Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes

Miles, Dale; Lacy, Steven; Wada, David R.; Milwee, Steve; Yaron, Yifah; Nguyen, Linh T.

doi:10.1007/s00280-017-3349-y

Cited by 9 publications

(5 citation statements)

References 33 publications

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“…Treatment with cabozantinib 60 mg/day was not associated with any incidents of prolongation of the corrected QT (QTc) interval in patients with the CABOSUN trial [ 31 ]. In a phase 3 trial in patients with medullary thyroid cancer, cabozantinib at the higher dosage of 140 mg/day increased the Δ–Δ Fridericia QTc interval by 10–15 ms, with this prolongation thought to be due to the effects of cabozantinib on serum calcium and potassium [ 31 ]. In the EU, caution is required when using cabozantinib in patients with a history of QT interval prolongation or relevant pre-existing cardiac disease, bradycardia or electrolyte disturbances, or who are taking antiarrhythmics [ 7 ].…”

Section: What Is the Tolerability Profile Of Cabozantinib In Arcc?mentioning

confidence: 99%

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use

Lyseng‐Williamson

2018

Drugs Ther Perspect

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Oral cabozantinib tablets (Cabometyx®) are an important option for the treatment of advanced renal cell carcinoma (RCC). Cabozantinib is an anti-angiogenic agent and potently inhibits multiple tyrosine kinases, including those implicated in the development of RCC. The previously approved indication of cabozantinib tablets (i.e. treatment of advanced RCC following prior VEGF-targeted therapy) has been extended to include the first-line treatment of advanced RCC in treatment-naïve adults with intermediate or poor risk (EU) and all patients with advanced RCC (USA). These label extensions are based on the results of a randomized, open-label phase 2 trial, in which adults with metastatic RCC of poor or intermediate risk received targeted first-line treatment with cabozantinib or standard-of-care sunitinib. Relative to sunitinib, cabozantinib significantly prolonged median progression-free survival (primary endpoint; investigator and independent assessments), and increased the objective response rate (investigator assessment). The tolerability profile of cabozantinib is comparable to those of other tyrosine kinase inhibitors, with adverse events being manageable with medical intervention, dosage reductions, treatment interruption and/or permanent discontinuation.

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Section: What Is the Tolerability Profile Of Cabozantinib In Arcc?mentioning

confidence: 99%

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use

Lyseng‐Williamson

2018

Drugs Ther Perspect

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“… 69 , 70 Clinically relevant QTc prolongation >500 ms was not appreciated in the cabozantinib phase III trial, as it was with vandetanib. 6 , 71 …”

Section: Nonselective Multikinase Inhibitorsmentioning

confidence: 99%

“…69,70 Clinically relevant QTc prolongation >500 ms was not appreciated in the cabozantinib phase III trial, as it was with vandetanib. 6,71 Selective RET inhibitors These are small molecule, ATP-competitive, potent, and highly selective RET inhibitors designed to overcome gatekeeper RET mutations and associated with less toxicity, dose reductions, and treatment discontinuations (Table 3). 72…”

Section: Ret Inhibitorsmentioning

confidence: 99%

RET kinase inhibitors forRET-altered thyroid cancers

Vodopivec

2022

Ther Adv Med Oncol

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Precision oncology has opened a new era in cancer treatment focused on targeting specific cellular pathways directly involved in tumorigenesis. The REarrangement during Transfection ( RET) proto-oncogene is involved in the pathogenesis of various thyroid cancer subtypes. Mutations in RET give rise to both hereditary and sporadic medullary thyroid cancer (MTC). RET fusions are found in follicular cell-derived thyroid cancers (papillary, poorly differentiated, and anaplastic). Hence, drugs that block the RET tyrosine kinase receptor have been explored in the management of locally advanced or metastatic thyroid cancer. The multikinase inhibitors (MKIs) with nonselective RET inhibition are sorafenib, lenvatinib, vandetanib, cabozantinib, and sunitinib. Although the efficacy of these drugs varies, a major issue is the lack of specificity resulting in a higher rate of drug-related toxicities, leading to dose reduction, interruption, or discontinuation. Moreover, MKIs are subject to drug resistance by RET Val804 residue gatekeeper mutations. In phase I/II clinical studies, the highly selective first-generation RET inhibitors, selpercatinib and pralsetinib, demonstrate high efficacy in controlling disease even in the presence of gatekeeper mutations combined with greater tolerability. However, resistance mechanisms such as RET solvent front mutations (SFMs) have evolved in some patients, giving the need to develop the selective second-generation RET inhibitors. Although the approval of selpercatinib and pralsetinib in 2020 has profoundly benefited patients with RET-altered thyroid cancer, further research into optimal treatment strategies, mechanisms of drug resistance, long-term consequences of potent RET-inhibition, and development of more effective agents against emergent mutations are much needed.

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“…Cabozantinib does not have a clinically significant effect on QTc interval; and therefore, coadministration with QTc-prolonging agents such as antiemetic therapy with serotonin inhibitors is not contraindicated. Clinicians should consider monitoring patients with a history of QT interval prolongation or at-risk patients (eg, patients with relevant cardiac disease) during cabozantinib treatment [6,7,29,41,43].…”

Section: Cyp3a4 Interactions)mentioning

confidence: 99%

Exposure-response modeling of cabozantinib in patients with renal cell carcinoma: Implications for patient care

Castellano

Maroto

Benzaghou

et al. 2020

Cancer Treatment Reviews

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Cabozantinib is an oral tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced renal cell carcinoma (RCC) at a dose of 60 mg/day. As with other TKIs, cabozantinib is associated with high interpatient variability in drug clearance and exposure that can significantly impact safety and tolerability across a patient population. To optimize cabozantinib exposure (maintaining efficacy and tolerability) for the individual, patients may require treatment interruption with dose reduction (40 mg/day and then 20 mg/day). In the pivotal Phase 3 METEOR trial, cabozantinib significantly improved overall survival, progression-free survival and the objective response rate compared with everolimus in patients with advanced RCC who had received previous treatment with a VEGFR TKI. Dose reductions were common for patients receiving cabozantinib (60%) but effective as only 9% discontinued treatment due to adverse events (AEs). In this review, we discuss pharmacometric analyses that evaluated the impact of cabozantinib dose on efficacy and safety outcomes during the METEOR study. Exposure-response models demonstrate that the risk of experiencing adverse events and dose reduction is increased in patients with low cabozantinib clearance versus typical clearance and decreased in patients with high clearance. Dose reduction of cabozantinib to manage AEs is predicted to have minimal impact on efficacy as AEs are more likely to occur in patients with low clearance and higher exposure to cabozantinib. These analyses further support a dose modification strategy to optimize cabozantinib exposure for individual patients.

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Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes

Cited by 9 publications

References 33 publications

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use

RET kinase inhibitors forRET-altered thyroid cancers

Exposure-response modeling of cabozantinib in patients with renal cell carcinoma: Implications for patient care

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