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.
Bibliographical noteFunding Information:
M. Schlumberger is a consultant/advisory board member for AstraZeneca, Bayer, Eisai, and Exelixis. M.E. Cabanillas is a consultant/advisory board member for and reports receiving commercial research grants fromEisai. B. Robinson has ownership interest (including patents) in Mayne Pharma and is a consultant/ advisory board member for AstraZeneca, Bayer, and Eisai. D.W. Ball is a consultant/ advisory board member for Eisai. K. Newbold reports receiving speakers bureau honoraria from and is a consultant/advisory board member for Astra- Zeneca, Eisai, and Genzyme. M.H. Shah reports receiving commercial research grants fromEisai and Exelixis. R. Elisei is a consultant/advisory boardmember for AstraZeneca, Bayer, Exelixis, and Genzyme. S.I. Sherman is a consultant/advisory boardmember forAstraZeneca, Bayer, Eisai, and Exelixis.No potential conflicts of interest were disclosed by the other authors. The authors thank Mark Matijevic and Tadashi Kadowaki for their assistance in the biomarker analyses. Medical editorial writing assistance was provided by Phase Five Communications Inc., and Oxford PharmaGenesis, Inc. The authors retained full editorial control over the article. This work was supported by Eisai Inc.