Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: A phase II study in Japanese patients with cytokine-refractory metastatic renal cell Carcinoma

Tomita, Yoshihiko; Uemura, Hirotsugu; Fujimoto, Hiroyuki; Kanayama, Hiro‐omi; Shinohara, Nobuo; Nakazawa, Hayakazu; Imai, Kazunori; Umeyama, Yoshiko; Ozono, Seiichiro; Naito, Seiji; Akaza, Hideyuki

doi:10.1016/j.ejca.2011.07.014

Cited by 114 publications

(109 citation statements)

References 34 publications

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“…In all, 18 patients developed proteinuria ‡2 g/24 hours during treatment and required dose reduction or treatment interruption/discontinuation. [58] Of note, the incidences of HFS and proteinuria in the Japanese study were higher than those reported in the Western study in cytokine-refractory mRCC patients.…”

Section: Safety and Tolerabilitycontrasting

confidence: 48%

“…[56,58] Results from this study demonstrated an ORR of , [55] with permission. Best response Cytokine refractory (n = 52) [56] Sorafenib refractory (n = 62) [57] Objective response rate 23 (44) Maximum percentage decrease in target lesion size, based on RECIST is shown in figure 4a.…”

Section: Efficacymentioning

confidence: 77%

“…In the Japanese phase II study, [58] patients with at least one recorded DBP reading ‡90 mmHg during the first 28 days of treatment had significantly longer PFS compared with those without a DBP reading ‡90 mmHg (median PFS, 14.6 vs 9.8 months; p = 0.02).…”

Section: Diastolic Blood Pressure and Clinical Efficacymentioning

confidence: 99%

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Axitinib for the Management of Metastatic Renal Cell Carcinoma

Escudier

Gore

2011

Drugs R D

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Section: Safety and Tolerabilitycontrasting

confidence: 48%

Section: Efficacymentioning

confidence: 77%

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Axitinib for the Management of Metastatic Renal Cell Carcinoma

Escudier

Gore

2011

Drugs R D

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“…In a retrospective analysis of pooled data [8] (two Phase II studies in which axitinib was evaluated in cytokinerefractory mRCC [n = 116] [28,29] and one Phase II study in which axitinib was evaluated in sorafenib-refractory mRCC [n = 62] [30]), variability in axitinib exposure (as measured by the area under the plasma concentrationtime curve [AUC]) was demonstrated in patients after they each received the same standard dose of 5 mg b.i.d. ; Figure 2A shows the extent to which variations occurred between patients.…”

Section: Interpatient Variability In Axitinib Exposurementioning

confidence: 99%

Individualized Dosing with Axitinib: Rationale and Practical Guidance

et al. 2017

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Axitinib is a potent, selective, vascular endothelial growth factor receptor inhibitor with demonstrated efficacy as second-line treatment for metastatic renal cell carcinoma. Analyses of axitinib drug exposures have demonstrated high interpatient variability in patients receiving the 5 mg twice-daily (b.i.d.) starting dose. Clinical criteria can be used to assess whether individual patients may benefit further from dose modifications, based on their safety and tolerability data. This review provides practical guidance on the 'flexible dosing' method, to help physicians identify who would benefit from dose escalations, dose reductions or continuation with manageable toxicity at the 5 mg b.i.d. dose. This flexible approach allows patients to achieve the best possible outcomes without compromising safety. Rationale for individualized dosingBefore the development of molecular targeted therapy, most available anticancer drugs, with hormone therapies and immunotherapies being notable exceptions, were chemotherapy agents: chemicals aimed at having a cytotoxic effect on cancer cells [1,2]. These drugs were dosed according to a patient's weight or body surface area, based on the observation that patients with a greater body size generally have a greater volume of distribution and require higher doses than smaller patients to reach equal drug concentrations [3]. It was thought this approach would deliver consistent systemic drug exposure, thereby optimizing treatment outcomes. This dosing approach was also chosen based on a lack of a better option at that time. However, it was known that multiple factors beyond patient size (including age, sex, renal function, hepatic function, concomitant medication, disease state and genetics) could have an impact on the actual concentration of a drug in an individual's bloodstream [4]. Consequently, there remains high variability between patients (interpatient variability) in systemic drug concentrations, even when normalized for weight/body surface area [5].When molecular targeted agents were first introduced for use in metastatic renal cell carcinoma (mRCC), these drugs were recommended at a fixed dose, based on an assumption that the maximum tolerated fixed dose would result in the best efficacy and that this same high dose would be appropriate for all patients. However, most tyrosine kinase inhibitors (TKIs) demonstrate high interpatient variability in drug exposure (depending on oral bioavailability and first-pass liver metabolism of drugs); therefore, the subsequent therapeutic effect and toxicity for the same administered dose may vary [6]. As a result, fixed dosing may result in suboptimal efficacy for some patients or excessive toxicity in others [7]. In addition, higher-than-needed doses may be excessive if therapeutic effects are already achieved at lower doses.

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“…In a Japanese Phase II study of 64 patients on axitinib 5 mg twice daily, baseline proteinuria ($1+) was associated with the development of significant proteinuria on treatment ($2 g/24 h). 45 In terms of thyroid dysfunction, a Japanese study observed that mRCC patients treated with axitinib developed incident thyroid dysfunction more commonly and within a shorter time frame when compared to those treated with sorafenib or sunitinib. 46 However, these findings were limited by the small retrospective nature of the study.…”

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confidence: 99%

Axitinib in the treatment of renal cell carcinoma: patient selection and perspectives

Narayan

Haas

2016

IJNRD

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Background: Axitinib is a next-generation, selective tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors. It is approved for the treatment of metastatic renal cell carcinoma (mRCC) based on a demonstrated progression-free survival advantage over sorafenib in the second-line treatment setting. However, given the variety of available targeted therapies for mRCC, appropriate patient selection for the available therapies remains a significant clinical challenge. Purpose: This review summarizes the available evidence on the clinical, toxicity, and pharmacologic considerations for determining appropriate patient selection for axitinib therapy. In addition, it describes recent data on the use of predictive biomarkers to guide clinical management. This paper consists of material obtained via PubMed and Medline literature searches through October 2015. Conclusion: Axitinib has a well-established role in the management of mRCC. Consistent clinical efficacy has been demonstrated across prognostic risk groups and prior therapeutic exposures. Although axitinib is generally well tolerated, appropriate toxicity management is critical to maximizing drug delivery and optimizing treatment outcomes. Although incident hypertension has been associated with improved clinical outcomes on axitinib, there are currently no validated clinical or genetic predictive biomarkers to guide patient selection.

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Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: A phase II study in Japanese patients with cytokine-refractory metastatic renal cell Carcinoma

Cited by 114 publications

References 34 publications

Axitinib for the Management of Metastatic Renal Cell Carcinoma

Axitinib for the Management of Metastatic Renal Cell Carcinoma

Individualized Dosing with Axitinib: Rationale and Practical Guidance

Axitinib in the treatment of renal cell carcinoma: patient selection and perspectives

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