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6 juni 2012: een review studie bevestigt goede resultaten van bexarotene plus Tarceva - erlotinib bij vormen van darmkanker met uitzaaiïngen in de longen onafhankelijk van KRAS mutatie zoals ook onderstaande studie aantoont. Onderaan staat het abstract van de review studie: Bexarotene plus erlotinib suppress lung carcinogenesis independent of KRAS mutations in two clinical trials and transgenic models.waarvan als u hier klikt het volledige studierapport gratis is in te zien.
18 januari 2006: Bron: J Clin Oncol. 2005 Dec 1;23(34):8757-64.
Bexarotene, een bewerkte vorm van vitamine A. met bijna geen bijwerkingen, geeft hoopvolle resultaten indien gegeven naast Tarceva bij kankerpatiënten met kanker aan de spijsverteringsorganen en met uitzaaiïngen in de longen. De 1 jaarsoverleving was maar liefst 73,8% bij deze groep van kankerpatiënten. Hier het abstract van deze studie die echt heel hoopvol klinkt. Als u hier klikt kunt u het volledige studierapport van deze studie gratis inzien: Bexarotene and erlotinib for aerodigestive tract cancer.
Dragnev KH, Petty WJ, Shah S, Biddle A, Desai NB, Memoli V, Rigas JR, Dmitrovsky E. Hematology/Oncology Section, Department of Medicine, Norris Cotton Cancer Center, Lebanon, NH, USA.
PURPOSE: The epidermal growth factor receptor (EGFR) and cyclin D1 are overexpressed in lung carcinogenesis. The rexinoid, bexarotene, represses cyclin D1 and EGFR expression in vitro. It was hypothesized that combining bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity.
PATIENTS AND METHODS: In vitro studies and a phase I clinical trial were performed. Twenty-four patients with advanced aerodigestive tract cancers were enrolled; 79% had non-small-cell lung cancer (NSCLC). The primary objective was to determine the maximum-tolerated dose. Clinical activity was a secondary objective.
RESULTS: Combining erlotinib with bexarotene enhanced growth suppression in vitro compared with each single-agent treatment. This cooperatively repressed cyclin D1 expression. Clinically, the most frequent toxicities were mild hypertriglyceridemia and skin rash. Two serious treatment-related adverse events occurred (creatine phosphokinase elevation attributed to antilipid therapy and a case of generalized pain). Five objective responses (four partial and one minor) were observed in NSCLC patients. Responses were observed in males and smokers. EGFR sequence analyses did not reveal activating mutations in tumors from assessable responding patients. Median time to progression was 2.0 months; overall survival time was 14.1 months; and 1-year survival rate was 73.8%.
CONCLUSION: The recommended phase II doses are erlotinib 150 mg/d and bexarotene 400 mg/m2/d orally. These agents can be administered in combination at the recommended single-agent doses without added toxicity. Overall survival and clinical features of responding patients differ from prior reports of single-agent erlotinib treatment. These findings are encouraging and warrant further investigation of this regimen.
PMID: 16314636 [PubMed - in process]
Bexarotene plus Erlotinib Suppresses Lung Carcinogenesis Independent of KRAS Mutations in Two Clinical Trials and Transgenic Models
Cancer Prev Res (Phila). Author manuscript; available in PMC 2012 June 1.
Published in final edited form as:
PMCID: PMC3108499
NIHMSID: NIHMS293400
Bexarotene plus Erlotinib Suppresses Lung Carcinogenesis Independent of KRAS Mutations in Two Clinical Trials and Transgenic Models
Konstantin H. Dragnev,
1,2 Tian Ma,
3 Jobin Cyrus,
7 Fabrizio Galimberti,
3 Vincent Memoli,
2,4 Alexander M. Busch,
3 Gregory J. Tsongalis,
2,4 Marc Seltzer,
5 David Johnstone,
6 Cherie P. Erkmen,
6 William Nugent,
6 James R. Rigas,
1,2 Xi Liu,
3 Sarah Freemantle,
3 Jonathan M. Kurie,
8 Samuel Waxman,
9 and
Ethan Dmitrovsky1,2,3
1 Hematology/Oncology Section, Department of Medicine, Hanover, New Hampshire
2 Norris Cotton Cancer Center, Hanover, New Hampshire
3 Department of Pharmacology and Toxicology, Hanover, New Hampshire
4 Department of Pathology, Hanover, New Hampshire
5 Department of Radiology, Hanover, New Hampshire
6 Department of Surgery, Dartmouth Medical School (Hanover) and Dartmouth-Hitchcock Medical Center (Lebanon), Hanover, New Hampshire
7 Dartmouth College, Hanover, New Hampshire
8 MD Anderson Cancer Center, Houston, Texas
9 Mount Sinai School of Medicine, New York, New York
Corresponding Author: Ethan Dmitrovsky, M.D., Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755. Phone: 603-650-1707; FAX: 603-650-1129;
Email: ethan.dmitrovsky@dartmouth.edu
Abstract
The rexinoid bexarotene represses cyclin D1 by causing its proteasomal degradation. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib represses cyclin D1 via different mechanisms. We conducted a preclinical study and two clinical/translational trials (a window-of-opportunity and phase II) of bexarotene plus erlotinib. The combination repressed growth and cyclin D1 expression in cyclin-E– and KRAS/p53–driven transgenic lung cancer cells. The window-of-opportunity trial in early-stage non-small-cell lung cancer (NSCLC) patients (10 evaluable) repressed cyclin D1 (in tumor biopsies and buccal swabs) and induced necrosis and inflammatory responses including in cases with KRAS mutations. The phase II trial in heavily pre-treated, advanced NSCLC patients (40 evaluable; a median of two prior relapses per patient [range, 0–5]; 21% with prior EGFR-inhibitor therapy) produced three major clinical responses in patients with prolonged progression-free survival (583, 665, and 1460-plus days). Median overall survival was 22 weeks. Hypertriglyceridemia was associated with an increased median overall survival (P = 0.001). Early PET response did not reliably predict clinical response. The combination was generally well tolerated, with toxicities similar to those of the single agents. In conclusion, bexarotene plus erlotinib was active in KRAS-driven lung cancer cells, was biologically active in early-stage mutant-KRAS NSCLC, and was clinically active in advanced, chemotherapy-refractory mutant-KRAS tumors in this study and previous trials. Additional lung cancer therapy or prevention trials with this oral regimen are warranted.
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Tarceva, spijsverteringskanker, darmkanker, bexarotene, erlotinib
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