PMID- 35688358
OWN - NLM
STAT- MEDLINE
DCOM- 20220913
LR  - 20220915
IS  - 1569-8041 (Electronic)
IS  - 0923-7534 (Linking)
VI  - 33
IP  - 9
DP  - 2022 Sep
TI  - Pimitespib in patients with advanced gastrointestinal stromal tumor 
      (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III 
      trial.
PG  - 959-967
LID - S0923-7534(22)01718-5 [pii]
LID - 10.1016/j.annonc.2022.05.518 [doi]
AB  - 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.
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.
FAU - Kurokawa, Y
AU  - Kurokawa Y
AD  - Department of Gastroenterological Surgery, Osaka University Graduate School of 
      Medicine, Osaka, Japan. Electronic address: ykurokawa@gesurg.med.osaka-u.ac.jp.
FAU - Honma, Y
AU  - Honma Y
AD  - Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center 
      Hospital, Tokyo, Japan.
FAU - Sawaki, A
AU  - Sawaki A
AD  - Department of Medical Oncology, Fujita Health University Hospital, Aichi, Japan.
FAU - Naito, Y
AU  - Naito Y
AD  - Department of General Internal Medicine/Medical Oncology/Experimental 
      Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan.
FAU - Iwagami, S
AU  - Iwagami S
AD  - Department of Gastroenterological Surgery, Kumamoto University Hospital, 
      Kumamoto, Japan.
FAU - Komatsu, Y
AU  - Komatsu Y
AD  - Department of Cancer Center, Hokkaido University Hospital, Sapporo, Japan.
FAU - Takahashi, T
AU  - Takahashi T
AD  - Department of Gastroenterological Surgery, Osaka University Graduate School of 
      Medicine, Osaka, Japan.
FAU - Nishida, T
AU  - Nishida T
AD  - Department of Surgery, National Cancer Center Hospital, Tokyo, Japan; Department 
      of Surgery, Japan Community Health Care Organization Osaka Hospital, Osaka, 
      Japan.
FAU - Doi, T
AU  - Doi T
AD  - Department of Experimental Therapeutics, National Cancer Hospital East, Kashiwa, 
      Japan.
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20220608
PL  - England
TA  - Ann Oncol
JT  - Annals of oncology : official journal of the European Society for Medical 
      Oncology
JID - 9007735
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Indoles)
RN  - 0 (Pyrroles)
RN  - 8A1O1M485B (Imatinib Mesylate)
SB  - IM
CIN - Nat Rev Clin Oncol. 2022 Sep;19(9):568. PMID: 35750855
MH  - *Antineoplastic Agents/adverse effects
MH  - Diarrhea/chemically induced
MH  - Double-Blind Method
MH  - *Gastrointestinal Stromal Tumors/drug therapy/pathology
MH  - Humans
MH  - Imatinib Mesylate/therapeutic use
MH  - Indoles
MH  - Pyrroles
OTO - NOTNLM
OT  - HSP90 inhibitor
OT  - gastrointestinal stromal tumor
OT  - pimitespib
OT  - randomized phase III
OT  - refractory GIST
COIS- 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.
EDAT- 2022/06/11 06:00
MHDA- 2022/09/14 06:00
CRDT- 2022/06/10 19:26
PHST- 2022/01/15 00:00 [received]
PHST- 2022/04/06 00:00 [revised]
PHST- 2022/05/29 00:00 [accepted]
PHST- 2022/06/11 06:00 [pubmed]
PHST- 2022/09/14 06:00 [medline]
PHST- 2022/06/10 19:26 [entrez]
AID - S0923-7534(22)01718-5 [pii]
AID - 10.1016/j.annonc.2022.05.518 [doi]
PST - ppublish
SO  - Ann Oncol. 2022 Sep;33(9):959-967. doi: 10.1016/j.annonc.2022.05.518. Epub 2022 
      Jun 8.