1838 - Multicenter phase II trial of axitinib monotherapy for advanced biliary tract cancer refractory to gemcitabine-based chemotherapy

Background

Axitinib (AX) is an orally administered selective inhibitor of vascular endothelial growth factor (VEGF) receptor (R)-1/2/3. We previously reported that AX preliminarily showed promising activity against gemcitabine (GEM)-refractory biliary tract cancer (BTC), and we conducted this trial to confirm the efficacy and safety.

Methods

This single-arm phase II trial registered patients (pts) with advanced BTC refractory to GEM-based regimens. They were treated with an initial AX dose of 5 mg twice daily. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall response rate (ORR), overall survival (OS), and safety. Plasma biomarkers were measured at baseline and 1 month after treatment.

Results

Between July 2016 and August 2017, a total of 19 pts were enrolled from 3 centers; median age was 67 (range: 44–80) years, 10 (53%) were men. The ECOG performance status was 0 for 10 pts (53%) and 1 for 9 pts (47%). Nine pts (47%) had recurrent disease after surgery, 15 (79%) received GEM + cisplatin in first-line chemotherapy, and 13 (68%) received 2 or more chemotherapy regimens before enrollment. The primary sites were gallbladder, extrahepatic bile duct, and intrahepatic bile duct in 9 (47%), 6 (32%), and 4 (21%) pts, respectively. The median PFS was 2.8 months (95% confidence interval [CI]: 2.1–4.1), the ORR was 5.3% (95% CI: 0.0–15.3), and the median OS was 5.8 months (95% CI: 3.3–9.7). Treatment-related adverse events in this study were similar to those previously reported for renal cell carcinoma or thyroid cancer; however, ascites occurred in two pts possibly due to AX. Plasma biomarkers at both time points were evaluated in 16 pts. AX was associated with significant increases in VEGF-A and decreases in sVEGFR-1/2/3. Of the baseline biomarkers, high sVEGFR-2 and sVEGFR-3 were significantly associated with longer PFS and OS, respectively. High sVEGFR-3 and low VEGF-D tended to increase PFS, and high sVEGFR-2 and low VEGF-D tended to increase OS.

Conclusions

AX exhibited modest activity against GEM-refractory BTC. This trial suggested that ascites should be monitored as an adverse event. Baseline sVEGFR-2 and sVEGFR-3 may be useful biomarkers for AX.

Clinical trial identification

UMIN000023014.

Editorial acknowledgement

Legal entity responsible for the study

Kyorin University Faculty of Medicine.

Funding

Japan Agency for Medical Research and Development.

Disclosure

N. Okano: Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Merck Serono; Honoraria (self): Eisai; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Yakult Honsha; Honoraria (self): Takeda; Honoraria (self): J-Pharma; Honoraria (self): Kyowa Hakko Kirin. M. Ueno: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Shire; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): MSD; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): ASLAN Pharmaceuticals. C. Morizane: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Yakult Honsha; Honoraria (self): Lilly; Honoraria (self), Research grant / Funding (institution): Nobelpharma; Honoraria (self): Fujifilm; Honoraria (self): Teijin Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Eisai; Advisory / Consultancy: AbbVie; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): J-Pharma. T. Yamanaka: Honoraria (self): Pfizer. H. Ojima: Research grant / Funding (institution): Pfizer Inc; Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Taiho Pharmaceutical. M. Ozaka: Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Bayer; Honoraria (self): Yakult Honsha; Honoraria (self): Eisai; Honoraria (self): EA Pharma. S. Kobayashi: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Kyowa Hakko Kirin; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self), Research grant / Funding (institution): Eisai; Honoraria (self): Boston Scientific; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Dainippon Sumitomo Pharmaceutical; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Yakult Honsha; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Takara Bio; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Boeringer Ingelheim; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Takeda Pharmaceutical. Y. Nakai: Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Research grant / Funding (self): Eisai; Research grant / Funding (self): Yakult Honsha; Research grant / Funding (self): J-Pharma. M. Ikeda: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer Yakuhin; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly Japan; Research grant / Funding (institution): Yakult; Advisory / Consultancy: Otsuka Pharmaceutical; Advisory / Consultancy: Daiichi-Sankyo; Honoraria (self): Sumitomo Dainippon Pharma; Honoraria (self), Advisory / Consultancy: Teijin Pharma; Honoraria (self): EA Pharma; Honoraria (self): Kaken Pharmaceutical; Advisory / Consultancy: Shire; Honoraria (self): MSD; Advisory / Consultancy, Research grant / Funding (institution): ASLAN Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Nano Carrier; Honoraria (self): Gilead; Advisory / Consultancy: Astellas Pharma; Research grant / Funding (institution): Takeda Pharmaceutical; Research grant / Funding (institution): J-Pharma; Advisory / Consultancy: Micron. S. Maeno: Honoraria (self): Pfizer. F. Nagashima: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Serono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Yakult Honsha; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sumitomo Dainippon; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Kyowa Hakko Kirin; Speaker Bureau / Expert testimony: Mitsubishi Tanabe Pharma; Speaker Bureau / Expert testimony: Nestle health science; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Oncotherapy; Research grant / Funding (institution): Zeria Pharmaceutical; Research grant / Funding (institution): Lilly Japan; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Shionogi; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): J-Pharma; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Mochida Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Nano Carrier; Research grant / Funding (institution): Shire. T. Okusaka: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Novartis Pharma; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Eli Lilly Japan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Yakult Honsha; Honoraria (self): Teijin Pharma; Honoraria (self): Shire; Honoraria (self): AbbVie; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self): Takeda Pharmaceutical; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Dainippon Sumitomo Pharma; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers; Research grant / Funding (self), Research grant / Funding (institution): Pfizer Japan; Research grant / Funding (self): Kyowa Hakko Kirin; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), Research grant / Funding (institution): Chugai Pharmaceutical; Research grant / Funding (self), Research grant / Funding (institution): Nano Carrier; Research grant / Funding (self), Research grant / Funding (institution): Baxter. J. Furuse: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eisai; Honoraria (self), Research grant / Funding (self): Bayer Yakuhin; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Research grant / Funding (self): Yakult Honsha; Honoraria (self): Teijin Pharma; Honoraria (self): Shionogi; Honoraria (self): EA Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eli Lilly Japan; Honoraria (self), Research grant / Funding (self): Takeda; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Chugai Pharma; Honoraria (self), Research grant / Funding (self): Mochida Pharmaceutical; Honoraria (self): Nihon Servier; Honoraria (self), Research grant / Funding (self): Sanofi; Honoraria (self), Advisory / Consultancy: Fujifilm; Honoraria (self): Nobel Pharma; Honoraria (self), Research grant / Funding (self): Pfizer; Honoraria (self): Sawai Pharmaceutical; Honoraria (self), Research grant / Funding (self): Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Sumitomo Dainippon; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Astellas Pharma; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self): Nippon Kayaku; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: J-Pharma; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Research grant / Funding (self): Kyowa Hakko Kirin; Advisory / Consultancy: Takara Bio; Advisory / Consultancy: Otsuka; Research grant / Funding (self): Nano Carrier. All other authors have declared no conflicts of interest.