TAS-116, 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

4044 Background: Regulatory T cells (Tregs) potentially induce the resistance of anti-PD1/PD-L1 inhibitors (A-PD1). TAS-116, a novel HSP90 inhibitor, enhanced antitumor immunity via reducing Tregs in vitro and in vivo. Combination of TAS-116 plus A-PD1 showed a superior tumor growth suppression compared with either treatment alone in vivo. Based on the above, we investigated safety and efficacy of TAS-116 in combination with nivolumab in patients with solid tumors. Methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the maximum tolerated dose and the recommended phase 2 dose (RP2D). Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80mg on level 1, 120mg on level 2, and 160mg on level 3) was administrated for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLTs) during the first cycle (4 weeks). PD-L1 combined positive score (CPS) and tumor mutation burden (TMB) were assessed. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 44 patients with colorectal cancer (CRC, n = 29), gastric cancer (GC, n = 8), sarcoma (n = 5), non-small cell lung cancer (NSCLC, n = 1) and melanoma (n = 1) after standard of cares were enrolled. One patient had MSI-H CRC, but all other patients had MSS tumors. No DLTs were observed at all levels and TAS-116 160 mg was determined as RP2D. The common grade 3 or worse treatment-related adverse included AST/ALT increased (7%), creatinine increased (5%) and platelet count decreased (5%). Objective tumor response was observed in 6 patients including 4 MSS CRC, 1 MSI-H CRC and 1 sarcoma, resulting in objective response rate (ORR) of 16% in MSS CRC without prior A-PD-1. PD-L1 CPS and TMB could be evaluated in 18 and 17 MSS CRC without prior A-PD-1, respectively. ORR was 27% in patients with CPS ≥1 and 0% in patients with CPS < 1. ORR was 33% with TMB-high (median as the cut-off) and 12% with TMB-low. Analysis of tumor-infiltrating lymphocytes before treatment and after TAS-116 monotherapy demonstrated reduction of FoxP3hiCD45RA−Tregs fraction in the tumor microenvironment. Conclusions: 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. Clinical trial information: UMIN000032801 .

Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors

“…The National Comprehensive Cancer Network (NCCN) guidelines have adopted TMB as the recommended test for patients with NSCLC receiving immunotherapy. Although the results in some clinical studies of RCC [15], HPV-positive HNSCC [13], and melanoma receiving anti-PD-1 after recurrence [16] showed that TMB alone also did not clearly distinguish responders and predict OS, it is still exciting that multiple studies in the 2020 American Society of Clinical Oncology (ASCO) meeting have confirmed the predictive value of TMB in immunization or combination therapy (KEYNOTE-061 study [17,18], CONDOR study [19], EAGLE study [20], EPOC1704 study [21], etc. ), consolidating its status of TMB as an independent predictor.…”

Targeting Post-Translational Regulation of p53 in Colorectal Cancer by Exploiting Vulnerabilities in the p53-MDM2 Axis

“…TAS-116, another novel agent, is orally active and selective against cytoplasmic Hsp90. Although TAS-116 monotherapy shows limited antitumor effect [ 95 ], TAS-116 plus nivolumab, an immune checkpoint inhibitor, demonstrates an augmented treatment response against microsatellite-stable (MSS) CRC compared to TAS-116 monotherapy [ 96 ].…”

What makes TMB an ambivalent biomarker for immunotherapy? A subtle mismatch between the sample-based design of variant callers and real clinical cohort

“…On one hand, TMB has been approved as a companion diagnostic biomarker, and multiple clinical trials have demonstrated its relevance to immunotherapy efficacy ( 13 – 15 ). Multiple studies presented at the 2020 ASCO meeting confirmed the predictive value of TMB in immunization or combination therapy, including KEYNOTE-061 study ( 16 , 17 ), CONDOR study ( 18 ), EAGLE study ( 19 ), and EPOC1704 study ( 20 ), consolidating TMB as an independent predictor. On the other hand, several investigators have noted that TMB is not a perfect predictor of response to anti-PD-1/PD-L1 therapy, such as in KEYNOTE-158 study ( 21 ) and RATIONALE-304 study ( 22 ).…”