IO-108 Demonstrates Safety and Efficacy in Advanced Solid Tumors

Findings from a phase 1 study (NCT05054348) showed that the fully humanized IgG4 antibody IO-108 was well tolerated and displayed durable responses when given as a monotherapy as well as in combination with pembrolizumab (Keytruda), supporting further development of the agent alone or with PD-1/PD-L1 targeted therapy for patients with advanced solid tumors. Data were presented by Matthew H. Taylor, MD, during the 2023 AACR Annual Meeting.

At the March 13, 2023, data cutoff, evaluable patients monotherapy (n = 11) and combination cohorts (n = 13), experienced an overall response rate (ORR) of 9.1% vs 23.1%, respectively, with 1 patient in the monotherapy arm achieving the only complete response (CR) of the trial. Additionally, 36.4% vs 30.8% of patients had stable disease and 54.5% vs 46.1% experienced progressive disease, respectively. The populations were inclusive of 1 patient who crossed over from the monotherapy to combination regimen.

“The majority of the patients [who] participated in this clinical trial had tumors that are generally considered to be relatively insensitive to immune checkpoint inhibitor therapy,”noted Taylor, who added that there is a lot to learn about selecting patients who may respond to IO-108. He pointed to cholangiocarcinoma specifically, as both patients with the disease had partial responses (PRs). Taylor is an assistant member of the Developmental Cancer Therapeutics Laboratory, medical director of the Providence Cancer Institute Thyroid Cancer Program, and comedical director of the Providence Cancer Institute Melanoma Program at the Earle A. Chiles Research Institute at Providence Cancer Institute in Portland, Oregon.

IO-108 binds to LILRB2, which is predominately expressed on myeloid cells, blocking the binding of LILRB2 to cancer-relevant ligands such as HLA-G, ANGPTL2, SEMA4A, and CD1d. Investigators noted that the LILRB2 blockade causes reprogramming of immune suppressive myeloid cells to pro-inflammatory in the tumor microenvironment, leading to activation of the T cells.

Additional findings showed that PRs were observed in patients with microsatellite stable cholangiocarcinoma (n = 2) and colorectal cancer (n = 1). The CR was reported in a patient with Merkel cell carcinoma.

The patient who experienced the CR initially underwent surgical resection followed by radiation therapy and after developing metastatic disease was treated with pembrolizumab, but following continued progression, went on to ipilimumab (Yervoy) plus nivolumab (Opdivo). However, after the development of new metastases, palliative radiation therapy was given. The patient then enrolled in the IO-108 monotherapy cohort of the phase 1 trial 82 days after stopping ipilimumab/nivolumab and achieved an 82% reduction in sizes of the targeted lesions by CT scan after 6 weeks of treatment. At 7 months, a CR was achieved and, as of March 2023, has been ongoing for more than 13 months.

At data cutoff, 1 patient in the monotherapy cohort remained on treatment. Ten patients have discontinued treatment, 9 due to progressive disease and 1 due to patient withdrawal, and 1 patient crossed over to the combination arm following disease progression.

The patient who crossed over remains on treatment with 2 additional patients in the combination cohort. Eleven patients in the combination arm discontinued treatment with the doublet, including 10 forgoing treatment due to progressive disease and 1 due to an adverse event (AE).

In terms of safety, no serious AEs, deaths, or dose-limiting toxicities occurred related to IO-108 treatment. Serious treatment-emergent AEs (TEAEs) occurred in 8.3% and 61.5% of patients leading to discontinuation in 8.3% and 15.4% of patients in the monotherapy and combination cohorts, respectively. Grade 3 to 5 TEAEs occurred in 25.0% vs 61.5% of patients, respectively, with 2 deaths in the combination arm.

Treatment-related AEs (TRAEs) of any grade occurred in 50.0% of patients in the monotherapy arm and 46.2% in the combination group, with no TRAEs occuring at grade 3 or 4 led to discontinuation or death. Overall, grade 1 or 2 TRAEs included pruritus (n = 4), myalgia (n = 3), and diarrhea (n = 2).

The recommended phase 2 dose (RP2D) was determined to be 1200 mg, which is projected to achieve full receptor occupancy at Ctrough in 90% or more of patients in blood circulation following the first dose. Investigators noted that saturation of clearance and LILRB2 receptors were observed following first doses at the dose range examined. There was a dose proportional increase in exposure with IO-108 at doses ranging from 180 mg to 1800 mg and full receptor occupancy was achieved at 600 mg or higher doses.

“Clinical benefit correlated with baseline gene expression profiles and posttreatment changes in pharmacodynamic biomarkers,” Taylor said.

In the monotherapy cohort, NanoString profiling of tumor tissues at baseline and post treatment demonstrated increased markers of T cell activation as well as baseline inflammation scores which both correlated with clinical benefit. Additionally, similar trends were observed in the combination therapy cohort with increased markers of T cell activation and clinical benefit also correlated with baseline tumor inflammation scores.

Dose escalation proceeded through a modified toxicity probability interval starting with IO-108 monotherapy given intravenously every 3 weeks at 60 mg, then 180 mg every 3 weeks, 600 mg every 3 weeks, and finally 1800 mg every 3 weeks. Patients in the doublet arm received pembrolizumab at a dose of 200 mg every 3 weeks with IO-108, which was escalated from 180 mg to 600 mg to 1800 mg. The maximum-tolerated dose was not reached in the trial. Dose escalation was completed in the United States with expansion cohorts currently open in the United States and China.

In the monotherapy and combination arms, patients had a median age of 54 years (range, 26-79) and 66 years (range, 54-71), respectively. The median number of prior lines of therapy was 4.5 and 3.5, respectively, and 33% and 46% had previously received a prior PD-L1 or PD-1 immune checkpoint inhibitor, respectively. Overall, tumor types included colorectal (n = 9), pancreas (n = 5), cholangiocarcinoma (n = 2), and other (n = 9).

Patients with advanced or metastatic solid tumors measurable by RECIST 1.1 were enrolled if they had received, were intolerant to, or were ineligible for standard systemic therapy and pre- and on-treatment biopsies were required as well. In addition to allowing crossover for patients who experienced disease progression into the doublet arm, intrapatient dose escalation was allowed as well.

The coprimary end points were safety, tolerability, and determination of the RP2D. Secondary end points included pharmacokinetics, efficacy, and immunogenicity. Pharmacodynamics, biomarkers, and long-term efficacy served as exploratory end points.

Disclosures: This study was funded by Immune-Onc Therapeutics Inc. Dr Taylor is a consultant for Bristol Myers Squibb, Eisai Inc, Bayer, Pfizer, Merck, Genzyme, Regeneron, Array Biopharma, Blueprint Medicines, Immune-Onc Therapeutics, Exelixis, and Cascade Prodrug. He receives grant/research support from Bristol Myers Squibb, Eisai Inc, Merck, Pfizer, ISA Therapeutics, Exelixis, and Simcha.

Reference

Taylor MH, Patel MR, Powderly JD, et al. A first-in-human phase 1 trial of IO-108, an antagonist antibody targeting LILRB2 (ILT4), as monotherapy and in combination with pembrolizumab in adult patients with advanced relapsed or refractory solid tumors: dose escalation study. Cancer Res.2023;83(suppl8):CT040. doi:10.1158/1538-7445.AM2023-CT040