ZD1839 (Iressa™) In Non–Small-Cell Lung Cancer

Herbst, Roy S.; Khuri, Fadlo R.; Fossella, Frank V.; Glisson, Bonnie S.; Kies, Merrill S.; Pisters, Katherine M.W.; Riddle, Jeanne R.; Terry, K; Lee, Jin Soo

doi:10.3816/clc.2001.n.014

Cited by 22 publications

(18 citation statements)

References 29 publications

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“…Clinical data have already demonstrated that the prevention of EGFR-mediated signal transduction by the small molecule inhibitor gefitinib provides a promising new treatment option for a variety of cancer types (Barton et al 2001, Cohen et al 2002, Fukuoka et al 2002, Goss et al 2002, Herbst & Kies 2002, Ranson 2002. Such studies have also indicated, however, that responses to gefitinib were heterogenous with not all patients responding to treatment and, even in responders, disease relapse was inevitable (Barton et al 2001, Cohen et al 2002, Fukuoka et al 2002, Goss et al 2002, Herbst & Kies 2002, Ranson 2002.…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, even with responders to gefitinib, it was observed that disease progression could occur within a few months of therapy (Barton et al 2001, Cohen et al 2002, Fukuoka et al 2002, Goss et al 2002, Herbst & Kies 2002, Ranson 2002 resulting from the development of acquired resistance to the TKI. The acquisition of resistance to gefitinib has also been demonstrated in vitro, with the establishment of a gefitinib-resistant PC-9 NSCLC cell line, being observed following a stepwise dose escalation of the compound over 1 year (Yamakoa et al 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Gefitinib presents much therapeutic promise for the treatment of numerous human cancer types; however, the clinical data demonstrated that not all patients responded to the inhibitor, indicating the existence of an intrinsic or de novo resistance to the drug (Barton et al 2001, Cohen et al 2002, Fukuoka et al 2002, Goss et al 2002, Herbst & Kies 2002, Ranson 2002. Furthermore, even with responders to gefitinib, it was observed that disease progression could occur within a few months of therapy (Barton et al 2001, Cohen et al 2002, Fukuoka et al 2002, Goss et al 2002, Herbst & Kies 2002, Ranson 2002 resulting from the development of acquired resistance to the TKI.…”

Section: Introductionmentioning

confidence: 99%

“…Gefitinib has been shown to inhibit the growth of a range of human tumour xenografts including breast, prostate, colon and lung and, furthermore, significantly potentiates the antitumour activity of a variety of cytotoxic agents when used in combination (Ciardiello et al 2000. Recent phase II/III clinical studies have demonstrated that gefitinib monotherapy was well tolerated and provided anti-tumour activity in patients with advanced non-small cell lung carcinoma (NSCLC), prostate and breast cancer and also colorectal, renal and head and neck cancers (Barton et al 2001, Cohen et al 2002, Fukuoka et al 2002, Goss et al 2002, Herbst & Kies 2002, Ranson 2002. Additionally, studies are also currently evaluating the effect of gefitinib in combination with other therapies in a range of tumour types including prostate, breast, NSCLC, colorectal, head and neck, ovarian, bladder and cervical cancers (Hammond et al 2001, Gonzalez-Larriba et al 2002, Herbst et al 2002, Trump et al 2002.…”

Section: Introductionmentioning

confidence: 99%

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Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells

Jones

Goddard²,

Gee³

et al. 2004

Endocr Relat Cancer

277

189

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De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 mM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinibresistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)d, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 mM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinibresistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells

Jones

Goddard²,

Gee³

et al. 2004

Endocr Relat Cancer

277

189

View full text Add to dashboard Cite

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“…Once the maximal cytotoxic effect has been attained, the targeted agents can then be used alone as maintenance therapy to prevent new or further metastatic spread. If this paradigm becomes a reality several Epidermal Growth Factor Receptor (EGFR) antagonists are now in Phase III study), 46 then it will be critical to employ chemotherapeutic agents with the least possible side effects to allow for the best long term quality of life. Nonplatin, nontaxane regimens such as gemcitabine and vinorelbine could be perfectly suited for this next era of cancer care.…”

Section: Discussionmentioning

confidence: 99%

The novel and effective nonplatinum, nontaxane combination of gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma

Herbst

Khuri

et al. 2002

Cancer

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BACKGROUNDGemcitabine and vinorelbine are two of the most active third‐generation agents for the treatment of advanced nonsmall cell lung carcinoma (NSCLC). The authors conducted a formal Phase II trial to evaluate the efficacy of this combination in both untreated and previously treated patients with Stage IIIB (with pleural effusion) or Stage IV NSCLC.METHODSA total of 78 patients were treated on the current Phase II trial of front‐line or second/third‐line therapy with gemcitabine and vinorelbine in NSCLC. Eligible patients manifested either untreated disease (n = 42) or had received at least one but not more than two prior chemotherapy regimens (n = 36). The median age was 59 years (range, 33–79) with 57 men (73%) and 21 women (27%). The median performance status was one (range, one to two). The initial eight patients (four untreated and four previously treated) were treated at a previously established maximum tolerated dose of vinorelbine (30 mg/m2) and gemcitabine (1000 mg/m2) on Days 1, 8, and 15, with significant myelosuppression seen in five out of eight patients requiring dose omission in the first cycle. The next 70 patients received a reduced dose of vinorelbine (25 mg/m2) followed by gemcitabine (900 mg/m2) on Days 1, 8, and 15.RESULTSSeventy eight patients were treated. Fifteen (36%) of the 42 evaluable patients who received front‐line therapy had objective responses and 14 (33%) had stable disease. In the patients with prior treatment, 6 (17%) of 36 patients had partial response and 18 patients (50%) had stable disease. Median survival time for the previously untreated patient group was 10.1 months, with a one year survival of 43% and a two year survival rate of 32%. For the previously treated patients, the median survival time was 8.5 months, with a one year survival rate of 30%. Toxic effects were notable for significant myelosuppression, with ≥Grade 3 granulocytopenia seen in 55% of the patients on the untreated arm and 67% of the patients on the previously untreated arm. Additionally, 9.5% and 13.9% (untreated and previously treated), respectively, of these patients experienced Grades 3 and 4 thrombocytopenia at some point in their treatment. A full dose delivery analysis showed that this myelosuppression resulted in Course 1, Day 15 skipped doses (even at the reduced dose level) in 42% of previously untreated patients and 47% of pretreated patients. Other side effects seen at Grades 3 and 4 in previously untreated and treated patients included anemia (9.5% and 2.8%), asthenia (4.8% and 5.5%), infection (14.3% and 5.6%), pain (9.5% and 19.4%), and pulmonary complications (4.8% and 13.8%).CONCLUSIONSGemcitabine/vinorelbine is an active, well‐tolerated combination in both front‐line and second/third‐line therapy for Stage IIIB/IV NSCLC. The response rate, median survival rate, and one year survival rate compare favorably with platinum‐based regimens. The toxicity profile of the gemcitabine/vinorelbine combination was quite favorable, with minimal Grade 3 and 4 toxic effects aside from granulocytopenia, which resulted in numerous Day 15 skipped doses but no significant febrile neutropenia or infection. The combination of gemcitabine and vinorelbine could be a useful regimen in standard clinical practice and has the potential for efficient combination with biologic/targeted therapy. Multiple randomized trials of this combination versus platinum combinations are now ongoing. Cancer 2002;95:340–353. © 2002 American Cancer Society.DOI 10.1002/cncr.10629

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Gefitinib and chemotherapy combination studies in five novel human non small cell lung cancer xenografts. Evidence linking EGFR signaling to gefitinib antitumor response

Judde

Rebucci

Vogt

et al. 2007

Intl Journal of Cancer

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The epidermal growth factor receptor (EGFR) signaling pathway is often activated in NSCLC, and thus represents a promising therapeutic target. We studied the antitumor activity of gefitinib (Iressa TM ), an orally active EGFR-tyrosine kinase inhibitor, alone and in combination with standard chemotherapy in 5 recently established human NSCLC xenografts with wild-type EGFR. Mice were treated with 2 protocols of chemotherapy based on cisplatin (CDDP) combined with either gemcitabine (GEM) or vinorelbine (VNR). Gefitinib alone significantly inhibited tumor growth (TGI) in 4 of the 5 tumor xenografts (mean TGI of 58%, range: 25-70%). CDDP1VNR alone failed to achieve any significant responses, while CDDP1GEM achieved significant responses in 2 xenografts (TGI of 93 and 47%). Addition of gefitinib to CDDP1GEM potentialized chemotherapy in the 3 CDDP1GEM-resistant xenografts, but did not potentialize the CDDP1VNR combination. The effect of gefitinib treatment on the activity of extra cellular-regulated kinase (Erk), Akt, JNK and p38 kinases was assessed in IC9LC11 and IC1LC131, two NSCLC xenografts selected for their sensitivity and resistance to gefitinib, respectively. In IC9LC11, gefitinib strongly inhibited Erk, Akt and Jnk phosphorylation, but P38 remained active. Inversely, in IC1LC131, Erk and Akt pathways remained active, while Jnk and P38 pathways were inhibited by gefitinib. The data indicate that the antitumor activity of gefitinib in NSCLC, alone or in combination with chemotherapy, is tumor-dependent and is influenced by downstream signaling events independent of EGFR status. ' 2007 Wiley-Liss, Inc.Key words: non small cell lung cancer; epidermal growth factor receptor; chemotherapy; gefitinib; MAPK; akt In 2000, it was estimated that over 1 million lung cancer deaths occurred worldwide, making it the leading cause of cancer deaths. Chemotherapy is the standard first-line treatment option for advanced/metastatic NSCLC and usually comprises a platinum agent (cisplatin, carboplatin) in combination with gemcitabine or vinorelbine, or taxanes (paclitaxel or docetaxel).3 Although chemotherapy is associated with a modest increase in survival compared to best supportive care, 4 4 of the most commonly used chemotherapy regimens demonstrate similar results in terms of response rate and survival, indicating that the efficacy of existing first-line treatment has reached a plateau.5 Relapse of patients with NSCLC who have received first-line chemotherapy is commonly observed.Thus, in NSCLC, there is an urgent need for rationally designed, targeted agents displaying improved efficacy and tolerability compared to existing treatments. The epidermal growth factor receptor (EGFR) has been a leading focus for the clinical development of such new agents. This tyrosine kinase receptor is involved in key tumorigenic processes, such as proliferation, invasion, survival and angiogenesis, 6 and is often highly expressed in NSCLC. Several EGFR inhibitors are now in clinical development or approved in NSCLC, including small molecul...

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ZD1839 (Iressa™) In Non–Small-Cell Lung Cancer

Cited by 22 publications

References 29 publications

Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells

Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells

The novel and effective nonplatinum, nontaxane combination of gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma

Gefitinib and chemotherapy combination studies in five novel human non small cell lung cancer xenografts. Evidence linking EGFR signaling to gefitinib antitumor response

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