What went wrong with Iressa?

Burton, Adrian

doi:10.1016/s1470-2045(02)00938-5

Cited by 24 publications

(14 citation statements)

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“…The confusion about how well EGFR inhibitors work has increased because it was reported that gefitinib combined with chemotherapy showed no survival advantage over chemotherapy alone in two large, randomized phase III lung cancer trials (Burton 2002;Dancey and Freidlin 2003). Essentially identical conclusions were reached recently in a similar set of trials using a second EGFR inhibitor OSI-774 (Tarceva; Genentech press release, http://www.gene.com/gene/news/press-releases/display.…”

Section: Complications In Interpreting Clinical Results With Kinase Imentioning

confidence: 95%

“…In contrast, EGFR inhibitors were initially studied in a range of tumors, such as lung, colon, and head and neck cancers, but were only recently approved for lung cancer after a prolonged debate at the FDA (Cohen et al 2003). A brief review of this clinical development path is instructive in pointing out potential pitfalls in designing kinase inhibitor trials (for more detailed reviews, see also Burton 2002;Dancey and Freidlin 2003).…”

Section: Complications In Interpreting Clinical Results With Kinase Imentioning

confidence: 99%

“…A detailed discussion of these complex issues is beyond the scope of this review. Interested readers should consult other recent commentaries for more in-depth analysis (Burton 2002;Dancey and Freidlin 2003;Dancey and Sausville 2003). The premise (and bias) underlying this review, however, is that kinase inhibitors are likely to be effective only in patients with molecular lesions that predispose to kinase dependency.…”

Section: Complications In Interpreting Clinical Results With Kinase Imentioning

confidence: 99%

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Opportunities and challenges in the development of kinase inhibitor therapy for cancer

Sawyers¹

2003

Genes Dev.

162

101

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Section: Complications In Interpreting Clinical Results With Kinase Imentioning

confidence: 95%

Section: Complications In Interpreting Clinical Results With Kinase Imentioning

confidence: 99%

Section: Complications In Interpreting Clinical Results With Kinase Imentioning

confidence: 99%

See 1 more Smart Citation

Opportunities and challenges in the development of kinase inhibitor therapy for cancer

Sawyers¹

2003

Genes Dev.

162

101

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“…Given that we and others recently determined the crystal structure of the extracellular domain of the EGFR, it should be possible to identify regions of the receptor that represent potential targets (50,51). Finally, if there are some aspects of EGFR function that are not inhibited by antibodies such as mAb 528, it may explain why some EGFR therapeutics have had less clinical success than anticipated (52). Therefore, combination therapy with mAb 806 and agents such as IMC-C225 or Iressa may increase the response rate seen in patients.…”

Section: Discussionmentioning

confidence: 99%

Treatment of Human Tumor Xenografts with Monoclonal Antibody 806 in Combination with a Prototypical Epidermal Growth Factor Receptor–Specific Antibody Generates Enhanced Antitumor Activity

Perera

Narita

Furnari

et al. 2005

Clinical Cancer Research

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Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27 KIP1 and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo.Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.

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“…Epidermal growth factor receptor (EGFR) is overexpressed inthemajorityofnon-smallcelllungcarcinomas(NSCLCs), therefore its down-regulation seems a promising treatment strategy [1].Twolow-weightEGFRtyrosinekinaseinhibitors (TKIs), gefitinib (Iressa™, AstraZeneca, Wedel, Germany) and erlotinib (Tarceva ® , Roche, Roche Pharma AG, Grenzach-Whylen,Germany),enteredclinicaltrialsalmostadecade ago, but, contrary to some initial expectations, showed rathermodestresponseratesinnon-selectedNSCLCpatients [2,3].Itwasnoted,however,thatthedegreeandspeedofthe disease improvement in the subset of TKI responders were absolutelyfascinating,thussuggestingthecontributionofyet unrecognized factors to drug sensitivity [4]. The clue to this enigmawasdiscoveredin2004,when3independentresearch groups reported the presence of previously unknown intragenic EGFR mutations in virtually all TKI-responding tumors, but not in the NSCLCs who failed treatment [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

High Efficacy of First-Line Gefitinib in Non-Asian Patients with EGFR-Mutated Lung Adenocarcinoma

et al. 2010

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Background: Several Asian studies demonstrated feasibility of front-line administration of gefitinib for the treatment of non-small cell lung carcinomas (NSCLCs) harboring intragenic epidermal growth factor receptor (EGFR) mutations. The experience of the use of this EGFR tyrosine kinase inhibitor (TKI) in non-Asian subjects remains limited. Patients and Methods: The study included lung adenocarcinoma (AC) patients treated at the N.N. Petrov Institute of Oncology (Russia). Results: DNA analysis of 192 consecutive AC revealed 38 (20%) TKI-sensitizing mutations. Presence of the exon 19 deletion (del19) or L858R was strongly correlated with nonsmoking status (smokers: 8/98 (8%); non-smokers: 30/94 (32%); p = 0.00004). The efficacy of first-line gefitinib therapy was evaluated in 25 patients with EGFR-mutated advanced AC. Twelve (48%) cases demonstrated tumor response (1 (4%) complete response, 11 (44%) partial responses; 10/17 (59%) patients with del19 mutation vs. 2/8 (25%) cases with L858R substitution, p = 0.11). The remaining 13 (52%) patients experienced disease stabilization. Median progression-free survival was 8.0 months. Grade 3 toxicity was the maximal adverse event, being observed only in 4 (16%) cases. Conclusion: Gefitinib may be considered as an upfront treatment option for EGFR-mutated NSCLC.

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What went wrong with Iressa?

Cited by 24 publications

References 0 publications

Opportunities and challenges in the development of kinase inhibitor therapy for cancer

Opportunities and challenges in the development of kinase inhibitor therapy for cancer

Treatment of Human Tumor Xenografts with Monoclonal Antibody 806 in Combination with a Prototypical Epidermal Growth Factor Receptor–Specific Antibody Generates Enhanced Antitumor Activity

High Efficacy of First-Line Gefitinib in Non-Asian Patients with EGFR-Mutated Lung Adenocarcinoma

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