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.
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 (ORRwk24). ORRwk24 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.
The ORRwk24 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.
This study did not show noninferiority of LEN 18 mg vs LEN 24 mg based on the ORRwk24 analysis. ORRwk24 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.
NCT02702388.
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.
Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Eisai Inc., Woodcliff Lake, NJ, USA, and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
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.