A phase II trial of the multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer

Martin Schlumberger, Barbara Jarzab, Maria E. Cabanillas, Bruce Robinson, Furio Pacini, Douglas W Ball, Judith McCaffrey, Kate Newbold, Roger Allison, Renato G. Martins, Lisa F. Licitra, Manisha H. Shah, Donald Bodenner, Rossella Elisei, Lynn Burmeister, Yasuhiro Funahashi, Min Ren, James P. O'Brien, Steven I. Sherman

Research output: Contribution to journalArticle

Abstract

Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC). Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review. Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%- 89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction. Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.

Original languageEnglish (US)
Pages (from-to)44-53
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number1
DOIs
StatePublished - Jan 1 2016

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Protein-Tyrosine Kinases
Confidence Intervals
Disease-Free Survival
Angiopoietin-2
Neoplasms
Hepatocyte Growth Factor
Proto-Oncogenes
Appetite
Deglutition Disorders
Alanine Transaminase
Interleukin-8
Thyroid Neoplasms
Vascular Endothelial Growth Factor A
Fatigue
Disease Progression
Diarrhea
Research Design
Therapeutics
Hypertension
lenvatinib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase II trial of the multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer. / Schlumberger, Martin; Jarzab, Barbara; Cabanillas, Maria E.; Robinson, Bruce; Pacini, Furio; Ball, Douglas W; McCaffrey, Judith; Newbold, Kate; Allison, Roger; Martins, Renato G.; Licitra, Lisa F.; Shah, Manisha H.; Bodenner, Donald; Elisei, Rossella; Burmeister, Lynn; Funahashi, Yasuhiro; Ren, Min; O'Brien, James P.; Sherman, Steven I.

In: Clinical Cancer Research, Vol. 22, No. 1, 01.01.2016, p. 44-53.

Research output: Contribution to journalArticle

Schlumberger, M, Jarzab, B, Cabanillas, ME, Robinson, B, Pacini, F, Ball, DW, McCaffrey, J, Newbold, K, Allison, R, Martins, RG, Licitra, LF, Shah, MH, Bodenner, D, Elisei, R, Burmeister, L, Funahashi, Y, Ren, M, O'Brien, JP & Sherman, SI 2016, 'A phase II trial of the multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer', Clinical Cancer Research, vol. 22, no. 1, pp. 44-53. https://doi.org/10.1158/1078-0432.CCR-15-1127
Schlumberger, Martin ; Jarzab, Barbara ; Cabanillas, Maria E. ; Robinson, Bruce ; Pacini, Furio ; Ball, Douglas W ; McCaffrey, Judith ; Newbold, Kate ; Allison, Roger ; Martins, Renato G. ; Licitra, Lisa F. ; Shah, Manisha H. ; Bodenner, Donald ; Elisei, Rossella ; Burmeister, Lynn ; Funahashi, Yasuhiro ; Ren, Min ; O'Brien, James P. ; Sherman, Steven I. / A phase II trial of the multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 1. pp. 44-53.
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T1 - A phase II trial of the multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer

AU - Schlumberger, Martin

AU - Jarzab, Barbara

AU - Cabanillas, Maria E.

AU - Robinson, Bruce

AU - Pacini, Furio

AU - Ball, Douglas W

AU - McCaffrey, Judith

AU - Newbold, Kate

AU - Allison, Roger

AU - Martins, Renato G.

AU - Licitra, Lisa F.

AU - Shah, Manisha H.

AU - Bodenner, Donald

AU - Elisei, Rossella

AU - Burmeister, Lynn

AU - Funahashi, Yasuhiro

AU - Ren, Min

AU - O'Brien, James P.

AU - Sherman, Steven I.

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N2 - Purpose: Positive results of phase I studies evaluating lenvatinib in solid tumors, including thyroid cancer, prompted a phase II trial in advanced medullary thyroid carcinoma (MTC). Experimental Design: Fifty-nine patients with unresectable progressive MTC per Response Evaluation Criteria In Solid Tumors (RECIST) v1.0 within the prior 12 months received lenvatinib (24-mg daily, 28-day cycles) until disease progression, unmanageable toxicity, withdrawal, or death. Prior anti-VEGFR therapy was permitted. The primary endpoint was objective response rate (ORR) by RECIST v1.0 and independent imaging review. Results: Lenvatinib ORR was 36% [95% confidence interval (CI), 24%-49%]; all partial responses. ORR was comparable between patients with (35%) or without (36%) prior anti-VEGFR therapy. Disease control rate (DCR) was 80% (95% CI, 67%- 89%); 44% had stable disease. Among responders, median time to response (TTR) was 3.5 months (95% CI, 1.9-3.7). Median progression-free survival (PFS) was 9.0 months (95% CI, 7.0-not evaluable). Common toxicity criteria grade 3/4 treatment-emergent adverse events included diarrhea (14%), hypertension (7%), decreased appetite (7%), fatigue, dysphagia, and increased alanine aminotransferase levels (5% each). Ret proto-oncogene status did not correlate with outcomes. Low baseline levels of angiopoietin-2, hepatocyte growth factor, and IL8 were associated with tumor reduction and prolonged PFS. High baseline levels of VEGF, soluble VEGFR3, and platelet-derived growth factor BB, and low baseline levels of soluble Tie-2, were associated with tumor reduction. Conclusions: Lenvatinib had a high ORR, high DCR, and a short TTR in patients with documented progressive MTC. Toxicities were managed with dose modifications and medications.

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