Cabozantinib in Progressive Medullary Thyroid Cancer
Open accessAbstract
Purpose: Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. Patients and Methods: We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. Results: The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients. Conclusion: Cabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.
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The selected recommended phase II dose using conventional pharmacokinetic/pharmacodynamic modeling may be associated with an unnecessarily high safety risk, necessitating collection of postmarketing data related to dose optimization for regulatory agencies.
“As a result, the selected RP2D using conventional PK/PD modeling may be associated with an unnecessarily high safety risk, necessitating collection of postmarketing data related to dose optimization for regulatory agencies. 8 , 9 , 10”
From Semimechanistic Physiologically‐Based Pharmacokinetic/Pharmacodynamic Model Informing Epcoritamab Dose Selection for Patients With <scp>B‐Cell</scp> Lymphomas (2022) · cites this paper as [9]
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- Authors
- Elisei, R., Schlumberger, M. J., Müller, S. P., Schöffski, P., Brose, M. S., Shah, M. H., Licitra, L., Jarzab, B., Medvedev, V., Kreissl, M. C., Niederle, B., Cohen, E. E. W., Wirth, L. J., Ali, H., Hessel, C., Yaron, Y., Ball, D., Nelkin, B., & Sherman, S. I.
- Affiliations
- University of Pisa (IT)
- Rossella Elisei, University of Pisa, Pisa; Lisa Licitra, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico-Istituto Nazionale dei Tumori, Milan, Italy; Martin J. Schlumberger, Institut Gustave Roussy, University Paris-Sud, Villejuif, France; Stefan P. Müller, Universitatsklinikum Essen, Essen; Michael C. Kreissl, Universitätsklinikum Würzburg, Würzburg, Germany; Patrick Schöffski, University Hospitals Leuven, Leuven, Belgium; Marcia S. Brose, University of Pennsylvania Abramson Cancer Center...
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2013-10-10
- Volume
- 31
- Issue
- 29
- Pages
- 3639-3646
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC4164813
- OpenAlex
- W2122956665
- Semantic Scholar
- f3215e3d8a74faf4555d5b6c4447c789a8de5df3
- Cited by
- 1,217
- References
- 38
- Citations by year
- 2026: 49 · 2025: 69 · 2024: 75 · 2023: 102 · 2022: 120 · 2021: 108 · 2020: 88 · 2019: 77 · 2018: 83 · 2017: 109 · 2016: 117 · 2015: 124 · 2014: 82 · 2013: 8 · 2012: 2
- FWCI
- 87.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, other-oa)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Exelixis
- Eisai
- National Cancer Institute (P30CA016672)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079637)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- cabozantinib, medullary thyroid carcinoma, tyrosine kinase inhibitors, MET inhibition, RET mutations, progression-free survival, metastatic disease, drug toxicity
- MeSH terms
- Adult, Aged, Aged, 80 and over, Anilides, Calcitonin, Carcinoembryonic Antigen, Double-Blind Method, Female, Humans, Male, Middle Aged, Pyridines, Thyroid Neoplasms, Carcinoma, Neuroendocrine, Disease-Free Survival, Protein Kinase Inhibitors
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