Pr4 ISEL: A Phase III survival study comparing gefitinib (IRESSA) plus best supportive care (BSC) with placebo plus BSC, in patients with advanced non-small-cell lung cancer (NSCLC) who had received one or two prior chemotherapy regimens

Thatcher, Nicholas; Chang, Amy; Parikh, Purvish; Pemberton, Kristine; Archer, V.

doi:10.1016/s0169-5002(05)80130-8

Cited by 62 publications

(37 citation statements)

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“…In contrast, a similar placebo-controlled randomised trial using gefitinib (ISEL trial) failed to show an overall survival advantage in the gefitinib treatment group (MST of 5.6 months vs 5.1 months; P ¼ 0.087) (Thatcher et al, 2005). However, gefitinib prolonged survival in never-smokers (MST 8.9 months vs 6.1 months; P ¼ 0.012) as well as in Asian patients (MST 9.5 months vs 5.5 months; P ¼ 0.010) in preplanned subset analyses (Thatcher et al, 2005). Following these results, the US Food and Drug Administration limits the indication of gefitinib to cancer patients who are currently benefiting or have previously benefited from gefitinib treatment or are enrolled in clinical trials as of June 2005.…”

Section: Tkis and Clinical Trialsmentioning

confidence: 88%

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

Uramoto

Mitsudomi

2007

Br J Cancer

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Subsets of patients with non-small cell lung cancer respond remarkably well to small molecule tyrosine kinase inhibitors (TKI) specific for epidermal growth factor receptor (EGFR) such as gefitinib or erlotinib. In 2004, it was found that EGFR mutations occurring in the kinase domain are strongly associated with EGFR-TKI sensitivity. However, subsequent studies revealed that this relationship was not perfect and various predictive markers have been reported. These include EGFR gene copy numbers, status of ligands for EGFR, changes in other HER family genes or molecules downstream to EGFR including KRAS or AKT. In this review, we would like to review current knowledge of predictive factors for EGFR-TKI. As all but one phase III trials failed to show a survival advantage of the treatment arm involving EGFR-TKIs, it is necessary to select patients by these biomarkers in future clinical trials. Through these efforts, it would be possible to individualise EGFR-TKI treatment for patients suffering from lung cancer.

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Section: Tkis and Clinical Trialsmentioning

confidence: 88%

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

Uramoto

Mitsudomi

2007

Br J Cancer

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“…On the basis of these clinical trials, gefitinib was licensed for the third-line treatment of platinum-and docetaxel-refractory advanced NSCLC in several countries, including Japan, Australia, and the U.S. However, very recently, Thatcher et al [9] reported on a phase III trial named Iressa Survival Evaluation in Lung Cancer (ISEL), which compared gefitinib with best supportive care in patients with advanced NSCLC who had received one or two prior chemotherapy regimens. In 1,692 patients (ISEL is the largest study conducted in the refractory advanced NSCLC population), a difference between gefitinib and placebo was reported, although this did not reach statistical significance in the overall or adenocarcinoma histology populations.…”

Section: Targeted Agents As Monotherapymentioning

confidence: 99%

Combining Targeted Therapies and Drugs with Multiple Targets in the Treatment of NSCLC

Maione

Gridelli

Troiani³

et al. 2006

The Oncologist

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The first generation of clinical trials of targeted agents in non-small cell lung cancer (NSCLC) treatment has concluded. To date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. Nevertheless, clinically meaningful advances have already been achieved. In chemotherapy-refractory advanced NSCLC patients, gefitinib and erlotinib, two epidermal growth factor receptor tyrosine kinase inhibitors, represent a further chance for tumor control and symptom palliation. In chemotherapy-naive, advanced, nonsquamous NSCLC patients, the combination of the anti-vascular endothelial growth factor monoclonal antibody bevacizumab with chemotherapy was demonstrated to produce better survival outcomes than with chemotherapy alone. The relative failure of first-generation targeted therapies in lung cancer may be a result of multilevel crossstimulation among the targets of the new biological agents. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Preclinical evidence of the synergistic antitumor activity achievable by combining targeted agents that block multiple signaling pathways has recently been emerging. Clinical trials of multitargeted therapy may represent the second generation of studies in this field, and some of these are already ongoing. In a recent phase I/II trial, the combination of erlotinib and bevacizumab demonstrated very promising activity in the treatment of advanced NSCLC pretreated with chemotherapy. Whether the multitargeted approach is best performed using combinations of selective agents or agents that intrinsically target various targets is a matter of debate.

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“…4 However, there was no increase in response rate or overall survival in NSCLC for the combination of gefitinib with conventional chemotherapy compared with chemotherapy alone (21,22). Furthermore, the randomized, placebo-controlled phase III Iressa Survival Evaluation in Lung Cancer trial of gefitinib in advanced NSCLC patients who had received at least one previous chemotherapy regimen did not show a significant overall survival benefit for gefitinib in either the whole study population, or an adenocarcinoma subgroup (23).…”

mentioning

confidence: 99%

Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer

Adjei

Molina

Mandrekar

et al. 2007

Clinical Cancer Research

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Purpose: To evaluate the combination of sorafenib and gefitinib in patients with advanced nonŝ mall cell lung cancer. Experimental Design: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21days followed by a 7-day washout with crossover to the other agent for an additional 21days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed. Results: Thirty-one patients were treated (n = 12, part A; n = 19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib C max (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n = 8, part A; n = 12, part B) had stable disease z4 months.The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily. Conclusions: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non^small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.

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Pr4 ISEL: A Phase III survival study comparing gefitinib (IRESSA) plus best supportive care (BSC) with placebo plus BSC, in patients with advanced non-small-cell lung cancer (NSCLC) who had received one or two prior chemotherapy regimens

Cited by 62 publications

References 0 publications

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

Combining Targeted Therapies and Drugs with Multiple Targets in the Treatment of NSCLC

Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer

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