Phase 2 Trial Expanded to Examine AGEN1181 Plus Balstilimab in Colon Cancer

December 3, 2020 - A phase 2 trial has expanded to examine the use of the CTLA-4 antibody AGEN1181 in combination with the novel anti–PD-1 human monoclonal antibody balstilimab in patients with colon cancer.

A phase 2 trial has expanded to examine the use of the CTLA-4 antibody AGEN1181 in combination with the novel anti–PD-1 human monoclonal antibody balstilimab (AGEN2034) in patients with colon cancer, according to an announcement from Agenus Inc.1

The decision follows a new objective clinical response observed in a patient with colorectal cancer (CRC). AGEN1181 with or without balstilimab has resulted in 4 clinical responses. A fifth patient with microsatellite stable (MSS) colon cancer who received the combination experienced a significant 27% reduction in tumor size, along with a reduction in carcinoembryonic antigen biomarker from 298 to 2. Moreover, out of 41 patients who received treatment in the dose-escalation study, 19 achieved disease stabilization.

“These early data are very exciting, particularly in aggressive tumors that have traditionally been unresponsive to immune therapies, like CRC,” Joseph Grossman, MD, vice president and head of exploratory medicine at Agenus, stated in a press release. “AGEN1181 has potential to not only broaden the population of responders to checkpoint inhibitors, but also to reach tumors traditionally considered ‘cold’ or unresponsive to immune therapies.”

AGEN1181 is a multipurpose, second-generation Fc-engineered anti–CTLA-4 antibody that was developed to have enhanced antitumor activity and to elicit responses in more patients while improving immunogenicity.2 Moreover, investigators recently identified a new mechanism of action where a specialized domain of the antibody engages with receptors on other immune cells to substantially augment antitumor immunity.3

By leveraging this mechanism of action, investigators altered the Fc region of the antibody, which is known to interact with other immune cells to enhance antitumor immunity. Data from preclinical studies have indicated that the antibody notably improves the interaction between antigen-presenting cells and T cells; this is needed to generate a deep immune response against cancer cells.

Recently, the first report of intratumoral T-reg depletion with a CTLA-4 antibody was delivered by the clinical-stage immuno-oncology company. Results showed that 1 patient with PD-L1–negative MSS endometrial cancer experienced a complete response (CR) to single-agent AGEN1181, while another patient with the same disease achieved a CR with AGEN1181 plus balstilimab. 

One patient with CRC and another patient with PD-L1–negative, refractory ovarian cancer achieved a partial response with AGEN1181 plus balstilimab, although the patient with ovarian cancer achieved stable disease for 66 weeks with AGEN1181 monotherapy. 

Moreover, patients with polymorphism in FcyRIIIA alleles who did not achieve a response when treated with first-generation CTLA-4 antibodies were found to achieve clinical benefit and respond to ANGEN1181, according to results from a phase 1 trial (NCT03860272).

In the open-label, multicenter phase 1 trial, investigators set out to evaluate the safety and tolerability, determine the pharmacokinetics and pharmacodynamics profiles, and establish the maximum-tolerated dose and recommended phase 2 dose of AGEN1181 as a single agent and in combination with balstilimab in patients with advanced solid tumors.4 Investigators sought to enroll a total of 86 evaluable patients who had refractory solid tumors, irrespective of diagnosis.

The key objective of the trial was to examine the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the monotherapy and the combination regimen in selected cancer types at dose levels that were determined to potentially be effective. Some indications of interest included non–small cell lung cancer that is refractory to prior PD-1 or PD-L1 inhibition, melanoma that is refractory to previous PD-1/PD-L1 treatment, hepatocellular carcinoma, endometrial cancer, and angiosarcoma.

The primary outcome measures of the study were incidence of adverse effects, dose-limiting toxicity, and establishing the recommended phase 2 dose of the agent. Key secondary outcome measures comprised overall response rate by RECIST v1.1 criteria, duration of response, disease control rate, progression-free survival, and overall survival, among others.

To be eligible for enrollment, patients had to be aged 18 or older with a histologically or cytologically confirmed diagnosis of a metastatic or locally advanced solid tumor. They also had to either have progressed on a standard therapy or had a condition for which no standard therapy was available. Patients also needed to have measurable disease, a life expectancy of 3 months or more, an ECOG performance status of 0 or 1, and acceptable organ and bone marrow reserve function.

Participants were enrolled into 1 of 3 cohorts. In cohort 1, patients received AGEN1181 every 3 weeks at escalating doses of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg. In cohort 2, AGEN1181 was given every 6 weeks at 1 mg/kg, 2 mg/kg, and 3 mg/kg. In cohort 3, patients were given balstilimab every 2 weeks at 3 mg/kg and AGEN1181 every 6 weeks at a dose of 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 2 mg/kg, and 4 mg/kg.

Patients received treatment on the trial for 2 years or more or until progressive disease, unacceptable toxicity, or meeting any criterion that would warrant discontinuing treatment with the drug or withdrawing from the trial.

In the phase 2 open-label, multicenter study, investigators will focus on examining the agent specifically in patients with colorectal cancer. However, patients with other solid tumor types, such as lung cancer and melanoma, will also be evaluated.


1. Agenus launches phase 2 trial expansion in colon cancer for AGEN1181 in combination with balstilimab. News release. Agenus. December 1, 2020. Accessed December 2, 2020.

2. AGEN1181 multipurpose, second-generation CTLA-4. Agenus. Accessed December 2, 2020.

3. Waight JD, Chand D, Sietrich S, et al. Selective FcγR co-engagement on APCs modulates the activity of therapeutic antibodies targeting T cell antigens. Cancer Cell. 2018;33(6):1033-1047.e5. doi:10.1016/j.ccell.2018.05.005

4. Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. Updated November 30, 2020. Accessed December 2, 2020.