Jeselhy (pimitespib)

P1, N=0, Withdrawn, Brown University | N=27 --> 0 | Trial completion date: Aug 2025 --> Aug 2024 | Recruiting --> Withdrawn

Notably, the selective inhibitor TAS-116 has already been successfully marketed. In this Perspective, we summarize the structure, biological functions, and roles of HSP90 in cancer, analyze the clinical status of HSP90 inhibitors, and highlight the latest advancements in novel strategies, offering insights into their future development.

PIM provides a novel approach for treating ccRCC and holds promise for future clinical strategies. Further in vivo and clinical research is required to elucidate the detailed relationship between the effects of PIM and ccRCC.

Planned enrollment of 9-18 patients for the dose-escalation part and 30 patients for the dose-expansion part, from September 2022 to August 2024. The dose-escalation part has been completed, the RD has been determined, and the dose-expansion part has commenced.

P1, N=31, Completed, Taiho Oncology, Inc. | Phase classification: P1a/1b --> P1

P1, N=78, Recruiting, Taiho Pharmaceutical Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=715, Recruiting, Taiho Pharmaceutical Co., Ltd. | N=367 --> 715 | Trial completion date: May 2024 --> May 2026 | Trial primary completion date: May 2024 --> May 2026

We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment.

Pimitespib (TAS-116) is the first heat shock protein 90 (HSP90) inhibitor approved in Japan, and it is indicated for the treatment of gastrointestinal stromal tumors (GIST) that have progressed after treatment with imatinib, sunitinib and regorafenib. Common treatment-related adverse events were diarrhoea, decreased appetite, increase in serum creatinine, malaise, nausea and eye disorders. The efficacy and safety of pimitespib are being investigated in other tumour types and in combination with other anticancer therapies.

P1, N=27, Recruiting, Brown University | Not yet recruiting --> Recruiting

P1, N=27, Not yet recruiting, Brown University | Trial completion date: Apr 2025 --> Aug 2025 | Initiation date: May 2023 --> Aug 2023 | Trial primary completion date: Apr 2024 --> Aug 2024

The active agents in our analysis as post-first-line therapies are able to provide superior clinical efficacy, with improved PFS rate and OS rate at certain time points, as well as absolute values of PFS and OS for advanced GIST. Ripretinib might be the optimal recommendation as a post-first-line treatment for advanced GIST following imatinib failure.

P1, N=78, Recruiting, Taiho Pharmaceutical Co., Ltd. | Trial primary completion date: Apr 2023 --> Dec 2024

Numerous clinical trials have used HSP90 inhibitors to treat several cancers, and pimitespib (an HSP90 inhibitor) is covered by insurance for advanced gastrointestinal stromal tumor in Japan...Although there was no significant difference in HSP90 mRNA levels between 24 paired lesional and nonlesional tissues, microRNA-inhibiting HSP90 levels in tumor tissues were significantly decreased compared with those in normal tissues. Thus, HSP90 may play an important role in the pathogenesis of EMPD and may be a novel therapeutic target for EMPD.

Pimitespib, a heat shock protein 90α/β inhibitor, and Telaglenastat, a selective glutaminase 1 inhibitor, inhibited proliferation of DeGISTL1 cells and the combination of these showed an additive effect. DeGISTL1 cells might be a good model of dedifferentiated GISTs, and combination of Pimitespib and Telaglenastat could be a possible candidate for treatment strategy for them.

CDK4/6i (palbociclib at dose previously tolerated up to 125 mg daily PO D1-21 of 28 day cycle) in combination with HSP90i (TAS-116/pimitespib starting at 120 mg 5 days on 2 days off, for D1-28 of cycle) is used in 3+3 dose-de-escalation design. OS, PFS, TTP, and DOR will be summarized using methods of Kaplan and Meier. Clinical trial information: NCT05655598.

Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.

We report the first case of long-term response to PIMI in PDGFRA D842V mutant GIST. Pimitespib may be effective for treating GIST harboring this mutation by inhibiting HSP90.

Pimitespib, a selective heat shock protein 90 inhibitor, induced apoptosis in Ba/F3-C797S cells in vitro and inhibited growth of Ba/F3-C797S tumors in vivo. Ba/F3 cells with A763_Y764insFQEA-C797S remained sensitive to erlotinib. We conclude that the EGFR C797S mutation confers resistance to CLN-081. Our preclinical data suggest a potential small molecule to overcome CLN-081 resistance, which may benefit patients with lung cancer with EGFR exon 20 insertions.

P1, N=27, Not yet recruiting, Brown University | Trial completion date: Mar 2026 --> Apr 2025 | Trial primary completion date: Mar 2025 --> Apr 2024

P1, N=27, Not yet recruiting, Brown University

Pimitespib is undergoing phase I development for the treatment of solid tumours in the EU and the USA. This article summarizes the milestones in the development of pimitespib leading to this first approval for GIST that has progressed after chemotherapy.

P1, N=292, Recruiting, Taiho Pharmaceutical Co., Ltd. | N=180 --> 292

TAS-116 suppressed the activator protein-1 and tumor necrosis factor pathways in all examined cells. These findings strongly demonstrate the efficacy of TAS-116, regardless of the stage of ATL progression, and its potential application as a novel clinical anti-ATL therapeutic agent.

In the model mice, we reported that tyrosine kinase inhibitor, imatinib, could stabilize but not decrease the cecal tumor volume. Thus, pimitespib seemed to inhibit in vivo tumor progression effectively in the model mice. These results suggest that the progression of multiple GISTs in patients with germline KIT-Asp820Tyr might be controllable by pimitespib.

TAS-116 160mg plus nivolumab had manageable safety profiles and anti-tumor activity especially for MSS CRC patients.

P1, N=170, Recruiting, Taiho Pharmaceutical Co., Ltd.

This randomized trial demonstrated that PIM significantly improved PFS with OS prolongation in pts with advanced GIST refractory to IM, SU, and REG, as a HSP90 inhibitor for the first time . PIM was tolerated and AEs were manageable . With a mechanism of action different from that of standard therapies, PIM has the potential to be a new standard treatment in GIST.

TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFR-mutated lung cancer.

Using the FDA-approved CDK4/6 inhibitors (palbociclib & abemaciclib), we observed that dual inhibition of CDK4 and HSP90 synergistically inhibits cancer viability in colorectal cancer cell lines (eg. HCT116, SW480, DLD1) under both normoxia and hypoxia. Multiple HSP90 inhibitors have been tested, including ganetespib, onalespib, XL888 and TAS116, which indicates such combinational inhibition as a class effect...Hypoxia sensitizes the Rb-deficient MDA-MB-468 breast cancer cell line to abemaciclib treatment. Our findings suggest a therapeutic potential for utilizing the combination of CDK4 and HSP90 inhibitors in cancer treatment.

The combination of TAS-116 160mg plus nivolumab had manageable safety profiles and anti-tumor activity especially for MSS CRC patients, which warrants further investigations in a large cohort. Research Funding: Taiho, Ono