A randomized phase III trial comparing bexarotene/cisplatin/vinorelbine versus cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small cell lung cancer (NSCLC)

Jassem, Jacek; Zatloukal, Petr; Ramlau, Rodryg; Schwarzenberger, Paul; Орлов, С. В.; Rodrigues-Pereira, José; Temperley, G.; Mabry, Mack; Negro‐Vilar, A.; Dziewanowska, Zofia E.

doi:10.1200/jco.2005.23.16_suppl.lba7024

Cited by 17 publications

(14 citation statements)

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“…Consistent with the close relationship between bexarotene intratumoral levels and biomarker responses observed in this study, subset analyses revealed that only patients who developed grade III and IV hypertriglyceridemia had benefited from bexarotene therapy (24,25). Similar findings are described by others (34) in a trial of single-agent Bexarotene concentrations in plasma were not measured.…”

Section: Discussionsupporting

confidence: 90%

“…Two recent phase III clinical trials in patients with advanced NSCLC undergoing first-line treatment showed no overall survival advantage from the addition of bexarotene to chemotherapy, although some subsets of patients may have benefited (24,25). Consistent with the close relationship between bexarotene intratumoral levels and biomarker responses observed in this study, subset analyses revealed that only patients who developed grade III and IV hypertriglyceridemia had benefited from bexarotene therapy (24,25).…”

Section: Discussionsupporting

confidence: 81%

“…It has shown activity in NSCLC in early trials (16, 20 -23). However, two phase III trials of first-line treatment for advanced NSCLC failed to show survival advantage from the addition of bexarotene to chemotherapy, although a subset of patients may have benefited (24,25). There is a need to understand better the pharmacodynamic and pharmacokinetic properties of bexarotene in lung cancer because this permits a mechanistic approach to clinical trial design, especially when combination regimens are used.…”

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confidence: 99%

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A Proof-of-Principle Clinical Trial of Bexarotene in Patients with Non–Small Cell Lung Cancer

Dragnev

Petty²,

Shah³

et al. 2007

Clinical Cancer Research

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Purpose: Bexarotene is a rexinoid (selective retinoid X receptor agonist) that affects proliferation, differentiation, and apoptosis in preclinical studies. The relationship between bexarotene levels and biomarker changes in tumor tissues has not been previously studied. Experimental Design: BEAS-2B human bronchial epithelial (HBE) cells, retinoid-resistant BEAS-2B-R1cells, A427, H226, and H358 lung cancer cells were treated with bexarotene. Proliferation and biomarker expression were assessed. In a proof-of-principle clinical trial, bexarotene tumor tissue levels and intratumoral pharmacodynamic effects were assessed in patients with stages I to II non^small cell lung cancer. Bexarotene (300 mg/m 2 /day) was administered p.o. for 7 to 9 days before resection. Results: Bexarotene-induced dosage-dependent repression of growth, cyclin D1, cyclin D3, total epidermal growth factor receptor (EGFR), and phospho-EGFR expression in BEAS-2B, BEAS-2B-R1, A427, and H358, but not H226 cells. Twelve patients were enrolled, and 10 were evaluable. Bexarotene treatment was well tolerated.There was nonlinear correlation between plasma and tumor bexarotene concentrations (r 2 = 0.77). Biomarker changes in tumors were observed: repression of cyclin D1, total EGFR and proliferation in one case; repression of cyclin D3, total and phospho-EGFR in another.The cases with multiple biomarker changes had high tumor bexarotene (107-159 ng/g). A single biomarker change was detected in one case with low tumor bexarotene. Conclusion: Bexarotene represses proliferation and biomarker expression in responsive, but not resistant HBE and lung cancer cells. Similar biomarker changes occur in lung tumors when therapeutic intratumoral bexarotene levels are achieved. This proof-of-principle trial approach is useful to uncover pharmacodynamic mechanisms in vivo and relate these to intratumoral pharmacokinetic effects.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 81%

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confidence: 99%

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A Proof-of-Principle Clinical Trial of Bexarotene in Patients with Non–Small Cell Lung Cancer

Dragnev

Petty²,

Shah³

et al. 2007

Clinical Cancer Research

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“…Jassem and Dr. Blumenschein presented the results of the SPIRIT (Studies Providing Investigational Research in Targretin) 1 and SPIRIT 2 trials, respectively [4,5]. These trials were conducted to assess the role of bexarotene (Targretin ® ; Ligand Pharmaceuticals, San Diego, http://www.…”

Section: Study Designs and Resultsmentioning

confidence: 99%

Lung Cancer Highlights from ASCO 2005

Belvedere¹,

Grossi²

2006

The Oncologist

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Learning ObjectivesAfter completing this course, the reader will be able to:1. Discuss the results of recent trials on the addition of a molecularly targeted agent to standard first-line chemotherapy in NSCLC.2. Explain the role of surgery in the treatment of stage III NSCLC.3. Discuss the current status of adjuvant chemotherapy in NSCLC. Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com CME CME This material is protected by U.S.

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“…159 However, it failed to improve OS in 2 phase 3 trials when it was combined with first-line chemotherapy administered for advanced NSCLC. 160,161 Apoptotic Pathways…”

Section: Transcriptional Regulation Pathwaysmentioning

confidence: 99%