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).

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.

• Authors: Akihito Kawazoe, Kota Itahashi, Noboru Yamamoto, Daisuke Kotani, Yasutoshi Kuboki, Hiroya Taniguchi, Kenichi Harano, Yoichi Naito, Mitsuko Suzuki, Miki Fukutani, Tsukiko Higuchi, Takashi Ikeno, Masashi Wakabayashi, Akihiro Sato, Shohei Koyama, Hiroyoshi Nishikawa, Kohei Shitara
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 24 Pg. 6709-6715 (12 15 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 34593531 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Benzamides
• Pyrazoles
• TAS-116
• Nivolumab

Topics

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