426P - A multicenter, randomized, double-blind, phase II study of lenvatinib (LEN) in patients (pts) with radioiodine-refractory differentiated thyroid cancer (RR-DTC) to evaluate the safety and efficacy of a daily oral starting dose of 18 mg vs 24 mg

Background

In SELECT, PFS was significantly longer with LEN 24 mg/d (median: 18.3 mos) vs placebo (median: 3.6 mos; HR 0.21, 99% CI: 0.14–0.31) in pts with RR-DTC; however, the dose-reduction rate due to TEAEs was 68%. This study was designed to evaluate if a starting dose of LEN 18 mg/d could maintain efficacy and reduce toxicity in pts with RR-DTC.

Methods

In this double-blind study, pts ≥18 years (N=152) were randomized 1:1 to receive daily oral LEN at a starting dose of 24 mg (n=75) or 18 mg (n=77): ‘LEN24’ and ‘LEN18’ arms, respectively. The primary efficacy endpoint was ORR as of week 24 (ORR_wk24). ORR_wk24 analysis was based on a noninferiority test on the odds ratio (OR; noninferiority margin of 0.4 on OR scale). Tumors were assessed by investigators per RECIST v1.1. The primary safety endpoint was the rate of TEAEs grade ≥3 as of wk 24.

Results

The ORR_wk24 was 57.3% (95% CI: 46.1–68.5) in LEN24 and 40.3% (95% CI: 29.3–51.2) in LEN18. OR (18/24 mg) 0.50 (95% CI: 0.26–0.96) did not meet criteria for noninferiority. Overall ORR was 64.0% (95% CI: 53.1–74.9) in LEN24 and 46.8% (95% CI: 35.6–57.9) in LEN18 (OR [18/24 mg] 0.50, 95% CI: 0.26–0.95). Median PFS was not reached (NR) in LEN24 (95% CI: 22.1–NR) vs 24.4 mos in LEN18 (95% CI: 14.7–NR) (HR: 1.44, 95% CI: 0.76–2.74). As of wk 24, there was a nonclinically relevant difference in the rate of TEAEs grade ≥3 of 4.2% (95% CI: −19.8–11.4 [LEN24, 61.3% of pts; LEN18, 57.1% of pts]). The most common TEAE grade ≥3 (24/18 mg) as of wk 24 was hypertension (25.3%/19.5%). Overall, TEAEs resulted in dose reduction in 69.3% of pts in LEN24 and 59.7% of pts in LEN18; 14.7% of pts in LEN24 and 16.9% of pts in LEN18 had a TEAE that led to discontinuation.

Conclusions

This study did not show noninferiority of LEN 18 mg vs LEN 24 mg based on the ORR_wk24 analysis. ORR_wk24 for LEN24 (57%) was consistent with that seen by investigator assessment in SELECT (59%). Incidences of grade ≥3 TEAEs through wk 24 were similar between treatment arms, and no new or unexpected safety signals were observed. These data support selection of LEN 24 mg/d as an appropriate starting dose for pts with RR-DTC.

Clinical trial identification

NCT02702388.

Editorial acknowledgement

Medical writing support was provided by Heather A. Mitchell, PhD, of Oxford PharmaGenesis, Newtown, PA and was funded by Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

M.S. Brose: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): Eisai; Advisory/Consultancy, Research grant/Funding (self): Blueprint Medicines; Advisory/Consultancy, Research grant/Funding (self): Loxo; Advisory/Consultancy, Research grant/Funding (self): Novartis; Advisory/Consultancy: Genzyme; Advisory/Consultancy: Bristol-Myers Squibb; Research grant/Funding (self): Roche/Genentech; Research grant/Funding (self): Exelixis. B. Konda: Research grant/Funding (institution): Advanced Accelerator Applications; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Xencor; Research grant/Funding (institution): Bristol-Myers Squibb. C. de la Fouchardiere: Honoraria (self): Eisai; Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self), Non-remunerated activity/ies: Servier; Honoraria (self), Non-remunerated activity/ies: Amgen; Honoraria (self), Non-remunerated activity/ies: Pierre Fabre Oncologie; Honoraria (self), Non-remunerated activity/ies: Bayer; Honoraria (self), Non-remunerated activity/ies: Bristol-Myers Squibb. B.G.M. Hughes: Advisory/Consultancy: Roche; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Merck Sharp and Dohme; Advisory/Consultancy: Eisai; Advisory/Consultancy: Takeda; Research grant/Funding (self): Amgen. A.G. Gianoukakis: Advisory/Consultancy: Eisai; Advisory/Consultancy: Bayer; Advisory/Consultancy: Loxo-Lilly. I. Romanov: Honoraria (self): Eisai; Honoraria (self): Merck Serono; Honoraria (self): Bristol-Myers Squibb. M.K. Krzyzanowska: Advisory/Consultancy, Research grant/Funding (self): Eisai; Advisory/Consultancy: Bayer; Research grant/Funding (self): Exelixis; Research grant/Funding (self): Ipsen. T. Binder, R. Xie: Full/Part-time employment: Eisai Inc. C. Dutcus: Leadership role, Research grant/Funding (self), Full/Part-time employment: Eisai Inc. M.H. Taylor: Advisory/Consultancy, Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eisai; Advisory/Consultancy: Array BioPharma; Advisory/Consultancy: Loxo; Advisory/Consultancy: Bayer; Advisory/Consultancy: ArQule; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: Novartis; Advisory/Consultancy: Sanofi/Genzyme. All other authors have declared no conflicts of interest.