News Releases

Taiho Pharmaceutical Co., Ltd. announced today that it has submitted to the Japanese Ministry of Health, Labour and Welfare a new drug application for TAS-116 (Oral Heat Shock Protein [HSP] 90 inhibitor; generic name: Pimitespib) for gastrointestinal stromal tumor (GIST) that has progressed after chemotherapy.

The new drug application is based on the results of a Phase III trial (CHAPTER-GIST-301 trial) comparing the efficacy and safety of Pimitespib versus placebo in patients with previously treated GIST. In the trial, Pimitespib prolonged progression-free survival (PFS), the primary endpoint, and demonstrated a safety profile consistent with that observed in earlier clinical trials. The results of the trial were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2021.^*1

Taiho Pharmaceutical will continue to work towards obtaining approval, aiming to deliver this new therapeutic agent to patients.

This was a randomized, double-blind, Phase III clinical trial comparing TAS-116 to placebo in patients with GIST refractory to standard treatments. The primary endpoint in this trial was PFS, and the secondary endpoint measures included overall survival (OS) and safety, as well as quality of life (QOL). The trial was conducted in Japan with the participation of 81 patients with GIST aged 20 or older who had been treated with imatinib, sunitinib, and regorafenib.

For more information on the CHAPTER-GIST-301 trial, please see Japic CTI-184094.

https://www.clinicaltrials.jp/cti-user/trial/Search.jsp

CHAPTER-GIST-301 trial: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER TRIAL OF TAS-116 IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMOR, CHAPTER; The molecular CHAperone heat shock protein 90 (HSP90) inhibitor, PimiTEspib

GIST develops in the walls of the gastrointestinal tract (frequently in the stomach and small intestine and rarely in the large intestine and esophagus) and is a type of malignant tumor (sarcoma) that causes metastasis and relapses. It has different characteristics than gastric and colorectal cancers that develop from mucous membrane.^*2 The incidence in Japan is estimated to be roughly 1,500 to 2,500 patients per year (calculated based on the annual incidence rate reported in different countries),^*3 making it a rare cancer. In many cases of GIST, there are mutations in the KIT and PDGFRA genes, which are involved in the growth and survival of cancer. All GIST treatments approved by the three regulatory authorities of Japan’s Ministry of Health, Labour and Welfare, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA) have as their main mechanism of action the inhibition of receptor tyrosine kinases KIT and PDGFRA. There is still a substantial medical need for a therapeutic agent to treat GIST that remains after treatment with the drugs currently approved.

Cells are constantly exposed to various stresses within the body. Cancer cells in particular are exposed to a lot of stress in the form of hypoxia, malnutrition, elimination by the immune system, and genetic instability. Expression of HSP90 increases in response to stress, protecting cells from stress and promoting cell survival by maintaining the structural and functional integrity of proteins. HSP90 is overexpressed and exists in a highly active state in cancer cells and tumor tissue, where it is known to be especially important in the survival and maintenance of cancer. Furthermore, it has been reported that the expression of HSP90 in GIST, bladder cancer, acute myelocytic leukemia, breast cancer, non-small cell lung cancer, colorectal cancer, and melanoma correlates with cancer progression and a patient’s prognosis.^*4

*1: References:

1. Honma Y, Kurokawa Y, Sawaki A, Naito Y, Iwagami S, Baba H, et al. Randomized, double-blind, placebo (PL)-controlled, phase III trial of pimitespib (TAS-116), an oral inhibitor of heat shock protein 90 (HSP90), in patients (pts) with advanced gastrointestinal stromal tumor (GIST) refractory to imatinib (IM), sunitinib (SU) and regorafenib (REG). J Clin Oncol (2021) 39(15):11524. doi: 10.1200/JCO.2021.39.15_suppl.11524

*2: See the Cancer Information Service of the National Cancer Center Japan.

*3: References:

1.Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, Hogendoorn PC. Incidence of gastrointestinal stromal tumours is underestimated: Results of a nation-wide study. Eur J Cancer. 2005;41:2868-2872.

2.Tryggvason G, Gíslason HG, Magnússon MK, Jónasson JG. Gastrointestinal stromal tumors in Iceland, 1990-2003: the icelandic GIST study, a population-based incidence and pathologic risk stratification study. Int J Cancer. 2005;117:289-293.

3.Nilsson B, Bümming P, Meis-Kindblom JM, Odén A, Dortok A, Gustavsson B, et al. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden. Cancer. 2005;103:821-829.

4.Chan KH, Chan CW, Chow WH, Kwan WK, Kong CK, Mak KF, et al. Gastrointestinal stromal tumors in a cohort of Chinese patients in Hong Kong. World J Gastroenterol. 2006;12:2223-2228.

*4: References:

1.Li CF, Huang WW, Wu JM, Yu SC, Hu TH, Uen YH, et al. Heat shock protein 90 over expression independently predicts inferior disease-free survival with differential expression of the alpha and beta isoforms in gastrointestinal stromal tumors. Clin Cancer Res. 2008;14:7822-7831.

2.Lebret T, Watson RW, Molinié V, O'Neill A, Gabriel C, Fitzpatrick JM, et al. Heat shock proteinsHSP27, HSP60, HSP70, and HSP90: expression in bladder carcinoma. Cancer. 2003;98:970-977

3.Thomas X, Campos L, Mounier C, Cornillon J, Flandrin P, Le QH, et al. Expression of heat-shock proteins is associated with major adverse prognostic factors in acute myeloid leukemia. Leuk Res.2005;29:1049-1058.

4.Pick E, Kluger Y, Giltnane JM, Moeder C, Camp RL, Rimm DL, et al. High HSP90 expression isassociated with decreased survival in breast cancer. Cancer Res. 2007;67:2932-2937.

5.Gallegos Ruiz MI, Floor K, Roepman P, Rodriguez JA, Meijer GA, Mooi WJ, et al. Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target. PLoS One. 2008;3:e0001722.

6. Milicevic Z, Bogojevic D, Mihailovic M, Petrovic M, Krivokapic Z. Molecular characterization ofhsp90 isoforms in colorectal cancer cells and its association with tumour progression. Int J Oncol.2008;32:1169-1178.

7. McCarthy MM, Pick E, Kluger Y, Gould-Rothberg B, Lazova R, Camp RL, et al. HSP90 as a marker of progression in melanoma. Ann Oncol. 2008;19:590-594.