CTLA-4 Inhibitor AGEN1181 Shows Early Activity in Heavily Pretreated Advanced Solid Tumors

AGEN1181, a next-generation CTLA-4 inhibitor, exhibited clinical activity both as a monotherapy and in combination with balstilimab in heavily pretreated patients with advanced solid tumors, according to data from the phase 1/1b Agenus C-800-01 trial (NCT03860272) presented during the 2021 SITC Annual Meeting.¹

As of a data cutoff of September 17, 2021, 4 patients who received AGEN1181 as a single agent achieved a confirmed objective response to treatment; this included 1 complete response (CR) in a patient with microsatellite stable (MSS) endometrial cancer, and partial responses (PRs) in 1 patient with pancreatic cancer, 1 patient with PD-1–refractory cervical cancer, and 1 patient with PD-1–refractory melanoma. Notably, 3 of the responders expressed low affinity FcγRIIIA receptor, which has been linked with a lack of response to first-generation CTLA-4 inhibitors.

When given at a dose of at least 1 mg/kg and paired with balstilimab, more than 60% of evaluable patients achieved disease control. Specifically, among 20 evaluable patients with MSS colorectal cancer (CRC), 3 patients achieved PRs and 1 had an unconfirmed PR. Ten patients achieved stable disease, with 1 patient experiencing a 27% reduction in tumor burden. The disease control rate (DCR) among patients with MSS CRC was 70%.

Among 9 patients with ovarian cancer who received at least 1 mg/kg of AGEN1181 plus balstilimab, the DCR was 56%; 3 patients achieved PRs and 2 experienced stable disease, with 1 patient experiencing a 28% reduction in tumor burden. In 3 patients with MSS endometrial cancer who received monotherapy or lower combination dosing, the DCR was 100%, with 1 CR and 2 PRs reported.

“AGEN1181 as monotherapy and in combination with balstilimab has shown promising activity in patients with poorly immunogenic tumors such as MSS-CRC, endometrial, and ovarian cancers; these are tumor types that do not traditionally respond well to single agent anti PD-1/PD-L1 therapy,” Anthony El-Khoueiry, MD, director of the Phase I Program and associate professor of clinical medicine at Keck School of Medicine of University of Southern California, stated in a press release.² “Importantly, multiple responders expressed the low affinity FcγRIIIA receptor, a feature that makes them less likely to respond to first-generation CTLA-4 antibodies. Together, this highlights the potential of AGEN1181 to fulfill unmet medical needs in the current treatment landscape by overcoming limitations of approved immunotherapies.”

AGEN1181 is an Fc-enhanced anti–CTLA-4 monoclonal antibody. Fc optimization permits coverage of all FcγRIIIA polymorphic variants and extends benefit by targeting patients who express the low-affinity allele while enhancing benefit for those with the high-affinity allele. The agent was designed to possess the following benefits: expand responses in poorly immunogenic tumor types, eliminate important contributors to immunotherapy resistance, produce durable antitumor immunity and disease control, and improve safety.

The trial enrolled a total of 116 patients with advanced solid tumors that were refractory to standard therapies. All patients had received at least 1 prior line of therapy. Previous treatment with PD-1 inhibitors was permitted.

In the dose-escalation portion of the trial, patients in the monotherapy cohort received AGEN1181 intravenously at doses of 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 2.0 mg/kg, and 3.0 mg/kg every 3 weeks or at 1.0 mg/kg or 2.0 mg/kg every 6 weeks. Those in the combination cohort received AGEN1181 intravenously at 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, or 2.0 mg/kg every 6 weeks in combination with intravenous balstilimab at 3 mg/kg every 2 weeks. In the dose-expansion portion of the trial, AGEN1181 was given at doses of 1.0 mg/kg or 2.0 mg/kg every 5 weeks plus balstilimab at 3 mg/kg every 2 weeks.

Notably, crossover to the combination arm was allowed.

The median age of study participants was 62 years (range, 28-82) and 64.7% of patients had an ECOG performance status of 1. Moreover, 28.4% of patients had CRC, 12.9% had ovarian cancer, 6.0% had hepatocellular carcinoma, 6.0% had angiosarcoma, 5.2% had pancreatic cancer, and 41.4% had a tumor classified as other. Notably, 58.6% of patients (n = 68) received 3 or more previous lines of therapy, and 31.0% of patients previously received treatment with a PD-1 or PD-L1 inhibitor.

Ultimately, 44 patients received AGEN1181 monotherapy and 85 patients received the agent in combination with balstilimab.

Pharmacologic data indicated that serum AGEN1181 terminal elimination half-life was 13.4 days, and clearance of the agent appears to be independent of dose, duration of treatment, dosing frequency, or co-administration with balstilimab. Moreover, AGEN1181 and balstilimab antidrug antibody frequency was low (3%) and there was no evidence of effect on drug exposure.

Beyond the clinical activity shown in both the AGEN1181 monotherapy and combination AGEN1181/balstilimab arms, El-Khoueiry said the drug performed consistently with its design to improve safety, compared with previous CTLA-4 inhibitors.

The maximum tolerated dose had not been reached in either the monotherapy or combination dosing cohorts. Across monotherapy and combination cohorts, 97.4% of patients (n = 113/116) experienced at least 1 treatment-emergent adverse effect (AE). Additionally, 55.2% of patients reported a serious AE with treatment, and 80.2% experienced a treatment-related AE. Furthermore, 61.2% of patients experienced a grade 3 to 5 TEAE, 48.3% had a grade 3 to 5 serious AE, and 20.7% experienced a grade 3 to 5 TRAE.

Among those who experienced grade 3 or higher TRAEs, the most common toxicities included fatigue (2.9%) followed by acute kidney injury, anemia, bicytopenia, confusional state, decreased appetite, dehydration, enterocolitis infection, hypotension, infusion-related reactions, large intestinal perforation, lymphocyte count decreased, nausea, stomatitis, and vomiting (1.0% each). Two grade 5 treatment-related toxicities were reported; these included intestinal perforation that was not surgically treated and chronic colitis.

The most common immune-related toxicities included diarrhea/colitis (any grade, 42.2%; grade 3 to 5, 10.8%), alanine aminotransferase increased (any grade, 3.9%), aspartate aminotransferase increased (any grade, 3.9%), rash (any grade, 23.5%; grade 3 to 5, 2.0%), adrenal insufficiency (any grade, 2.0%), hypothyroidism (any grade, 4.9%), and hyperthyroidism (any grade, 2.9%). Notably, no immune-related hypophysitis, pneumonia, or high-grade hepatitis were reported.

Sixteen percent of patients discontinued treatment due to toxicity; 12% did so because of diarrhea or colitis. Moreover, 31% of patients received 40 mg/kg or more of prednisone equivalent to daily treatment, with 92% of cases due to diarrhea.

"Consistent with its design, safety is favorable compared to the class," El-Khoueiry concluded. "Pivotal phase 2 programs are underway in MSS colorectal cancer, endometrial and ovarian cancer, and melanoma."

References

1. El-Khoueiry A, Bullock A, Tsimberidou A, et al. 479 AGEN1181, an Fc-enhanced anti-CTLA-4 antibody, alone and in combination with balstilimab (anti-PD-1) in patients with advanced solid tumors: phase 1 results. J ImmunoTher Cancer. 2021;9. doi:10.1136/jitc-2021-SITC2021.479
2. Clinical activity of AGEN1181 demonstrated across 9 treatment-resistant cancers at SITC. News release. Agenus Inc.; November 12, 2021. Accessed November 23, 2021. https://bit.ly/3cIVJg4