Investigators Seek to Push Combination Therapy to the Front-line Treatment of aGVHD

Corey S. Cutler, MD, MPH, FRCPC

High-dose systemic steroid administration has limited durability for patients who develop acute graft-vs-host disease (aGVHD). Novel agents seek to improve and expand the efficacy of the current standard of care for patients, specifically those with high-risk disease.

“We all want to find new agents that are more effective as frontline therapy for [patients with] aGVHD,” said Corey S. Cutler, MD, MPH, FRCPC, in an interview with OncologyLive^®. “Even with a very potent anti-inflammatory [such as] steroids, only 50% of our patients are getting a real benefit. Anything that we could use in the frontline setting that will help improve those response rates certainly seems like it will be a very welcome addition to our armamentarium.”

A complication of allogeneic hematopoietic stem cell transplant, aGVHD occurs in approximately 50% of patients who undergo this procedure. Onset of aGVHD usually occurs within 100 days of transplant and involves the skin, liver, and gastrointestinal (GI) tracts. Initiation of high-dose corticosteroids is the current standard of care; however, nearly half of patients become refractory to treatment.¹

Efficacy data for high-dose corticosteroids alone have demonstrated inferior response rates among individuals with high-risk aGVHD vs those with standard aGVHD. For example, a retrospective analysis stratified patients by risk status and reported that the overall response rate at day 28 after treatment was 44% (95% CI, 38%-50%) among 269 patients with high-risk aGVHD vs 68% (95% CI, 66%-70%) among 1454 patients with standard-risk aGVHD.2 The complete response rates (CR) were 27% (95% CI, 22%-33%) and 48% (95% CI, 45%-51%), respectively with partial response (PR) of 16% (95% CI, 12%-21%) and 21% (95% CI, 19%-23%).²

To address this unmet need, investigators have initiated the phase 3 pivotal EQUATOR trial (NCT05263999), which will evaluate the novel monoclonal antibody, itolizumab (Alzumab), in combination with standard-of-care corticosteroids vs placebo in patients with aGVHD.³

“We know that CD6 is a costimulatory receptor found on activated CD4 and CD8 T cells. We also know that the ligand called ALCAM, is expressed on antigen-presenting cells, as well as the inflamed tissues in the skin and GI tract. Since those [receptors] are [present in] the target organs of aGVHD, preventing these T cells from getting to their target makes a lot of sense [and] itolizumab is a promising compound,” said Cutler, who is medical director of the Adult Stem Cell Transplantation Program, director of clinical research, stem cell transplantation, and director of the Stem Cell Transplantation Survivorship Program at Dana-Farber Cancer Institute in Boston, Massachusetts.

Itolizumab, a first-in-class anti-CD6 monoclonal antibody targets the CD6–activated leukocyte cell adhesion molecule (ALCAM) pathway, which modulates the activity of T cells that drive immunoinflammatory diseases, and has demonstrated early activity as a first-line therapy for patients with high-risk aGVHD in the phase 1/2 EQUATE trial (NCT03763318).^4,5

“Itolizumab is a monoclonal antibody that binds to the CD6 [protein], which is expressed on immune effector, or proinflammatory T cells; it is part of the costimulation pathway,” John Koreth, MBBS, DPhil, said in an interview with OncologyLive^®. “Interestingly, [itolizumab] is slightly different [from other agents] in that it does not delete or kill the cells that it binds to, but results [in the] shedding of CD6 from the surface of the cells, and switches [these cells] from a CD6-high to a -low state. By doing so, it appears to switch them from a proinflammatory immune effector cell to a less inflammatory, regulatory T-cell phenotype. That is part of the mechanism [of action of the agent,] and interfering with the CD6 costimulation is another way of blunting the inappropriate immune activity that we believe is part of the underlying pathology in GVHD,” explained Koreth, who is the director of Translation Research and Stem Cell Transplantation and professor of medicine at Harvard Medical School.

Early Efficacy for High-Risk Patients

The EQUATE trial comprised 2 parts: a 3 + 3 dose-escalation portion and a randomized double-blind phase.⁶ “The phase 1b/2 trial tested 3 dose levels—0.4, 0.8, and 1.6 mg/kg,” Cutler said. “According to our pharmacokinetic and pharmacodynamic studies, the 0.4-mg/kg dose was probably insufficient, but there was really no advantage of the 1.6-mg/kg dose [compared with] 0.8 mg/kg.”

At the 48th Annual Meeting of the European Society for Blood and Marrow Transplantation, investigators reported updated data from the EQUATE study. At day 15 of treatment, the complete response rate was 52% among the 20 patients who received itolizumab and was maintained through day 29. The overall response rate was also assessed at days 15 and 29 and was reported at 74% and 65%, respectively. At day 29, 72% of patients were still receiving treatment with corticosteroids.⁵

End of treatment was considered day 57, at which time 50% of patients had durable response. In a follow-up analysis, 45% of patients had an ongoing response at day 169 and the nonrelapse mortality rate was 35% with an estimated overall survival rate of 65%.⁵

An observational end point of the EQUATE study was the reduction of corticosteroid use, which investigators reported that patients either maintained steroid reduction from day 29 and/or continued tapering through day 169. “These are the patients who we are concerned would not be likely to achieve a good response to the standard of care, which is corticosteroids alone,” Koreth said. “No FDA-approved therapies [are available] for this indication, but we do have patients who are routinely treated with steroids across the world.”

In terms of safety, at the interim analysis investigators reported that all participants experienced at least 1 adverse effect (AE), with serious AEs reported among 65% of patients. A concern for this patient population is infection, which was reported among 43% of participants.5 “I want to underscore that this is a sick population; these are patients with acute involvement, typically of the lower intestinal tract,” Koreth said noting that individuals often present with ulceration of the intestinal epithelium, risk of bleeding, and diarrhea. “

“We expect high rates of severe adverse effects [AEs] based on the nature of this illness. [That being said, we] did see infections [with the agent, although] the rates were not dramatically different than what we would have expected. Although there were rates of significant AEs, including a significant rate of infections, that did not differ from what we would have expected a priori going into the study, given the illness of these patients,” Koreth said.

EQUATOR Explores Benefit of First-Line Treatment

Building on the data from EQUATE, Koreth highlighted the data used to inform the protocol for the phase 3 design. “When [investigators] looked the specific subset of patients who were treated within 3 days of the onset of steroids, which is the trial design for the [phase 3] study, the CR rate was [61%] and the ORR was [67%]—again, this is across all dose levels,” Koreth said. “[These findings] did suggest a response rate that was substantial. [It is important to remember, however, that this] was an uncontrolled analysis, which is why the follow-up [phase 3] study is so critical.”

EQUATOR will enroll approximately 200 patients with grade 3/4 aGVHD, or grade 2 aGVHD with lower GI involvement, a population of patients at a higher risk to develop steroid refractory disease, Cutler said. “The randomized trial is an extension of the phase 1b/2 study [and] is the proof phase [in which] that we will [use] the preliminary data that we’ve gathered [to meet] the main objective [of the study]: to determine whether the addition of itolizumab to corticosteroids is in fact better than steroids alone for the initial therapy of aGVHD,” Cutler said.

EQUATOR will enroll approximately 200 patients with grade 3/4 aGVHD, or grade 2 aGVHD with lower GI involvement, a population of patients at a higher risk to develop steroid refractory disease, Cutler said. Staging will be determined using the Mount Sinai Acute GVHD International Consortium (MAGIC) grading criteria.3 Grade 3 disease is defined as stage II/III liver and/or stage II/III lower GI involvement with stage 0-III skin and/or stage 0/I upper GI involvement. Grade 4 disease is defined as stage IV skin, liver, or lower GI involvement with stage 0/I upper GI involvement.7 Additionally, patients must be 12 years or older and have undergone initial allogenic hematopoietic stem cell transplant, have evidenced of myeloid engraftment.3

Patients will be randomly assigned to receive itolizumab within 3 days of the first administration of high-dose corticosteroids or placebo. Based on the data from EQUATE, itolizumab administered at 0.8 mg/kg once every 2 weeks for 6 doses will be used in EQUATOR following an initial dose of 1.6 mg/kg.3 Steroid tapering is recommended.

“We’re [evaluating] to itolizumab in the frontline setting for [patients with] aGVHD [in an attempt to] both increase the response rate to initial therapy with corticosteroids, as well as prevent patients from having early relapses when we start tapering their corticosteroids,” Cutler said. “Steroids are very toxic in the acute setting and anything we can do to minimize our patients’ exposure to this class of drugs will be beneficial in the long term, as long as response rates are not compromised by giving lower doses of steroids.”

The primary end point is early disease response evaluated at 29 days after initiation of treatment. The secondary objectives include durability of response, corticosteroid use, survival outcomes, and chronic GVHD incidence.

“[Itolizumab] could be a potential game changer,” Koreth said. “If patients have a therapy that can rapidly induce a CR that is durable, allows us to taper steroids, and improves survival, then that would be the new standard of care for these patients, who, at this point, have a very significant unmet medical need. [This] is a rigorous trial design, and I hope, if successful, there will be a straight path to approval of the medication so that patients in need can receive it.”

References

1. Malard F, Huang XJ, Sim JPY. Treatment and unmet needs in steroid-refractory acute graft-versus-host disease. Leukemia. 2020;34(5):1229-1240. doi:10.1038/s41375-020-0804-2
2. MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21(4):761-767. doi:10.1016/j.bbmt.2015.01.001
3. A study of itolizumab in combination with corticosteroids for the first-line treatment of acute graft versus host disease (EQUATOR). ClinicalTrials.gov. Updated April 14, 2022. Accessed May 24, 2022. https://clinicaltrials.gov/ct2/show/NCT05263999
4. Ng C, Chinn L, Acevedo LM, et al. Itolizumab, a novel targeted anti-CD6 therapy, induces cleavage of cell surface CD6 and rapid onset of efficacy in subjects with newly diagnosed acute graft-versus-host disease. Presented at: 48th Annual Meeting of the European Society for Blood and Marrow Transplantation. March 19-23, 2022; Prague, Czech Republic. Accessed May 25, 2022. https://ebmt2022.abstractserver.com/program/#/details/presentations/638
5. Koreth J, Waller E, Nakamura R, et al. Updated interim results from the EQUATE study: preliminary safety and efficacy of itolizumab, a novel targeted anti-CD6 therapy, in newly diagnosed acute graft-versus-host disease. Presented at: 48th Annual Meeting of the European Society for Blood and Marrow Transplantation. March 19-23, 2022; Prague, Czech Republic. Accessed May 25, 2022. https://ebmt2022.abstractserver.com/program/#/details/presentations/637
6. A study to evaluate the safety, tolerability, PK, PD, and clinical activity of EQ001 in subjects with aGVHD (EQUATE). ClinicalTrials.gov. Updated October 8, 2021. Accessed May 25, 2022. https://clinicaltrials.gov/ct2/show/NCT03763318
7. Harris HC, Young R, Devine S, et al. International, multi-center standardization of acute graft-versus-host disease clinical data collection: a report from the MAGIC consortium. Biol Blood Marrow Transplant. 2016;22(1):4-10. doi:10.1016/j.bbmt.2015.09.001