Mutated KIT and PDGFRA in gastrointestinal stromal tumor (GIST) rely on HSP90 for their functional stability; therefore, HSP90 is a rational therapeutic target in treating GIST in patients (pts) acquired resistance to approved tyrosine kinase inhibitors. TAS-116 is an oral non-ansamycin, non-purine, non-resorcinol, highly selective inhibitor of HSP90α/β with antitumor activity in an imatinib-resistant human GIST xenograft mouse model. In a phase I study, TAS-116 demonstrated the acceptable safety and the efficacy signs in radiological imaging in pts with GIST including 1 partial response. Here, we conducted a phase II study to evaluate the safety and efficacy of TAS-116 in metastatic or unresectable GIST refractory to standard therapies.
This was a phase II, open label, single-arm, multi-center study. The key eligibility criteria were histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib; a measurable lesion per RECIST ver. 1.1; and adequate organ function. Pts received 160 mg/day TAS-116 on a 5-days-on/2-days-off schedule. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate, disease control rate, overall survival, and adverse events. An independent central review (ICR) committee assessed all responses. Sample size was 40 for full analysis set.
From 12 May 2016 to 26 April 2017, 40 pts were enrolled in this study. The numbers of prior treatments was 3 in 24 pts, 4 in 9 pts, and ≥5 in 7 pts. In 34 pts evaluated as of 26 April 2017, the most common adverse events were diarrhea (82%), anorexia (50%), increased serum creatinine (44%), and eye disorders (21%). All eye disorders recovered or resolved following dose interruption, and were limited to Grade 1. There were no treatment-related deaths. According to ICR, median PFS was 4.5 months (95% CI, 2.9–6.1 months). Although none had a partial response, 27 out of 34 pts (79%) had stable disease for ≥6 weeks.
TAS-116 was well tolerated and the initial efficacy results in a ≥ 4th-line treatment setting for metastatic or unresectable GIST, are encouraging. Updated data will be presented at the meeting.
Clinical trial identification
Legal entity responsible for the study
Taiho Pharmaceutical co., LTD.
Taiho Pharmaceutical co., LTD.
Y. Kurokawa: Honoraria: Taiho Pharmaceutical, Yakult Honsha, Eli Lilly, Novartis, Pfizer, Chugai Pharma. T. Doi: Consulting/advisory role: Eli Lilly, Chugai, Kyowa Hakko Kirin, Novartis, MSD, Daiichi Sankyo, Amgen. Research funding: Taiho, Novartis, Merck Serono, Astellas, MSD, Janssen, Boehringer Ingelheim, Takeda, Pfizer, Eli Lilly, Sumitomo Group, Chugai, Bayer, Kyowa Hakko Kirin, Daiichi Sankyo, Celgene. A. Sawaki: Speakers’ Bureau: Novartis, Pfizer, Bayer, Taiho Pharmaceutical, Lilly, Eisai, Chugai Pharma, Yakult, Honsha, Research funding: Taiho Pharmaceutical. Y. Komatsu: Speakers’ Bureau: Taiho, Eli Lilly, Chugai Pharma, Merck Serono, Novartis, Pfizer, Bayer. Honoraria: Novartis, Pfizer, Bayer Research funding: Taiho, Eli Lilly, MSD, Ono Pharmaceutical, Novartis, Bayer, Chugai Pharma, Yakult Honsha. M. Ozaka: Honoraria: Taiho Pharmaceutical, Pfizer, Novartis, Bayer, Yakult Honsha. T. Takahashi: Speakers’ Bureau: Novartis, Pfizer, Bayer, SBI pharma. Research funding: SBI Pharma. Y. Naito: Speakers’ Bureau: Eisai, Chugai Pharma, Taiho Phamaceutical, Novartis, Eli Lilly, Meiji Seika Pharma, Bayer, Roche Diagnostics K.K. Research funding: Merck Serono, AstraZeneca, Eli Lilly, Nippon Kayaku. S. Okubo: Employment: Taiho Pharmaceutical Patents, Royalties, other intellectual property: Taiho Pharmaceutical. T. Nishida: Honoraria: Pfizer, Novartis, Bayer, Eisai, Sysmex.