A review of erlotinib – an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor

Iyer, Renuka; Bharthuar, Anubha

doi:10.1517/14656560903551283

Cited by 36 publications

(32 citation statements)

References 31 publications

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“…10,11 EGFR activation may interfere with HCC response to sorafenib, [11][12][13] suggesting that EGFR inhibition may enhance tumor response. Erlotinib is an orally active inhibitor of EGFR tyrosine kinase 14,15 approved to treat patients with advanced nonsmall-cell lung and pancreatic cancers. 16 Moreover, in two single-arm, phase II trials, erlotinib showed modest antitumor activity but promising overall survival (OS) benefit in patients with unresectable HCC.…”

Section: 3mentioning

confidence: 99%

SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients With Advanced Hepatocellular Carcinoma

Zhu

Rosmorduc

Evans

et al. 2015

JCO

504

372

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Purpose To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial. Patients and Methods Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS). Results Median OS was similar in the sorafenib plus erlotinib and sorafenib plus placebo groups (9.5 v 8.5 months, respectively; hazard ratio [HR], 0.929; P = .408), as was median time to progression (3.2 v 4.0 months, respectively; HR, 1.135; P = .18). In the sorafenib/erlotinib arm versus the sorafenib/placebo arm, the overall response rate trended higher (6.6% v 3.9%, respectively; P = .102), whereas the disease control rate was significantly lower (43.9% v 52.5%, respectively; P = .021). The median durations of treatment with sorafenib were 86 days in the sorafenib/erlotinib arm and 123 days in the sorafenib/placebo arm. In the sorafenib/erlotinib and sorafenib/placebo arms, the rates of treatment-emergent serious AEs (58.0% v 54.6%, respectively) and drug-related serious AEs (21.0% v 22.8%, respectively) were similar. AEs matched the known safety profiles of both agents, but rates of rash/desquamation, anorexia, and diarrhea were higher in the sorafenib/erlotinib arm, whereas rates of alopecia and hand-foot skin reaction were higher in the sorafenib/placebo arm. Withdrawal rates for AEs during cycles 1 to 3 were higher in the sorafenib/erlotinib arm. Conclusion Adding erlotinib to sorafenib did not improve survival in patients with advanced HCC.

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Section: 3mentioning

confidence: 99%

SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients With Advanced Hepatocellular Carcinoma

Zhu

Rosmorduc

Evans

et al. 2015

JCO

504

372

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“…In a large randomized phase III clinical trial, erlotinib showed superior to placebo for survival, progression-free survival, and tumor response rate Bareschino et al, 2007;Iyer and Bharthuar, 2010). Based on these positive results, US FDA granted erlotinib regular approval in 2004 for the treatment of advanced NSCLC patients after failure of a platinum-containing chemotherapy.…”

Section: Epidermal Growth Factor Receptor (Egfr) Inhibitorsmentioning

confidence: 99%

“…Based on these positive results, US FDA granted erlotinib regular approval in 2004 for the treatment of advanced NSCLC patients after failure of a platinum-containing chemotherapy. The maximum tolerated dose of erlotinib was 150 mg in a daily administration schedule and the most common adverse events were the rash and diarrhea Bareschino et al, 2007;Iyer and Bharthuar, 2010). Erlotinib received additional approval for the combination with gemcitabine chemotherapy for the treatment of advanced pancreatic cancer in 2005.…”

Section: Epidermal Growth Factor Receptor (Egfr) Inhibitorsmentioning

confidence: 99%

“…The results from the various clinical trials, erlotinib has also shown the activity in head and neck tumors, in glioblastoma, and in other tumor types. The presence of a rash, epidermal growth factor receptor expression and mutation status are the predictive factors for response in patients Bareschino et al, 2007;Iyer and Bharthuar, 2010). On April 16, 2010, US FDA granted erlotinib approval for maintenance treatment of patients with stage IIIB/IV NSCLC whose disease had not progressed after four cycles of platinum-based fi rstline chemotherapy (Cohen et al, 2010).…”

Section: Epidermal Growth Factor Receptor (Egfr) Inhibitorsmentioning

confidence: 99%

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Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

Kim¹

2011

Biomolecules and Therapeutics

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In a pharmaceutical industry in which nine out of ten attempts to bring a product to market fail, oncology is among the most challenging therapeutic area (Kola and Landis, 2004;Kamb et al., 2007). In the recent article published in the Nature Rev. Drug Discov. (Arrowsmith, 2011), 83 Phase III and submission failures during 2007 to 2010 were divided according to therapeutic area and reason for failure. Largest numbers of failures was in the area of cancer (28%) followed by neurodegeneration (18%). The 66% of the failures across all therapeutic areas were attributed to lack of effi cacy and 21% of the failures were due to safety issues. Therefore, there is a desperate need for new drugs, especially in the cancer treatment.As a rational approach to cancer therapy in the middle of the last century, a new class of drug discoveries emerged to exploit the differential dependence of proliferating cancer cells on vital functions such as DNA metabolism, replication, chromosome segregation and cytokinesis. These efforts ultimately produced range of nucleoside analogues, DNA-modifying chemicals and natural products -the traditional chemotherapeutic (cytotoxic) agents. The mechanism of action of these Invited ReviewBiomol Ther 19(4), 371-389 (2011) www.biomolther.org drugs-inhibition of essential cellular functions-dictates a narrow therapeutic window (Kamb et al., 2007). A new strategy for cancer therapy has emerged during the past decade based on molecular targets that are less likely to be essential in all cells in the body, therefore more apt to confer a wider therapeutic window than traditional cytotoxic drugs (Kamb et al., 2007;Reichert and Wenger, 2008).In this review, some of the strategies and the opportunities in the molecular targeted oncology drug discovery are discussed. EXCEPTIONAL HETEROGENEITY AND ADAPTABIL-ITY OF CANCER: MAJOR CHALLENGES IN ONCOL-OGY DRUG DISCOVERYCancer is an extraordinarily heterogeneous disease with somatic alterations arise as individual cancer develops (Greenman et al., 2007;Kamb et al., 2007;Harris and McCormick, 2010). This exceptional heterogeneity of cancer is refl ected in observed differences in drug responses, and is the probable cause of acquired resistance. It is also presumably related to drug sensitivity and tumor aggressiveness which display a wide range of variation among malignancies.Due to the heterogeneity both among the cells of an individual tumor and among different cancers, the effi cacy predictions made from xenograft animal models often fail (Kamb, 2005), which presents signifi cant challenges in the oncology drug discovery where advancement of compounds largely based on a pharmacological effect in the xenograft models. Even though xenograft represents signifi cant aspects of the tumor from which it was derived, it probably captures only a fraction of the total genetic and epigenetic heterogeneity of a given tumor subtype. Low response rate in phase I oncology trials is refl ective of poor predictability of clinical effi cacy based on these xenograft mo...

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“…Erlotinib is administered to patients orally and the side effects are usually well tolerated (Li and Perez-Soler, 2009). Erlotinib has been approved by the FDA for treatment of recurrent non small cell lung cancer and for first-line treatment of advanced pancreatic cancer with gemcitabine (Iyer and Bharthuar, 2010). Given the importance of EGFR signaling to the HPV life cycle, we investigated whether erlotinib had activity against HPV-infected cervical cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the epidermal growth factor receptor by erlotinib prevents immortalization of human cervical cells by Human Papillomavirus type 16

Woodworth¹,

Diefendorf²,

Jette³

et al. 2011

Virology

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The Human Papillomavirus type-16 (HPV-16) E6 and E7 oncogenes are selectively retained and expressed in cervical carcinomas, and expression of E6 and E7 is sufficient to immortalize human cervical epithelial cells. Expression of the epidermal growth factor receptor (EGFR) is often increased in cervical dysplasia and carcinoma, and HPV oncoproteins stimulate cell growth via the EGF-R pathway. We found that erlotinib, a specific inhibitor of EGFR tyrosine kinase activity, prevented immortalization of cultured human cervical epithelial cells by the complete HPV-16 genome or the E6/E7 oncogenes. Erlotinib stimulated apoptosis in cells that expressed HPV-16 E6/E7 proteins and induced senescence in a subpopulation of cells that did not undergo apoptosis. Since immortalization by HPV E6/E7 is an important early event in cervical carcinogenesis, the EGFR is a potential target for chemoprevention or therapy in women who have a high risk for cervical cancer.

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A review of erlotinib – an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor

Abstract: This is a well-tolerated oral biologic agent with two approved clinical indications. More studies to individualize therapy and optimize dosing are needed.

Cited by 36 publications

References 31 publications

SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients With Advanced Hepatocellular Carcinoma

SEARCH: A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Sorafenib Plus Erlotinib in Patients With Advanced Hepatocellular Carcinoma

Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

Inhibition of the epidermal growth factor receptor by erlotinib prevents immortalization of human cervical cells by Human Papillomavirus type 16

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