A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer

Kobayashi, Takashi; Koizumi, Tomonobu; Agatsuma, Toshihide; Matsumura, Yasuo; Tsushima, Kenji; Kubo, Keishi; S, Eda; Kuraishi, Hiroshi; Koyama, Shigeru; Hachiya, Tsutomu; Ohura, Nariaki

doi:10.1007/s00280-012-1831-0

Cited by 38 publications

(20 citation statements)

References 26 publications

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“…The two first-generation EGFR inhibitors differ in their selectivity towards tumors with wild-type EGFR. Erlotinib has demonstrated activity in pre-treated patients with EGFR wild-type tumors [64], with modest improvement in survival outcomes as switch-maintenance therapy [65]. In contrast, gefitinib has only demonstrated activity in patients with activating mutations in EGFR.…”

Section: Introductionmentioning

confidence: 99%

Molecular pathways and therapeutic targets in lung cancer

et al. 2014

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Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review.

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Section: Introductionmentioning

confidence: 99%

Molecular pathways and therapeutic targets in lung cancer

et al. 2014

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“…Erlotinib is orally bioavailable and primarily metabolized by CYP3A (Ling et al, 2006;Li et al, 2007) and to a lesser extent by CYP1A1/CYP1A2 (Hughes et al, 2009). The side-effects profile of erlotinib includes burdensome skin (Ricciardi et al, 2009) and gastrointestinal tract, ocular, and rare but serious lung toxicities (Kobayashi et al, 2012;Borkar et al, 2013;Yoshida et al, 2013). Although tyrosine kinase inhibitors, such as erlotinib, do not commonly have the same lifethreatening side effects as the cytotoxic anticancer drugs, they do suffer from wide interpatient variability in pharmacokinetics [% coefficient of variation for area under the curve (AUC) and trough level is 64 and 51%, respectively] (Gao et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

et al. 2013

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Erlotinib is approved for the treatment of non-small cell lung and pancreatic cancers, and is metabolized by CYP3A4. Inducers and inhibitors of CYP3A enzymes such as ritonavir and efavirenz, respectively, may be used as part of the highly active antiretroviral therapy drugs to treat patients with human immunodeficiency virus (HIV). When HIV patients with a malignancy need treatment with erlotinib, there is a potential of as-yet-undefined drug-drug interaction. We evaluated these interactions using human hepatocytes benchmarked against the interaction of erlotinib with ketoconazole and rifampin, the archetype cytochrome P450 inhibitor and inducer, respectively. Hepatocytes were treated with vehicle [0.1% dimethylsulfoxide, ritonavir (10 mM)], ketoconazole (10 mM), efavirenz (10 mM), or rifampin (10 mM) for 4 days. On day 5, erlotinib (5 mM) was incubated with the above agents for another 24-48 hours. Concentrations of erlotinib and O-desmethyl erlotinib were quantitated in collected samples (combined lysate and medium) using liquid chromatography and tandem mass spectrometry. The half-life (t 1/2 ) of erlotinib increased from 10.6 6 2.6 to 153 6 80 and 23.9 6 4.8 hours, respectively, upon treatment with ritonavir and ketoconazole. The apparent intrinsic clearance (CL int, app ) of erlotinib was lowered 16-fold by ritonavir and 1.9-fold by ketoconazole. Efavirenz and rifampin decreased t 1/2 of erlotinib from 10.3 6 1.1 to 5.0 6 1.5 and 3.4 6 0.2 hours, respectively. Efavirenz and rifampin increased the CL int, app of erlotinib by 2.2-and 2-fold, respectively. Our results suggest that to achieve desired drug exposure, the clinically used dose (150 mg daily) of erlotinib may have to be significantly reduced (25 mg every other day) or increased (300 mg daily), respectively, when ritonavir or efavirenz is coadministered.

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“…The intracellular tyrosine kinase part of EGFR can be inhibited reversibly by the EGFR tyrosine kinase inhibitors (TKI) gefitinib and erlotinib. Both drugs have shown efficacy in tumors harboring an activating mutation in the EGFR gene but limited efficacy in EGFR wild type (4)(5)(6). Compared with cytotoxic treatment, TKI toxicity profiles are mild and treatment results in a benefit with respect to progression-free survival.…”

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confidence: 99%

Assessment of Simplified Methods to Measure ¹⁸F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

et al. 2014

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3′-deoxy-3′-18 F-fluorothymidine ( 18 F-FLT) PET/CT provides a noninvasive assessment of proliferation and, as such, could be a valuable imaging biomarker in oncology. The aim of the present study was to assess the validity of simplified quantitative parameters of 18 F-FLT uptake in non-small cell lung cancer (NSCLC) patients before and after the start of treatment with a tyrosine kinase inhibitor (TKI). Methods: Ten patients with metastatic NSCLC harboring an activating epidermal growth factor receptor mutation were included in this prospective observational study. Patients underwent 15 O-H 2 O and 18 F-FLT PET/CT scanning on 3 separate occasions: within 7 d before treatment, and 7 and 28 d after the first therapeutic dose of a TKI (gefitinib or erlotinib). Dynamic scans were acquired and venous blood samples were collected during the 18 F-FLT scan to measure parent fraction and plasma and whole-blood radioactivity concentrations. Simplified measures (standardized uptake value [SUV] and tumor-to-blood ratio [TBR]) were correlated with fully quantitative measures derived from kinetic modeling. Results: Twenty-nine of thirty 18 F-FLT PET/CT scans were evaluable. According to the Akaike criterion, a reversible 2-tissue model with 4 rate constants and blood volume parameter was preferred in 84% of cases. Relative therapy-induced changes in SUV and TBR correlated with those derived from kinetic analyses (r 2 5 0.83-0.97, P , 0.001, slope 5 0.72-1.12). 18 F-FLT uptake significantly decreased at 7 and 28 d after the start of treatment compared with baseline (P , 0.01). Changes in 18 F-FLT uptake were not correlated with changes in perfusion, as measured using 15 O-H 2 O. Conclusion: SUV and TBR could both be used as surrogate simplified measures to assess changes in 18 F-FLT uptake in NSCLC patients treated with a TKI, at the cost of a small underestimation in uptake changes or the need for a blood sample and metabolite measurement, respectively.

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A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer

Abstract: Erlotinib might be an alternative option for patients resistant to cytotoxic chemotherapy even in those with EGFR wild-type NSCLC.

Cited by 38 publications

References 26 publications

Molecular pathways and therapeutic targets in lung cancer

Molecular pathways and therapeutic targets in lung cancer

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

Assessment of Simplified Methods to Measure ¹⁸F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

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A phase II trial of erlotinib in patients with EGFR wild-type advanced non-small-cell lung cancer

Abstract: Erlotinib might be an alternative option for patients resistant to cytotoxic chemotherapy even in those with EGFR wild-type NSCLC.

Cited by 38 publications

References 26 publications

Molecular pathways and therapeutic targets in lung cancer

Molecular pathways and therapeutic targets in lung cancer

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

Assessment of Simplified Methods to Measure 18F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

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Assessment of Simplified Methods to Measure ¹⁸F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment