First-in-Class ICOS Agonist Alone or in Combination May Be Effective For Advanced Cancer

CHICAGO—JTX-2011 — an inducible co-stimulator (ICOS) of T-cells — may be a safe and effective treatment option alone or in combination with nivolumab among patients with heavily pretreated gastric (GC) and triple-negative breast cancer (TNBC), according to findings presented at the American Society of Clinical Oncology 2018 Annual Meeting on Saturday, June 2.¹

Previously conducted preclinical mouse studies demonstrated that JTX-2011 upregulated CD4 T-effector cells, depleted intratumoral T-regulatory cells, and may be effective as monotherapy or in combination with PD-1 or CTLA-4 inhibitors for tumors that have high ICOS expression.

In this first-in-human phase 1/2 ICONIC study (ClinicalTrials.gov Identifier: NCT02904226), researchers assigned 187 heavily pretreated patients with various types of relapsed/refractory cancer (including GC and TNBC) to receive escalating doses of JTX-2011 alone or plus nivolumab in phase 1, and administered the recommended phase 2 dose (0.3 mg/kg) alone or with nivolumab in phase 2. 

Of the patients who received at least 1 study dose, 71 patients and 116 patients were enrolled in phase 1 and phase 2, respectively. Of the 13 patients with GC who received combination therapy who had archived and fresh biopsy samples, 6 had high ICOS expression, and 5 changed from low to high expression. Of the 7 TNBC patients treated with combination therapy with archived and fresh biopsy samples, 5 and 4 patients showed high-ICOS expression on archival and fresh biopsies, respectively.

Among 7 patients treated with JTX-2011 alone in phase 1, 1 patient with GC achieved a partial response (PR) and 2 of 5 patients with TNBC achieved stable disease (SD). Among 19 patients with GC who received JTX-2011 combination therapy in phase 1/2, 2 patients had PR and 2 had ongoing SD; 1 patient had a PR among 15 patients with TNBC in phase 2.

Of 17 evaluable patients with high ICOS expression, 1 patient who achieved PR on monotherapy, 2 patients who had PR on combination therapy, and 1 with stable disease, had an emergence of peripheral CD4 T-cells.

JTX-2011 monotherapy produced a disease control rate (DCR) of 25% and 19% in phase 1 and phase 2, respectively, and the DCR with combination treatment was 29% and 32% in phase 1 and phase 2, respectively. Results suggested that disease control and tumor reductions may associated with a high ICOS score.

JTX-2011 was well-tolerated alone or in combination with nivolumab. Observed dose-limiting toxicities occurred with the highest dose of JTX-2011 (1.0 mg/kg) alone, and included grade 3 elevated liver enzymes and pleural effusion. Two grade 5 AEs were reported among patients receiving JTX-2011 plus nivolumab: increased bilirubin and encephalopathy. In phase 2, there were drug-related, immune-related, and infusion-related adverse events. 

The authors concluded that “JTX-2011 mono- and combo-therapy with nivolumab were well tolerated with antitumor responses in heavily pretreated GC and TNBC patients. Emergence of peripheral blood CD4 ICOS high T-cell subsets may be a surrogate biomarker of response. Further trials of JTX-2011 are planned.”

Read more of Cancer Therapy Advisor‘s coverage of the American Society of Clinical Oncology (ASCO) 2018 meeting by visiting the conference page.

Reference

1. Yap TA, Burris HA, Kummar S, et al. ICONIC: Biologic and clinical activity of first in class ICOS agonist antibody JTX-2011 +/- nivolumab (nivo) in patients (pts) with advanced cancers. Oral presentation at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL.