Phase 2 study of lenvatinib monotherapy as second-line treatment in unresectable biliary tract cancer: primary analysis results

Abstract

Background: Biliary tract cancer (BTC) has a poor prognosis and lacks a standardized second-line therapy. Vascular endothelial growth factor (VEGF), fibroblast growth factor receptor (FGFR) 4, and platelet-derived growth factor receptor (PDGFR) are highly expressed in BTC. Therefore, lenvatinib (a known inhibitor of VEGF receptors 1-3, FGFRs 1-4, and PDGFR-α) was evaluated for second-line treatment of BTC.

Methods: In this single-arm, multicenter, open-label, phase 2 study, patients with BTC received lenvatinib 24 mg orally once daily in 28-day cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), PFS rate at 12 weeks, disease control rate, clinical benefit rate, safety and pharmacokinetic profiles.

Results: Twenty-six Japanese patients were enrolled and treated; 3 had a confirmed partial response per investigator assessment and per independent imaging review (IIR); ORR was 11.5% (90% confidence interval [CI]: 3.2-27.2). Median PFS was 3.19 months (95% CI: 2.79-7.23) per investigator assessment and 1.64 months (95% CI: 1.41-3.19) per IIR. Median OS was 7.35 months (95% CI: 4.50-11.27). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 21 patients (80.8%) and included hypertension (n = 10 [38.5%]), proteinuria (n = 3 [11.5%]), palmar-plantar erythrodysesthesia (n = 3 [11.5%]), decreased appetite (n = 3 [11.5%]), and anemia (n = 3 [11.5%]). Two deaths occurred due to TEAEs between treatment initiation and 30 days after last dose, but neither were considered treatment related.

Conclusions: Lenvatinib demonstrated antitumor activity in BTC, with a tolerable safety profile, and should be further evaluated as potential second-line therapy for this difficult to treat population.

Trial registration: ClinicalTrials.gov NCT02579616 . Date of registration: October 19, 2015.

Keywords: Ampulla of Vater; Biliary tract cancer; Cholangiocarcinoma; Gallbladder cancer; Lenvatinib.

Conflict of interest statement

Makoto Ueno: reports honoraria from Taiho Pharmaceutical, Yakult Honsha, AstraZeneca, Novartis, Lilly, Teijin Pharma, Shire, Ono Pharmaceutical, and Merck Serono; consulting or advisory role for Shire; research funding from Taiho Pharmaceutical, Shire, Daiichi Sankyo, Eisai, AstraZeneca, Ono Pharmaceutical, MSD, Merck Serono, NanoCarrier, Dainippon Sumitomo Pharma, Incyte, ASLAN Pharmaceuticals, and Yakult Honsha.

Masafumi Ikeda: reports honoraria from Abbott, Bayer, Bristol Myers Squibb, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Nobelpharma, Novartis, Otsuka, Taiho Pharmaceutical, Teijin Pharma, and Yakult Honsha; consulting or advisory role for Bayer, Daiichi Sankyo, Eisai, Kyowa Hakko Kirin, MSD, NanoCarrier, Novartis, Shire, Teijin Pharma, and Eli Lilly; research funding from ASLAN Pharmaceuticals, AstraZeneca, Baxalta/Shire, Bayer, Bristol Myers Squibb, Chugai Pharma, Eisai, Kowa, Kyowa Hakko Kirin, Lilly, Merck Serono, MSD, NanoCarrier, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Takara Bio, and Yakult Honsha.

Takashi Sasaki: reports honoraria from Taiho Pharmaceutical and Eisai.

Fumio Nagashima: reports honoraria from ASKA pharma, Chugai Pharma, Hisamitsu, Kyowa Hakko Kirin, Merck Serono, Mochida, Ono Pharmaceutical, Shionogi, Taiho Pharmaceutical, Takeda, and Yakult Honsha; research funding from AstraZeneca, Baxalta, Bayer, Chugai Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, J Pharma, Kyowa Hakko Kirin, Merck Serono, MSD, NanoCarrier, Mochida, Ono Pharmaceutical, Pfizer, Sanofi, Takeda, Yakult Honsha, and Zeria Pharma.

Nobumasa Mizuno: reports grants from Eisai, Merck Serono, AstraZeneca, Zeria Pharma, NanoCarrier, MSD, Dainippon Sumitomo Pharma, Novartis, ASLAN Pharmaceuticals, Incyte, Yakult Honsha, Pharma Valley Center, and Taiho Pharmaceutical; personal fees from Novartis, Yakult Honsha, Ono Pharmaceutical, OncoTherapy Science, Inc., Kyowa Hakko Kirin, Pfizer, Teijin Pharma and Taiho Pharmaceutical; non-financial support from Novartis, Yakult Honsha, Pfizer, and Bristol Myers Squibb.

Satoshi Shimizu: reports research funding from NanoCarrier, Eisai, Baxalta, Taiho Pharmaceutical, Dainippon Sumitomo Pharma, AstraZeneca, IQVIA services Japan K.K., and Incyte.

Hiroki Ikezawa: is an employee of Eisai Co., Ltd.

Nozomi Hayata: is an employee of Eisai Co., Ltd.

Ryo Nakajima: is an employee of Eisai Inc.

Chigusa Morizane: reports honoraria from Taiho Pharmaceutical, MSD, Novartis, Teijin Pharma, Yakult Honsha, and Ono Pharmaceutical; consulting or advisory role for AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, MSD, Yakult Honsha, AbbVie, and Novartis; research funding from Eisai, Yakult Honsha, Ono Pharmaceutical, Taiho Pharmaceutical, J Pharma, Pfizer, AstraZeneca, and Merck Biopharma.

Figures

Fig. 1

Kaplan–Meier plot of PFS by investigator assessment (a) and IIR (b). CI, confidence interval; IIR, independent imaging review; PFS, progression-free survival

Fig. 2

Kaplan–Meier plot of OS. a17 Deaths occurred in this study; 2 deaths occurred within 30 days of administration of the last dose and 15 deaths occurred > 30 days after administration of the last dose. CI, confidence interval; OS, overall survival

Fig. 3

Percentage change from baseline in the sum of lesion diameters per investigator assessment (A) and IIR (B). aOne patient was assigned a BOR of “unknown” by IIR and was excluded from this analysis. BOR, best overall response; IIR, independent imaging review; PD, progressive disease; PR, partial response; SD, stable disease

Fig. 4

Comparison of lenvatinib plasma concentration in patients with BTC (this study) to patients with DTC (Study 303) [20]. aThere were 7 patients excluded from the pharmacokinetic analysis because their dose was reduced or interrupted before cycle 1 day 15. bBodyweight-adjusted plasma concentration was calculated as follows: individual plasma concentration × bodyweight [kg]/60 [kg]. BTC, biliary tract cancer; DTC, differentiated thyroid cancer