Taylor Highlights Safety and Efficacy of IgG4 Monoclonal Antibody IO-108 in Advanced Solid Tumors

When administered as monotherapy and in combination with pembrolizumab (Keytruda) in a phase 1 study (NCT05054348), the investigational, fully humanized IgG4 antibody IO-108 demonstrated promising efficacy and tolerability for patients with advanced solid tumors, according to Matthew H. Taylor, MD. Based on these data, Taylor noted that expansion cohorts are planned for further examination of the agent.

Patients receiving IO-108 monotherapy (n = 11) achieved an overall response rate of 9.1% compared with 23.1% in the combination therapy cohort (n = 13) with partial responses occuring in 2 patients with microsatellite stable cholangiocarcinoma and 1 patient with colorectal cancer. As of the March 13, 2023, data cutoff, 1 patient with Merkel cell carcinoma achieved a complete response (CR). Additionally, 36.4% vs 30.8% of patients had stable disease in the monotherapy and combination arms, respectively, and 54.5% vs 46.1% of patients had disease progression.

“It’s exciting to see a treatment that can be effective in patients who have already gone through so many prior lines of therapy and have very treatment-refractory cancers,” Taylor said. “The fact that the drug is well tolerated means it’ll be very easy to combine this with other immune checkpoint inhibitors, maybe with chemotherapy regimens, and even targeted therapies. [It’s] exciting to see the data so far.”

Any-grade treatment-related adverse events (AEs) occurred at rates of 50.0% in the monotherapy group and 46.2% in the combination arm, including grade 1/2 pruritus, myalgia, and diarrhea. Although no grade 3 or 4 treatment-related AEs led to discontinuation or death, patients in the monotherapy and combination cohorts experienced serious treatment-emergent AEs at rates of 8.3% vs 61.5%. These led to discontinuation in 8.3% and 15.4% of patients, respectively.

In an interview with OncLive^®, Taylor, the 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, discussed findings from the phase 1 trial presented during the 2023 AACR Annual Meeting.

What was the rationale for examining IO-108 in this trial?

Preclinical research [showed] that blockade of LILRB2 helps to activate T cells and overcome resistance mechanisms…. LILRB2 has been shown to have an immunosuppressive effect within the tumor microenvironment, so Immune-Onc Therapeutics developed an antibody to target this protein to try to overcome some of those immunosuppressive effects to further activate T cells to be able to fight and attack the cancer.

The LILRB2 receptor has 5 ligands, the most important [of which are] HLA-G and classical MHC class 1. [We hypothesized that] blockade of this receptor prevents interaction with those ligands which can help further create a pro inflammatory tumor microenvironment to activate the T cells.

What methods were used to conduct this research?

This was a phase 1 dose-escalation clinical trial [that included] patients with advanced metastatic treatment refractory cancers and there was a monotherapy dose escalation [cohort] and a combination cohort with IO-108 in combination with pembrolizumab.

Patients with a variety of different advanced solid tumors [were included]; there were patients with colon cancer, lung cancer, cholangiocarcinoma, Merkel cell carcinoma, and ovarian cancer, [among others], so lots of different advanced solid tumors. It was a very heavily pretreated patient population [as] the median was 4 prior lines of therapy and approximately 40% of the patients in the clinical trial had previously been treated with anti–PD-1 or anti–PD-L1 immune checkpoint inhibitors.

Please discuss the findings you presented at this year’s AACR meeting.

The primary objective of the trial was safety and tolerability and we found that the drug was very well tolerated. There were no dose-limiting toxicities [and] we did not achieve a maximum-tolerated dose. Escalation through the preplanned dose level [reached] up to 1800 mg intravenously every 3 weeks. That was great to see that it was very well tolerated, and [with a] very low AE profile.

One of the secondary objectives was efficacy and what was exciting to see is that [patients had] objective responses. There were 2 patients with advanced cholangiocarcinoma who had a partial response, 1 patient with colorectal carcinoma. All 3 of those patients had microsatellite stable disease.

We had 1 patient with advanced metastatic Merkel cell carcinoma who had a CR on the trial and what was so incredibly exciting about that patient’s case is that he had previously been treated with pembrolizumab in the metastatic setting. When his tumors progressed through that treatment, he was treated with ipilimumab [Yervoy] and nivolumab [Opdivo] and again his cancer progressed through that, [but] when he joined the clinical trial with monotherapy with IO-108, he [experienced] a CR. [It was] exciting to see such impressive activity as a monotherapy agent.

The company has decided on a recommended phase 2 dose of 1200 mg, and that’s going to [be used] going forward both in monotherapy cohorts as well as in combination with immune checkpoint inhibitors in a variety of different solid tumors.

What would you like colleagues to take away from your presentation?

The main take home messages are that the drug is extremely well tolerated, there was a very low AE profile with the drug as monotherapy as well as in combination with anti–PD-1 immune checkpoint inhibitors. It’s also very encouraging to see activity both as a monotherapy and in combination—we’re excited to see the future of this drug as it’s tested in further expansion cohorts.

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