1917MO - CHAPTER-GIST-101: A phase I study of pimitespib combined with imatinib in patients with imatinib-refractory gastrointestinal stromal tumor

Background

Pimitespib (PIMI), a novel heat shock protein 90 inhibitor, was approved in Japan for patients (pts) with advanced gastrointestinal stromal tumor (GIST) after chemotherapies based on the results of the phase 3 study (CHAPTER-GIST-301). PIMI showed anti-tumor activity in an imatinib (IMA)-resistant GIST xenograft model and enhanced the activity when combined with IMA. Thus, PIMI + IMA could be effective in pts resistant to IMA. Here, we will present the results from dose-escalation part of the study (NCT05245968), of PIMI + IMA in pts with IMA-refractory GIST.

Methods

Pts with histologically confirmed, IMA-refractory GIST in second-line setting were eligible. Once daily dose of 120 mg (DL1) or 160 mg (DL2) PIMI was administered orally on a 5-day on/2-day off schedule, and 400 mg of IMA was administered once daily on a standard 3+3 dose escalation. The primary endpoint was to determine dose-limiting toxicity (DLT) and maximum tolerable dose (MTD) of PIMI + IMA. The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.

Results

Twelve pts (DL1 [n=6] and DL2 [n=6]) who were treated with IMA in first-line setting for median 21.7 months (mos) were enrolled in Japan. No DLTs were observed at both doses and the MTD was at DL2. The common (≥ 60%) treatment-related adverse events (TRAEs) in DL1 and DL2 were diarrhea (83.3%/ 100%), nausea (50%/ 83.3%), night blindness (16.7%/ 83.3%), blood creatinine increased (33.3%/ 66.7%), dysgeusia (16.7%/ 66.7%) and decreased appetite (0%/ 66.7%), respectively. No serious TRAEs, TRAEs leading to study discontinuation or death were observed. The ORR was 8.3% (one confirmed partial response) and the DCR was 91.7%. 66.7% showed tumor shrinkage and 58.3% were stable for more than 6 mos. Median PFS was 12.9 mos (95% CI, 2.8 – not calculated).

Conclusions

PIMI + IMA combination was well tolerated with no new concerns at DL1 and DL2. It was effective despite pts being refractory to IMA, even when compared to those reported in previous studies on second-line setting with sunitinib. The expansion part of this study to evaluate safety and efficacy is currently recruiting pts globally at DL1, that has a better safety profile.

Clinical trial identification

NCT05245968.

Editorial acknowledgement

Legal entity responsible for the study

Taiho.

Funding

Taiho.

Disclosure

Y. Naito: Financial Interests, Personal, Invited Speaker, Speakers Bureau: Chugai, Pfizer, Eli Lilly, Eisai, AstraZeneca, PDR pharma, Novartis, Gardant, Ono, Takeda, Taiho, Bayer, Nihon Kayaku, Daiichi Sankyo, BMS, MSD; Financial Interests, Personal, Funding: Roche; Financial Interests, Personal, Local PI: AbbVie, Boehringer Ingelheim, Ono, Chugai, Taiho, Pfizer, AstraZeneca, Gilead, Takeda; Financial Interests, Personal, Steering Committee Member: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, JCOG: Natera. Y. Komatsu: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd., Daiichi Sankyo, Taiho, Chugai, Lilly, Merck, MSD, BMS, Takeda, Bayer Yakuhin, Moroo Co., Asahi Kasei, Pfizer, Nippon Zoki Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Incyte Corporation, Zeria Pharmaceutical Co., Ltd., Yakult Honsha, Nipro Corporation, Sanofi/Aventis, Astellas Pharma Inc., Nippon Kayaku Co., Ltd.; Financial Interests, Personal, Writing Engagement: Eli Lilly and Company, Yakult Honsha Co.,Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical CO., Ltd., Taiho Phamaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd., Taiho, Chugai, Sanofi, Nipro, Daiichi Sankyo, BMS, Sysmex Corporation, EPS Holdings, Inc., Asahi Kasei Pharma Corporation, Nippon Zoki Pharmaceutical Co., Ltd., Nippon Kayaku Co. Ltd.; Non-Financial Interests, Member: JSCO, JSMO, ASCO. Y. Kurokawa: Financial Interests, Institutional, Local PI: Taiho; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Personal, Invited Speaker: Taiho. H. Hirano: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Ono Pharmaceutical, Teijin Phama, Novartis; Financial Interests, Personal, Writing Engagement: Nichi-Iko; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Ono Pharmaceutical, Janssen Pharmaceutical, Merck Biopharma, BMS, Pfizer, Eisai, AMGEN, Astellas, Seagen, MSD, Insyte, BeiGene, Novartis. T. Nishida: Financial Interests, Institutional, Invited Speaker, Speaker's Bureau: Taiho; Financial Interests, Institutional, Invited Speaker: Pfizer, Eisai. T. Doi: Financial Interests, Personal, Other, Advisory Role: Noil-Immune Biotech, Oncolys BioPharma, Boehringer Ingelheim, A2 Healthcare, Nano Carrier, PRA Health Sciences, Kaken Pharma, Chugai Pharma, Sumitomo Pharma, Shionogi, Otsuka Pharma, Takeda, Kyowa Kirin, Rakuten Medical, Giliad; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Taiho, MSD, AbbVie, Eisai, Pfizer, BMS, Janssen Pharma, Daiichi Sankyo, Chugai Pharma, Boehringer Ingelheim, PRA Health Sciences, Amgen, GSK, Shionogi, RIN Institute, Ono Pharma.