Frontline Itolizumab Elicits Durable Responses in aGVHD

First-line treatment with itolizumab produced rapid, durable responses and favorable safety in patients with acute graft-vs-host disease (aGVHD), according to final safety and efficacy data from the phase 1//2 EQUATE trial (NCT03763318) presented at the 2023 Transplantation & Cellular Therapy Meetings.

The first-in-class monoclonal antibody itolizumab targets the CD6-ALCAM pathway and was associated with high rates of overall clinical response in patients with aGVHD when combined with systemic corticosteroids.

EQUATE is an open-label, 3 plus 3 dose-escalation phase 1b trial that is evaluating 5 doses of itolizumab administered biweekly through the first 57 days of treatment. The initial dose levels of 0.4 mg/kg, 0.8 mg/kg, and 1.6 mg/kg were evaluated in patients with grade 3-4 aGVHD within 72 hours of the onset of systemic corticosteroids. In the cohort expansion portion of the study, 1.6 mg/kg (n = 6) and 0.8 mg/kg (n = 5) doses were evaluated in patients with grade 2 disease with Ann Arbor stage 2 or 3 or those with grade 3-4 disease; these patients received steroids within 7 days of itolizumab administration. In the final expansion cohort, patients received steroids within 72 hours of 0.8 mg/kg itolizumab (n = 9). The primary end points were safety, tolerability, and recommended dose levels, and the secondary end points measured pharmacokinetics, pharmacodynamics, and clinical activity.

Patients (n = 30) were a mean age of 56 years and the majority (67%) were male. Seventy percent of patients had grade 3 aGVHD and 27% had grade 4 disease. Patients had a mix of organ involvement including skin, liver, and gastrointestinal (GI) with 83% having lower GI and 43% having upper GI involvement.

Among 29 evaluable patients, high clinical response rates were reported on day 15 and 29.

“By day 29, we saw response rates of close to 70% and the majority of responders had a complete response by day 15,” John Koreth, MBBS, DPhil, director of translational research, stem cell transplantation, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School, both in Boston, Massachusetts, said during the presentation. “This was sustained, including the complete responses on day 29, which was the primary readout point of the study.”

On day 15, early responses to itolizumab demonstrated a total overall response rate (ORR) of 69%, with a 45% complete response (CR) rate, 7% very good partial response (VGPR) rate, and 17% partial response (PR) rate. For the 0.4-mg/kg dose level (n = 4), investigators reported a 50% CR rate and a 25% PR rate. For the 0.8-mg/kg dose level (n = 16), the ORR was 63%, with a 38% CR rate, 6% VGPR rate, and a 19% PR rate. For the 1.6-mg/kg dose level (n = 9), the ORR was 78% with an 56% CR rate, 11% VGPR rate, and 11% PR rate.

On day 29, the total ORR was 63% with CRs in 43%, VGPRs in 7%, and PRs in 13%. For the 0.4-mg/kg dose level (n = 4), the ORR and CR rate was 50%. For the 0.8-mg/kg dose level (n = 17), the ORR was 59% with a 41% CR rate and 18% PR rate, and in the 1.6-mg/kg dose level (n = 9), the ORR was 78% with a 44% CR rate, 22% VGPR rate, and 11% PR rate.

High response rates were also reported in patients who were treatment naïve, Koreth said. Total ORR was 77% with a 50% CR rate, 5% VGPR rate, and 23% PR rate on day 15. For patients who received the 0.4-mg/kg dose (n = 4), the ORR was 75% with a 50% CR rate and 25% PR rate. For patients who received the 0.8-mg/kg dose (n = 13), the ORR was 69% with a 38% CR rate, an 8% VGPR rate, and a 23% PR rate. For the patients who received the 1.6-mg/kg dose (n = 5), the ORR was 100% with an 80% CR rate and 20% PR rate.

By day 29, the total ORR was 65% with a 48% CR rate, 4% VGPR rate, and 13% PR rate. By day 29, the patients treated with 0.4 mg/kg itolizumab (n = 4) had an ORR and CR rate of 50%. For patients treated with 0.8 mg/kg (n = 14), the ORR was 64% with a 43% CR rate and 21% PR rate, and for the patients treated with 1.6 mg/kg (n = 5), the ORR was 80% with a 60% CR rate and 20% VGPR rate.

Median progression-free survival for all patients was 4.6 months and in responders, the responses were sustained with a mean duration of response of 206 days. Sixteen patients survived one-year post initial dose and of these, 14 had responded by day 29. “This suggests that if you did not respond to this combination, your outcomes were dismal,” Koreth said.

Treatment-emergent adverse events (TRAEs) were expected for this population with 13.3% experiencing infusion-site reactions and 66.7% experiencing infection-related AEs. About 23% discontinuation treatment due to AEs and 63.3% experienced severe AEs. One patient experienced a dose-limiting toxicity and 14 deaths (46.7%) were reported, with 11 from AEs (36.7%), but none were related to the treatment, Koreth said.

“Importantly, these metrics weren’t just read outs reflecting rates of diarrhea or liver abnormalities,” Koreth said. “This was associated with the capability of reducing concurrent steroid usage. Steroid usage was down 70% by day 29, and furthermore, it was sustained out to 6 months in which 99% dose reduction was achieved.”

In the first-line treatment of aGVHD, itolizumab provided a rapid, durable response with a favorable benefit-risk profile. “We believe that these data support the ongoing pivotal phase 3 EQUATOR study [NCT05263999],” Koreth concluded.

Reference

Koreth J, Loren SW, Nakamura R, et al. Final Safety and Efficacy Results from Equate, an Open-Label Study Evaluating Itolizumab, a Novel Targeted Anti-CD6 Therapy, in Newly Diagnosed Acute Graft-Versus-Host Disease. Presented at: 2023 Tandem Meetings Transplantation & Cellular Therapy Meetings; Orlando, FL; February 15-19, 2023. Abstract 36.