Phase II trial of erlotinib in patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations: additive analysis of pharmacokinetics

Motoshima, Kohei; Nakamura, Yoichi; Sano, Kazumi; Ikegami, Yoji; Ikeda, Takaya; Mizoguchi, Kosuke; Takemoto, Shinnosuke; Fukuda, Minoru; Nagashima, Seiji; Iida, Takuya; Tsukamoto, Kazuhiro; Kohno, Shigeru

doi:10.1007/s00280-013-2307-6

Cited by 12 publications

(10 citation statements)

References 22 publications

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“…Including this result, some reports indicated that a high ratio of the late (reaching a steady-state level of gefitinib) and early (after the first or second administrations) plasma trough levels of EGFR-TKIs predicts their antitumor activity [5,8]. As mentioned above, this high ratio might reflect the change in the t 1/2 of EGFR-TKIs in the early treatment phase.…”

Section: Discussionmentioning

confidence: 80%

Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations

Mizoguchi

Nakamura

Sano

et al. 2016

Cancer Chemother Pharmacol

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Section: Discussionmentioning

confidence: 80%

Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations

Mizoguchi

Nakamura

Sano

et al. 2016

Cancer Chemother Pharmacol

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“…We next examined growth-inhibitory effects of erlotinib and PS, alone and in combination. NSCLC patients usually receive a daily dose of 150 mg erlotinib, which results in plasma levels between 1 and 3 μM [ 27 ]. Thus we chose to treat the EGFR wildtype cells with an erlotinib concentration of 2 μM.…”

Section: Resultsmentioning

confidence: 99%

The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells

et al. 2015

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BackgroundThe receptor tyrosine kinase (RTK) EGFR is overexpressed and mutated in NSCLC. These mutations can be targeted by RTK inhibitors (TKIs) such as erlotinib. Chromatin-modifying agents may offer a novel therapeutic approach by sensitizing tumor cells to TKIs.MethodsThe NSCLC cell lines HCC827 (EGFR mutant, adenocarcinoma), A549 (EGFR wt, adenocarcinoma) and NCI-H460 (EGFR wt, large cell carcinoma) were analyzed by SNP6.0 array. Changes in proliferation after panobinostat (LBH-589, PS) and erlotinib treatment were quantified by WST-1 assay and apoptosis by Annexin V/7-AAD flow cytometry. Abundance of target proteins and histone marks (acH3, H3K4me1/2/3) was determined by immunoblotting.ResultsAs expected, the EGFR wt cell lines A549 and NCI-H460 were quite insensitive to the growth-inhibitory effect of erlotinib (IC50 70-100 μM), compared to HCC827 (IC50 < 0.02 μM). All three cell lines were sensitive to PS treatment (IC50: HCC827 10 nM, A549 20 nM and NCI-H460 35 nM). The combination of both drugs further reduced proliferation in HCC827 and in A549, but not in NCI-H460. PS alone induced differentiation and expression of p21WAF1/CIP1 and p53 and decreased CHK1 in all three cell lines, with almost no further effect when combined with erlotinib. In contrast, combination treatment additively decreased pEGFR, pERK and pAKT in A549. Both drugs synergistically induced acH3 in the adenocarcinoma lines. Surprisingly, we also observed induction of H3K4 methylation marks after erlotinib treatment in HCC827 and in A549 that was further enhanced by combination with PS.ConclusionPS sensitized lung adenocarcinoma cells to the antiproliferative effects of erlotinib. In these cell lines, the drug combination also had a robust, not previously described effect on histone H3 acetylation and H3K4 methylation.

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“…A direct relationship between exposure to erlotinib and observed clinical response must be proven [65]. Some authors describe a statistically significant correlation between exposure and efficacy [66,67], while others only point to a non-statistically significant trend or relationship between both parameters [68,69]. The preclinical study carried out by Hidalgo et al [61] suggested that a target C trough greater than 500 mg/L in humans would be adequate for the inhibition of EGFR receptors, so this target concentration was adopted for later studies.…”

Section: Erlotinibmentioning

confidence: 99%

Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study

et al. 2022

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Introduction: The main goal of treatment in cancer patients is to achieve the highest therapeutic effectiveness with the least iatrogenic toxicity. Tyrosine kinase inhibitors (TKIs) are anticancer oral agents, usually administered at fixed doses, which present high inter- and intra-individual variability due to their pharmacokinetic characteristics. Therapeutic drug monitoring (TDM) can be used to optimize the use of several types of medication. Objective: We evaluated the use of TDM of TKIs in routine clinical practice through studying the variability in exposure to erlotinib, imatinib, lapatinib, and sorafenib and dose adjustment. Materials and methods: We conducted a retrospective analytical study involving patients who received treatment with TKIs, guided by TDM and with subsequent recommendation of dose adjustment. The quantification of the plasma levels of the different drugs was performed using high-performance liquid chromatography (HPLC). The Clinical Research Ethics Committee of the Hospital Quirónsalud Torrevieja approved this study. Results: The inter-individual variability in the first cycle and in the last monitored cycle was 46.2% and 44.0% for erlotinib, 48.9 and 50.8% for imatinib, 60.7% and 56.0% for lapatinib and 89.7% and 72.5% for sorafenib. Relationships between exposure and baseline characteristics for erlotinib, imatinib, lapatinib and sorafenib were not statistically significant for any of the variables evaluated (weight, height, body surface area (BSA), age and sex). Relationships between height (p = 0.021) and BSA (p = 0.022) were statistically significant for sorafenib. No significant relationships were observed between Ctrough and progression-free survival (PFS) or overall survival (OS) for any drug, except in the case of sunitinib (correlation between Ctrough and PFS p = 0.023) in the exposure–efficacy analysis. Conclusions: Erlotinib, imatinib, lapatinib and sorafenib show large inter-individual variability in exposure. TDM entails a significant improvement in exposure and enables more effective and safe use of TKIs in routine clinical practice.

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Phase II trial of erlotinib in patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations: additive analysis of pharmacokinetics

Abstract: Background We conducted a phase II trial of erlotinib in patients with

Cited by 12 publications

References 22 publications

Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations

Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations

The pan-HDAC inhibitor panobinostat acts as a sensitizer for erlotinib activity in EGFR-mutated and -wildtype non-small cell lung cancer cells

Relevance of Therapeutic Drug Monitoring of Tyrosine Kinase Inhibitors in Routine Clinical Practice: A Pilot Study

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