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Clinical Trial
. 2022 Sep;33(9):959-967.
doi: 10.1016/j.annonc.2022.05.518. Epub 2022 Jun 8.

Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial

Y Kurokawa  1 , Y Honma  2 , A Sawaki  3 , Y Naito  4 , S Iwagami  5 , Y Komatsu  6 , T Takahashi  7 , T Nishida  8 , T Doi  9
Affiliations
Free article
Clinical Trial

Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial

Y Kurokawa et al. Ann Oncol. 2022 Sep.
Free article

Abstract

Background: Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.

Patients and methods: Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.

Results: From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months [95% confidence interval (CI) 1.6-2.9 months] with pimitespib versus 1.4 months (0.9-1.8 months) with placebo [hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006]. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo [HR 0.42 (0.21-0.85), one-sided P = 0.007]. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.

Conclusions: Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.

Keywords: HSP90 inhibitor; gastrointestinal stromal tumor; pimitespib; randomized phase III; refractory GIST.

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Conflict of interest statement

Disclosure YK has received research funding from Taiho Pharmaceutical, Ono Pharmaceutical, and MSD, and lecture fees from Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Yakult Honsha, Nippon Kayaku, Bristol-Myers Squibb, Takeda Pharmaceutical, and Daiichi Sankyo outside of the submitted work. YH has received research funding from Taiho Pharmaceutical during the study. AS has received research funding from Taiho Pharmaceutical during the study. YN has received research funding from Taiho Pharmaceutical during the study; grants (study fund) from Roche, consulting fees from Pfizer, Eli Lilly, Bayer, Chugai, and AstraZeneca; lecture fees from Chugai, Pfizer, Eli Lilly, Novartis, Eisai, AstraZeneca, Fuji Film Toyama Chemistry, Guardant, Ono, and Takeda; patents planned of Takeda and Taiho Pharmaceutical; participation on Data Safety Monitoring Board of TORG and Taiho Pharmaceutical outside of the submitted work. SI has received research funding from Taiho Pharmaceutical during the study. YK has received research funding from Taiho Pharmaceutical during the study; and speakers fee from Taiho Pharmaceutical outside of the submitted work. TT has received research funding from Taiho Pharmaceutical during the study. TN has received lecture fees from Pfizer, Otsuka, and EA Pharma outside of the submitted work. TD has received grants for institution from Eli Lilly, MSD, Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Novartis, Merck Serono, Janssen Pharma, Boehringer Ingelheim, Pfizer, BMS, AbbVie, IQVIA, and Eisai; consulting fees from Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, Chugai, AbbVie, Bayer, Rakuten Medical, and Otsuka; lecture fees from BMS, Rakuten Medical, Ono, Oncolys Bio Pharma, and Taiho Pharmaceutical; participation on Data Safety Monitoring Boards or Advisory Boards for MSD, Daiichi Sankyo, Amgen, Novartis, Boehringer Ingelheim, Janssen Pharma, AbbVie, Bayer, and Astellas outside of the submitted work. Data sharing Data will not be shared according to the sponsor policy on data sharing because of this being a small study. The sponsor policy on data sharing may be found at https://www.taiho.co.jp/en/science/policy/clinical_trial_information_disclosure_policy/index.html.

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