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JTX-2011 shows activity for gastric, triple-negative breast cancers
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CHICAGO — JTX-2011 monotherapy or in combination with nivolumab appeared well-tolerated and induced antitumor responses among patients previously treated for gastric cancer and triple-negative breast cancer, according to results presented at ASCO Annual Meeting.
JTX-2011 (Jounce Therapeutics) is a monoclonal antibody that targets inducible T-cell co-stimulator (ICOS), a protein on the surface of certain T cells. JTX-2011 monotherapy and in combination with an anti-PD-1 showed preclinical efficacy in mouse models with ICOS-positive tumors.
“ICOS is an expression on T cells associated with favorable outcomes,” Timothy A. Yap, MBBS, PhD, physician-scientist and associate professor in the department for investigational cancer therapeutics at The University of Texas MD Anderson Cancer Center, said during his presentation. “[It] is upregulated by a variety of targets [and is] an ideal combination target.”
Yap and colleagues assigned patients with relapsed or refractory gastric or triple-negative breast cancer to escalating doses of JTX-2011 monotherapy or JTX-2011 in combination with nivolumab (Opdivo, Bristol-Myers Squibb).
In phase one of the trial, 71 patients received standard monotherapy (n = 40) or combination therapy (n = 31). Researchers evaluated safety, efficacy and maximum tolerated dose, and defined the recommended phase 2 dose.
In phase two, 93 patients received escalated doses of 0.3 mg/kg JTX-2011 monotherapy (n = 25) every 3 weeks or 0.3 mg/kg JTX-2011 with 240 mg nivolumab every 3 weeks (n = 68). In this phase, researchers assessed preliminary efficacy by RECIST 1.1, and they sought to confirm safety, tolerability and the maximum tolerated dose.
A total 164 patients received at least one dose of JTX-2011, including 71 from phase one of the trial (monotherapy, n = 40; combination, n = 31) and 93 in phase two (monotherapy, n = 25; combination, n = 68).
Many patients in the trial at received at least three prior therapies, including 57% of those with gastric cancer who received JTX-2011 monotherapy, 48% with gastric cancer who received JTX-2011 with nivolumab, and 56% with triple-negative breast cancer who received JTX-2011 with nivolumab.
Among patients receiving monotherapy, one of seven with gastric cancer achieved a partial response, and two of five patients with triple-negative breast cancer had stable disease in phase one.
Among patients receiving combination therapy, researchers observed two partial responses — one at 0.1 mg/kg and one at 0.3 mg/kg — and two ongoing cases of stable disease among 19 patients with gastric cancer in phases one and two of the trial. Partial response occurred among 15 patients with triple-negative breast cancer in phase 2.
Dose-limiting toxicities at 1 mg/kg JTX-2011 monotherapy included pleural effusion and elevated aspartate aminotransferase and alanine aminotransferase. At 0.3 mg/kg, more than 70% of targeted engagement was maintained through 3 weeks with no significant change in the number of peripheral effector or regulatory T cells.
Treatment-related grade 3 or grade 4 adverse events in phase two occurred among 8% of patients in the JTX-2011 monotherapy group and 13% in the combination group. Four percent of patients in the monotherapy group and 21% in the combination group experienced immune-related events, and 12% in the monotherapy and 19% in the combination group experienced infusion-related events.
Researchers also assessed ICOS by immunohistochemistry in archival and fresh pretreatment tumor biopsies, or by flow in peripheral blood.
Among 13 patients with gastric cancer with paired archival and fresh biopsy who received JTX-2011 with nivolumab, six had high ICOS on both, and another five changed from low to high.
Among seven patients with triple-negative breast cancer with paired biopsies who received JTX-2011 with nivolumab, five archival and four fresh biopsies were ICOS high.
“[These] preliminary data suggest a relationship between archival and fresh pretreatment biopsy ICOS scores may vary,” Yap said, adding that it may suggest ICOS has an inducible nature, with differences in expression between primary tumor and nodal and visceral metastases.
Among 17 evaluable patients, four showed emerged peripheral CD4 T-cell ICOS-high subsets during JTX-2011 therapy. Of these, one patient who received monotherapy had a partial response, two patients who received a combination had a partial response and one had stable disease.
“We identified a potential on-mechanism ICOS biomarker,” Yap said. “The emergence of ICOS CD4 T-cell [subsets] appeared to be associated with antitumor activity.”
Researchers did not observe partial response or stable disease among patients with progressive disease.
“An ongoing clinical trial includes a planned combination with ipilimumab [Yervoy, Bristol-Myers Squibb],” Yap said. – by Melinda Stevens
Reference:
Yap TA, et al. Abstract 3000. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Disclosures: Yap reports employment with The Institute of Cancer Research; consultant/advisory roles with Aduro Biotech, AstraZeneca, Atrin Pharmaceuticals, Clovis Oncology, EMD Serono, Ignyta, Janssen, Pfizer and Tesaro; honoraria from and a speaker role with AstraZeneca; research funding from AstraZeneca, Clearbridge Biomedics, Pfizer, Roche and Vertex; and travel, accommodations and expenses from Vertex. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Steven J. Cohen, MD
For a study like this, it’s hard to come up with a definitive conclusion. The backdrop to this is, immunotherapy in gastric cancer works a little bit for some patients. Nivolumab and pembrolizumab (Keytruda, Merck) both generate 15% response rates, but is it going to work for most people? No, but there is a subgroup that has prolonged responses.
The question is, how do we get this drug that seems to have a hint of activity working better? That’s the premise behind this study, to take this immune modulator, bump up the protein expression and increase T-cell stimulation to make nivolumab work better.
I don’t think we can conclude from these results that the combination is going to be better than nivolumab monotherapy, nor that the single-agent drug will ultimately show benefit. That is a little overstated here.
A follow-up with a purely gastric cancer subset — or a randomized phase 2 trial that evaluates JTX-20911 as a single agent, nivolumab and the combination — would be beneficial. However, it would cost money to confirm that.
Conversely, a single-arm trial of JTX-2011 that included 20 or 30 patients that saw a number of responses would be eye-opening. The combination data are not that exciting, because we know immunotherapy has that range of response. The one response to JTX-2011 monotherapy is more interesting to me, but, still, more responses would be more eye-opening.
This is a robust study, but it is a bit too small to look just at the gastric patients. Still, there is a signal and it supports looking further, particularly into the monotherapy.
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