Cabozantinib in progressive medullary thyroid cancer

Rossella Elisei, Martin J. Schlumberger, Stefan P. Müller, Patrick Schöffski, Marcia S. Brose, Manisha H. Shah, Lisa Licitra, Barbara Jarzab, Viktor Medvedev, Michael C. Kreissl, Bruno Niederle, Ezra E W Cohen, Lori J. Wirth, Haythem Ali, Colin Hessel, Yifah Yaron, Douglas W Ball, Barry D Nelkin, Steven I. Sherman

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3639-3646
Number of pages8
JournalJournal of Clinical Oncology
Volume31
Issue number29
DOIs
StatePublished - Oct 10 2013

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Placebos
Disease-Free Survival
Transfection
Protein-Tyrosine Kinases
cabozantinib
Medullary Thyroid cancer
Proto-Oncogene Proteins c-met
Vascular Endothelial Growth Factor Receptor-2
Mutation
Kaplan-Meier Estimate
Appetite
Rare Diseases
Nausea
Fatigue
Diarrhea
Therapeutics
Survival Rate
Outcome Assessment (Health Care)
Safety
Weights and Measures

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Elisei, R., Schlumberger, M. J., Müller, S. P., Schöffski, P., Brose, M. S., Shah, M. H., ... Sherman, S. I. (2013). Cabozantinib in progressive medullary thyroid cancer. Journal of Clinical Oncology, 31(29), 3639-3646. https://doi.org/10.1200/JCO.2012.48.4659

Cabozantinib in progressive medullary thyroid cancer. / Elisei, Rossella; Schlumberger, Martin J.; Müller, Stefan P.; Schöffski, Patrick; Brose, Marcia S.; Shah, Manisha H.; Licitra, Lisa; Jarzab, Barbara; Medvedev, Viktor; Kreissl, Michael C.; Niederle, Bruno; Cohen, Ezra E W; Wirth, Lori J.; Ali, Haythem; Hessel, Colin; Yaron, Yifah; Ball, Douglas W; Nelkin, Barry D; Sherman, Steven I.

In: Journal of Clinical Oncology, Vol. 31, No. 29, 10.10.2013, p. 3639-3646.

Research output: Contribution to journalArticle

Elisei, R, Schlumberger, MJ, Müller, SP, Schöffski, P, Brose, MS, Shah, MH, Licitra, L, Jarzab, B, Medvedev, V, Kreissl, MC, Niederle, B, Cohen, EEW, Wirth, LJ, Ali, H, Hessel, C, Yaron, Y, Ball, DW, Nelkin, BD & Sherman, SI 2013, 'Cabozantinib in progressive medullary thyroid cancer', Journal of Clinical Oncology, vol. 31, no. 29, pp. 3639-3646. https://doi.org/10.1200/JCO.2012.48.4659
Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH et al. Cabozantinib in progressive medullary thyroid cancer. Journal of Clinical Oncology. 2013 Oct 10;31(29):3639-3646. https://doi.org/10.1200/JCO.2012.48.4659
Elisei, Rossella ; Schlumberger, Martin J. ; Müller, Stefan P. ; Schöffski, Patrick ; Brose, Marcia S. ; Shah, Manisha H. ; Licitra, Lisa ; Jarzab, Barbara ; Medvedev, Viktor ; Kreissl, Michael C. ; Niederle, Bruno ; Cohen, Ezra E W ; Wirth, Lori J. ; Ali, Haythem ; Hessel, Colin ; Yaron, Yifah ; Ball, Douglas W ; Nelkin, Barry D ; Sherman, Steven I. / Cabozantinib in progressive medullary thyroid cancer. In: Journal of Clinical Oncology. 2013 ; Vol. 31, No. 29. pp. 3639-3646.
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AU - Elisei, Rossella

AU - Schlumberger, Martin J.

AU - Müller, Stefan P.

AU - Schöffski, Patrick

AU - Brose, Marcia S.

AU - Shah, Manisha H.

AU - Licitra, Lisa

AU - Jarzab, Barbara

AU - Medvedev, Viktor

AU - Kreissl, Michael C.

AU - Niederle, Bruno

AU - Cohen, Ezra E W

AU - Wirth, Lori J.

AU - Ali, Haythem

AU - Hessel, Colin

AU - Yaron, Yifah

AU - Ball, Douglas W

AU - Nelkin, Barry D

AU - Sherman, Steven I.

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N2 - 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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