Cabozantinib in hepatocellular carcinoma: Results of a phase 2 placebo-controlled randomized discontinuation study

R. K. Kelley, C. Verslype, A. L. Cohn, T. S. Yang, W. C. Su, H. Burris, F. Braiteh, N. Vogelzang, Alexander Spira, P. Foster, Y. Lee, Eric Van Cutsem

Research output: Contribution to journalArticle

Abstract

Background: Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumortype cohorts. Patients and methods: Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS). Results: Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (> 50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients. Conclusions: Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.

Original languageEnglish (US)
Pages (from-to)528-534
Number of pages7
JournalAnnals of Oncology
Volume28
Issue number3
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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Hepatocellular Carcinoma
Placebos
alpha-Fetoproteins
Disease-Free Survival
cabozantinib
Hand-Foot Syndrome
Vascular Endothelial Growth Factor Receptor
Random Allocation
Thrombocytopenia
Protein-Tyrosine Kinases
Diarrhea
Neoplasms
Survival
Liver
Therapeutics

Keywords

  • Cabozantinib
  • Hepatocellular carcinoma
  • Overall survival
  • Progression-free survival
  • Tumor response
  • Vascular endothelial growth factor receptor

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Kelley, R. K., Verslype, C., Cohn, A. L., Yang, T. S., Su, W. C., Burris, H., ... Van Cutsem, E. (2017). Cabozantinib in hepatocellular carcinoma: Results of a phase 2 placebo-controlled randomized discontinuation study. Annals of Oncology, 28(3), 528-534. https://doi.org/10.1093/annonc/mdw651

Cabozantinib in hepatocellular carcinoma : Results of a phase 2 placebo-controlled randomized discontinuation study. / Kelley, R. K.; Verslype, C.; Cohn, A. L.; Yang, T. S.; Su, W. C.; Burris, H.; Braiteh, F.; Vogelzang, N.; Spira, Alexander; Foster, P.; Lee, Y.; Van Cutsem, Eric.

In: Annals of Oncology, Vol. 28, No. 3, 01.01.2017, p. 528-534.

Research output: Contribution to journalArticle

Kelley, RK, Verslype, C, Cohn, AL, Yang, TS, Su, WC, Burris, H, Braiteh, F, Vogelzang, N, Spira, A, Foster, P, Lee, Y & Van Cutsem, E 2017, 'Cabozantinib in hepatocellular carcinoma: Results of a phase 2 placebo-controlled randomized discontinuation study', Annals of Oncology, vol. 28, no. 3, pp. 528-534. https://doi.org/10.1093/annonc/mdw651
Kelley, R. K. ; Verslype, C. ; Cohn, A. L. ; Yang, T. S. ; Su, W. C. ; Burris, H. ; Braiteh, F. ; Vogelzang, N. ; Spira, Alexander ; Foster, P. ; Lee, Y. ; Van Cutsem, Eric. / Cabozantinib in hepatocellular carcinoma : Results of a phase 2 placebo-controlled randomized discontinuation study. In: Annals of Oncology. 2017 ; Vol. 28, No. 3. pp. 528-534.
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abstract = "Background: Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumortype cohorts. Patients and methods: Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS). Results: Among the 41 HCC patients enrolled, the week 12 ORR was 5{\%}, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66{\%} (Asian subgroup: 73{\%}). Of patients with ≥1 post-baseline scan, 78{\%} had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (> 50{\%} reduction from baseline) occurred in 9 of the 26 (35{\%}) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20{\%}), hand-foot syndrome (15{\%}), and thrombocytopenia (15{\%}). Dose reductions were utilized in 59{\%} of patients. Conclusions: Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.",
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AU - Yang, T. S.

AU - Su, W. C.

AU - Burris, H.

AU - Braiteh, F.

AU - Vogelzang, N.

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N2 - Background: Cabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumortype cohorts. Patients and methods: Eligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS). Results: Among the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (> 50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients. Conclusions: Cabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.

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KW - Vascular endothelial growth factor receptor

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