First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors

Abstract

HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a "3þ3" design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m 2 /day for QD, and 210.7 mg/m 2 /day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD Â 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non-small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor. This is a result from a first-inhuman study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST.

Pan-Cancer Analysis of the Mitophagy-Related Protein PINK1 as a Biomarker for the Immunological and Prognostic Role

“…Generally, the gene changes in the same cancer may be different. Similarly, the expression and function of the same gene in different cancers are also different (42,43). Above all, these findings could provide a view on the utility of the mitophagy-related protein PINK1 as a prognostic factor across cancers.…”

Efficacy and safety of TAS-116, an oral inhibitor of heat shock protein 90, in patients with metastatic or unresectable gastrointestinal stromal tumour refractory to imatinib, sunitinib and regorafenib: a phase II, single-arm trial

“…BIIB021 and HSP990) that have neurological toxicities [19e21]. In a phase I study [22], TAS-116 was well tolerated, three confirmed partial responses were observed in patients with solid tumours including GIST and the inhibition of HSP90 was confirmed by the induction of HSP70 expression. The recommended dose for phase II was determined to be 160 mg/body/day with dosing 5 days on/2 days off per week.…”

HSP90 inhibition overcomes EGFR amplification‐induced resistance to third‐generation EGFR‐TKIs

“…Additionally, the viability of both H1975‐LR/TM and PC9‐COR cells was compromised by treatment with the HSP90 inhibitor (Figure 4(b) and Figure 5(b)). Importantly, TAS‐116 was highly active against these cell lines at therapeutic concentrations of 1–3 μM 33,34 . In contrast, the combination efficacy of TAS‐121 and TAS‐116 was not observed in both the H1975 and H1975‐LR/TM cell lines (Figure S1).…”

“…TAS‐116 possesses a distinct advantage over other HSP90 inhibitors, as its distribution in retinal tissue is lower than that in plasma, and it is rapidly eliminated from the retina 27 . Indeed, eye disorders were not clinically significant in trials for patients with advanced solid tumors 33,34 . Therefore, further studies should focus on TAS‐116 as a promising therapeutic option for EGFR ‐mutated lung cancer.…”