TAS-116 (Pimitespib), an Oral HSP90 Inhibitor, in Combination with Nivolumab in Patients with Colorectal Cancer and Other Solid Tumors: An Open-Label, Dose-Finding, and Expansion Phase Ib Trial (EPOC1704)

Clin Cancer Res. 2021 Dec 15;27(24):6709-6715. doi: 10.1158/1078-0432.CCR-21-1929. Epub 2021 Sep 30.

Abstract

Purpose: This is a phase Ib trial of TAS-116, an oral HSP90 inhibitor, plus nivolumab for colorectal cancer and other solid tumors.

Patients and methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the recommended dose. Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80-160 mg) was administered for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLT). We also conducted biomarker research using paired samples from repeated blood collections and tumor biopsies.

Results: A total of 44 patients with colorectal cancer (n = 29), gastric cancer (n = 8), sarcoma (n = 5), non-small cell lung cancer (n = 1), and melanoma (n = 1) were enrolled. Eleven patients had previously received immune-checkpoint inhibitors. No DLTs were observed at all dose levels, and TAS-116 160 mg was determined as recommended dose. The common grade 3 or worse treatment-related adverse events included liver transaminase increased (7%), creatinine increased (5%), and platelet count decreased (5%). Objective tumor response was observed in 6 patients, including 4 microsatellite stable (MSS) colorectal cancers, 1 microsatellite instability-high colorectal cancer, and 1 leiomyosarcoma, resulting in an objective response rate of 16% in MSS colorectal cancer without prior immune-checkpoint inhibitors. Biomarker analysis showed that TAS-116 inhibited the activity of regulatory T cells in peripheral blood mononuclear cells and tumor-infiltrating lymphocytes.

Conclusions: TAS-116 160 mg plus nivolumab had manageable safety profiles and antitumor activity, especially for MSS colorectal cancer patients.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Benzamides
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Humans
  • Leukocytes, Mononuclear / pathology
  • Lung Neoplasms* / drug therapy
  • Nivolumab
  • Pyrazoles

Substances

  • Benzamides
  • Pyrazoles
  • TAS-116
  • Nivolumab