGFR TKIs in combination with chemotherapy in large-scale phase III lung cancer trials in 2003 underscores a major challenge in anti-EGFR oncology therapeutics; namely to identify those tumors and patients that will respond predictably to EGFR inhibitor approaches. Newly identified mutations in the EGFR catalytic domain that appear to confer sensitivity to EGFR TKIs promise to open new doors of investigation regarding response prediction. Advances will also require enhanced molecular understanding of the overall EGFR signaling network, and improved methods to gauge the dependence of individual tumors on EGFR signaling pathways for growth advantage. Results from newly reported phase III trials in 2004 now confirm a survival advantage for the use of EGFR inhibitors in combination with high-dose radiation in head and neck cancer, and in refractory lung cancer respectively. It appears likely that EGFR inhibitors (and other rationally designed molecular growth inhibitors) will play a meaningful role in cancer therapy in the years to come.
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PMID:Epidermal growth factor receptor inhibition strategies in oncology. 1561 46

Erlotinib (OSI-774; Tarceva) is an orally available, highly specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The results of 3 phase II studies with erlotinib in non-small-cell lung cancer (NSCLC) are reviewed herein: (1) in patients with chemotherapy-resistant, HER1/EGFR-expressing NSCLC of all histologies, (2) in patients with bronchoalveolar carcinoma previously untreated or treated with chemotherapy, and (3) as first-line therapy in elderly patients with NSCLC of all histologies. These studies have evaluated tumor response, survival, and symptom improvement. Erlotinib was given as an oral, continuous daily dose of 150 mg. The drug was well tolerated; drug-related cutaneous rash and diarrhea were observed in approximately two thirds of patients. Withdrawals caused by toxicity were rare. The response rates were 12.3%, 25%, and 13.3%, respectively. Mature survival data are available for the first trial. The median survival was 8.4 months, and the 1-year survival rate was 40%. All responding patients in the first and second trials presented skin rash. In addition, survival correlated with the occurrence and severity of rash in the first trial. No data on the correlation between rash and survival are available for the second and third trials. Erlotinib is active and well tolerated in patients with NSCLC as first- and second-line therapy. Cutaneous rash appears to be a surrogate marker of clinical benefit, but this finding needs to be confirmed in ongoing and future studies.
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PMID:Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. 1563 53

Lung cancer is primarily diagnosed during the advanced stage of disease, at which stage treatment options are severely limited. It is primarily for this reason that lung cancer carries a higher mortality rate than breast, prostate, and colon cancers combined. Traditional treatments for metastatic non-small-cell lung cancer (NSCLC) include chemotherapy; however, this approach, although the standard of care, is toxic and nonspecific, thereby rendering treatment inaccessible to those with a poor performance status. Alternatively, there are recent emerging treatment options that involve inhibiting specific molecular targets. This includes the epidermal growth factor receptor (EGFR), which is known to potentiate tumor cell proliferation and metastases, while also attenuating apoptosis. This target is especially important because approximately 85% of all lung cancers are categorized as NSCLC, which expresses EGFR at a rate of 40%-85%. In addition, newly developed EGFR-specific tyrosine kinase inhibitors (TKIs) have been used in clinical trials with encouraging results. To date, gefitinib and erlotinib (OSI-774; Tarceva) are the most studied of the EGFR TKIs for the treatment of NSCLC. In this article we have focused on 3 recently completed trials involving erlotinib as monotherapy (BR.21 study) or in combination with standard chemotherapeutic regimens (TALENT and TRIBUTE trials) for the treatment of NSCLC. When used in combination with carboplatin/paclitaxel (TALENT) or cisplatin/gemcitabine (TRIBUTE), erlotinib was found not to improve survival. These results contrast with what would be predicted from preclinical data outcomes, but they complement recent phase III reports involving similar combinations with gefitinib. Subset analysis of the TRIBUTE trial revealed that never-smokers had the greatest survival benefit. Conversely, erlotinib has exhibited overall survival benefits when used as monotherapy (BR.21 study). In addition, recent information involving mutations within the kinase domain of the EGFR may be implicated in the response seen with EGFR TKIs in recent trials.
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PMID:Select clinical trials of erlotinib (OSI-774) in non-small-cell lung cancer with emphasis on phase III outcomes. 1563 54

Erlotinib (Tarceva) is an orally available HER1 (epidermal growth factor receptor, EGFR) tyrosine kinase inhibitor advancing through clinical trials for the treatment of a range of human malignancies. In this study, we examine the capacity of erlotinib to modulate radiation response and investigate specific mechanisms underlying these interactions in human tumor cell lines and xenografts. The impact of erlotinib on cell cycle kinetics was analyzed using flow cytometry, and the impact on apoptosis was evaluated via fluorescein-labeled pan-caspase inhibition and poly(ADP-ribose) polymerase cleavage. Radiation-induced EGFR autophosphorylation and Rad51 expression were examined by Western blot analysis. Radiation survival was analyzed using a clonogenic assay and assessment of in vivo tumor growth was done using a mouse xenograft model system. Microarray studies were carried out using 20 K human cDNA microarray and select genes were validated using quantitative reverse transcription-PCR (RT-PCR). Independently, erlotinib and radiation induce accumulation of tumor cells in G(1) and G(2)-M phase, respectively, with a reduction of cells in S phase. When combined with radiation, erlotinib promotes a further reduction in S-phase fraction. Erlotinib enhances the induction of apoptosis, inhibits EGFR autophosphorylation and Rad51 expression following radiation exposure, and promotes an increase in radiosensitivity. Tumor xenograft studies confirm that systemic administration of erlotinib results in profound tumor growth inhibition when combined with radiation. cDNA microarray analysis assessing genes differentially regulated by erlotinib following radiation exposure identifies a diverse set of genes deriving from several functional classes. Validation is confirmed for several specific genes that may influence radiosensitization by erlotinib including Egr-1, CXCL1, and IL-1beta. These results identify the capacity of erlotinib to enhance radiation response at several levels, including cell cycle arrest, apoptosis induction, accelerated cellular repopulation, and DNA damage repair. Preliminary microarray data suggests additional mechanisms underlying the complex interaction between EGFR signaling and radiation response. These data suggest that the erlotinib/radiation combination represents a strategy worthy of further examination in clinical trials.
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PMID:Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). 1583 66

Specific and reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib are clinically active in advanced or metastatic NSCLC and both are approved in various countries for the treatment of patients that failed prior chemotherapy. Erlotinib has also prolonged survival in pancreatic cancer patients when added to gemcitabine and regulatory approval in this disease is being sought. Additional promising activity has been seen in other tumor types, such as ovarian cancer or head and neck malignancies, and phase III trials in these malignancies are ongoing or planned. Despite these successes, these agents have exhibited anecdotal or modest activity when used as single agents in unselected patients with various other tumor types. We have learned that the clinical development of these agents is far from simple and we need to better understand biological and clinical criteria for patient selection and how to best use the different available agents. The recent discovery of EGFR mutations and the potential identification of other markers that might predict patient response could help to optimize the use of these agents in the future. Irreversible EGFR inhibitors, dual EGF/HER2 and pan-ErbB receptor inhibitors may have greater antitumor activity although the tolerance of these compounds compared to specific EGFR TKIs needs further characterization. HER2 specific TKIs are also in development. Lapatinib, a dual EGFR/HER2 TK inhibitors, is particularly promising in breast cancer. Newer agents, such as BMS-599626, have recently entered into the clinic. In addition to the use of these agents as single agents, many clinical studies are addressing the role of combining them with hormonal agents, biological agents or chemotherapy.
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PMID:Small molecules with EGFR-TK inhibitor activity. 1585 87

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.
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PMID:Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. 1589 64

Cancer chemotherapy has been one of the major medical advances in the last few decades. However, the drugs used for this therapy have a narrow therapeutic index, and often the responses produced are only just palliative as well as unpredictable. In contrast, targeted therapy that has been introduced in recent years is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. Tyrosine kinases are an especially important target because they play an important role in the modulation of growth factor signaling. This review focuses on small molecule inhibitors of tyrosine kinase. They compete with the ATP binding site of the catalytic domain of several oncogenic tyrosine kinases. They are orally active, small molecules that have a favorable safety profile and can be easily combined with other forms of chemotherapy or radiation therapy. Several tyrosine kinase inhibitors (TKIs) have been found to have effective antitumor activity and have been approved or are in clinical trials. The inhibitors discussed in this manuscript are imatinib mesylate (STI571; Gleevec), gefitinib (Iressa), erlotinib (OSI-1774; Tarceva), lapatinib (GW-572016), canertinib (CI-1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), sutent (SU11248), and leflunomide (SU101). TKIs are thus an important new class of targeted therapy that interfere with specific cell signaling pathways and thus allow target-specific therapy for selected malignancies. The pharmacological properties and anticancer activities of these inhibitors are discussed in this review. Use of these targeted therapies is not without limitations such as the development of resistance and the lack of tumor response in the general population. The availability of newer inhibitors and improved patient selection will help overcome these problems in the future.
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PMID:Role of tyrosine kinase inhibitors in cancer therapy. 1600 63

In many solid tumors, overexpression of human epidermal growth factor receptors (e.g., HER1/EGFR and HER2) correlates with poor prognosis. Erlotinib (Tarceva) is a potent HER1/EGFR tyrosine kinase inhibitor. Pertuzumab (Omnitarg), a novel HER2-specific, recombinant, humanized monoclonal antibody, prevents heterodimerization of HER2 with other HERs. Both mechanisms disrupt signaling pathways, resulting in tumor growth inhibition. We evaluated whether inhibition of both mechanisms is superior to monotherapy in tumor cell lines expressing different HER levels. Human non-small cell lung cancer (NSCLC) cells (Calu-3: HER1/EGFR 0+, HER2 3+; QG56: HER1/EGFR 2-3+, HER2 0+) and breast cancer cells (KPL-4: HER1/EGFR 2-3+, HER2 3+) were implanted into BALB/c nu/nu mice and severe combined immunodeficient beige mice, respectively. Tumor-bearing mice (n = 12 or 15 per group) were treated with vehicle (Captisol or buffer), erlotinib (orally, 50 mg/kg/d), pertuzumab (i.p. 6 mg/kg/wk with a 2-fold loading dose), or erlotinib and pertuzumab for 20 (QG56), 27 (KPL-4), or 49 (Calu-3) days. Drug monotherapy had antitumor activity in all models. Tumor volume treatment-to-control ratios (TCR) with erlotinib were 0.36 (Calu-3), 0.79 (QG56), and 0.51 (KPL-4). Pertuzumab TCR values were 0.42, 0.51, and 0.64 in Calu-3, QG56, and KPL-4 models, respectively. Combination treatment resulted in additive (QG56: TCR 0.39; KPL-4: TCR 0.38) or greater than additive (Calu-3: TCR 0.12) antitumor activity. Serum tumor markers for NSCLC (Cyfra 21.1) and breast cancer (soluble HER2) were markedly inhibited by combination treatment (80-97% in Calu-3 and QG56; 92% in KPL-4), correlating with decreased tumor volume. Overall, erlotinib and pertuzumab are active against various human xenograft models, independently of HER1/EGFR or HER2 expression. A combination of these HER-targeted agents resulted in additive or greater than additive antitumor activity.
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PMID:Combination treatment with erlotinib and pertuzumab against human tumor xenografts is superior to monotherapy. 1603 49

The aim of this single-arm, phase II study was to estimate the tumor response rate and safety profile of erlotinib HCl (erlotinib, Tarceva, OSI-774) monotherapy in patients with refractory, recurrent, HER1/EGFR-positive epithelial ovarian tumors, who had failed prior taxane and/or platinum-based chemotherapy. Thirty-four patients received 150 mg erlotinib orally once daily for up to 48 weeks or until disease progression or dose-limiting toxicity. Two patients had partial responses, lasting 8+ and 17 weeks, giving an objective response rate of 6% (95% confidence interval [CI], 0.7-19.7%). Fifteen patients (44%) had stable disease, and 17 patients (50%) had progressive disease. Median overall survival was 8 months (95% CI, 5.7-12.7 months), with a 1-year survival rate of 35.3% (95% CI, 19.8-53.5%). Patients with rash survived significantly longer than those without (P= 0.009), correlating with rash grade. Erlotinib was generally well tolerated. The most frequent erlotinib-related adverse events were rash (68%) and diarrhea (38%). Erlotinib had marginal activity but was generally well tolerated. The safety profile appears more favorable than typically experienced with standard chemotherapeutic agents, which is encouraging in these heavily pretreated patients. Combination of erlotinib with chemotherapy or other targeted agents should be considered.
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PMID:Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. 1617 25

Bevacizumab (Avastin) has unprecedented survival benefit in patients with metastatic colorectal cancer. Trials are already in progress to investigate the potential of bevacizumab in indications including metastatic renal cell cancer (RCC), non-small cell lung cancer (NSCLC), pancreatic cancer, breast and ovarian cancer. Bevacizumab offers the potential to increase survival without substantially altering the toxicity profile in these tumor types. Bevacizumab has shown activity in patients with refractory metastatic RCC, where progression-free survival (PFS) was significantly longer in patients treated with bevacizumab (10 mg/kg every 2 weeks) than those treated with placebo (hazard ratio=2.55, p<0.001). In addition, combining bevacizumab with erlotinib (Tarceva) has shown a median time to progression of more than 11 months. In NSCLC, a phase II trial revealed that adding bevacizumab to chemotherapy increased therapeutic benefit compared with chemotherapy alone. Adverse events were mild and easily managed, but six patients receiving bevacizumab developed severe hemoptysis. Entry criteria for NSCLC trials have been adjusted to exclude patients with squamous cell histology to try to avoid this issue. Adding bevacizumab (10 mg/kg) to the current standard of care, gemcitabine, in stage IV pancreatic cancer has also shown promising efficacy. Partial responses were seen in 19% of patients, with a further 48% having stable disease. Several ongoing clinical trials are also studying bevacizumab with various chemotherapy and radiotherapy regimens. Bevacizumab combined with carboplatin (Paraplatin)/paclitaxel (Taxol) was further examined in a phase III randomized trial that accrued 878 patients with advanced non-squamous cell NSCLC. Patients given chemotherapy (paclitaxel and carboplatin) plus bevacizumab had a higher response rate, longer PFS and an increase in survival compared with patients on chemotherapy alone. Both regimens were generally well tolerated. Bevacizumab has also shown activity in patients with metastatic breast cancer. In 715 patients, a significant, 2-fold increase in response rate was observed in patients receiving bevacizumab plus paclitaxel compared with paclitaxel alone. Median PFS was also significantly increased (p<0.001). Bevacizumab has the potential to provide significant efficacy benefits for patients with metastatic RCC, NSCLC, pancreatic cancer, and other tumor types when used first line in combination with standard therapy.
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PMID:Investigating the potential of bevacizumab in other indications: metastatic renal cell, non-small cell lung, pancreatic and breast cancer. 1630 35


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