Investigators Seek to Expand Treatment Options for aGVHD with Novel Anti-CD6 Agent

Corey S. Cutler, MD, MPH, FRCPC

The development of graft-vs-host disease (GVHD) in is a major contributing factor to morbidity among transplant recipients. For those who develop severe cases (grade 3 or 4), options to improve up front treatment are necessary, and investigators are seeking to improve on standard treatments which typically involve corticosteroids administered at 2 mg/kg per day. One avenue of exploration is the use of combination therapies up front to induce more rapid, durable outcomes.

One such approach is using the first-in-class CD6-targeted therapy, itolizumab.^1,2

“We know that CD6 is a costimulatory receptor found on activated CD4 and CD8 T cells,” Corey S. Cutler, MD, MPH, FRCPC, said in an interview with OncLive^®.“We also know that the ligand called ALCAM [activated leukocyte cell adhesion molecule], is expressed on antigen-presenting cells, as well as the inflamed tissues in the skin and gastrointestinal 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.”

Cutler, an investigator on the phase 1/2 EQUATE trial (NCT03763318) which evaluated itolizumab, noted that the agent has demonstrated efficacy for the treatment of psoriasis and its utility as a treatment for severe aGVHD has the potential to change the standard of care. “Itolizumab is a monoclonal antibody directed against the CD6 receptor, which is commonly found on activated T cells. CD6 is a receptor found on lymphocytes, which helps them traffic to areas of inflammation. Targeting a marker of activation and proliferation helps us specifically target the T cells we think might be pathologic in aGVHD.”

Investigators of EQUATE evaluated the safety and efficacy of itolizumab at 3 dose levels: 0.4 mg/kg, 0.8 mg/kg, and 1.6 mg/kg once every 2 weeks. At the 48th Annual Meeting of the European Society for Blood and Marrow Transplantation, investigators reported updated data that demonstrated among 25 patients who received itolizumab, the overall response rate was 71% at day 15 and 64% at day 29 with a complete response rate of 50% at day 15 that was maintained through day 29. Responses at day 29 were durable, with most patients maintaining a response off-treatment (79% through day 169 and 50% through day 337).

Further, investigators reported that a 73% reduction in median corticosteroid dose was seen at day 29 (for the 16 responders). Finally, at month 12 among day 29 responders, the progression-free survival rate was estimated at 50% with an overall survival probability of 72% (compared with 14% for day 29 nonresponders).²

In his discussion with OncLive^®, 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, noted the clinical benefit observed with itolizumab in EQUATE and the observations that informed the design of the phase 3 EQUATOR trial (NCT05263999).

Please explain the outcomes investigators are attempting to improve on with the addition of itolizumab with the current standard of care corticosteroids.

We treat [patients with] aGVHD that involves the visceral organs with intravenous steroids and that response rate is approximately 50% in terms of [eliciting a] durable response. An additional 25% [of patients] will have GVHD that initially responds but recurs rather quickly [and] then the final 25% will have primary resistant aGVHD.

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.

What was the rationale for combining itolizumab in combination with corticosteroids and what were the highlights of the study?

We don’t have enough data to suggest that using itolizumab alone is a good enough approach. We rely on the very potent and very rapid anti-inflammatory activity of corticosteroids for the initial management of aGVHD. That might change in the coming years but at the moment, the strategy is to add agents to the initial therapy for aGVHD. [However, if] the disease is very mild and restricted to the skin, in which case we can sometimes [use alternative agents such as monotherapy with sirolumus [Rapamune].

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. 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 key takeaway [from EQUATE] was that there was a very reasonable response rate. Approximately half of patients had a complete response by 4 weeks from the initiation of therapy and the overall response rate was a little bit higher at approximately two-thirds, 64% to be exact.

We know that the earlier we start novel agents, the more likely they are to work, so using an agent [such as] itolizumab up front is the best place to [start]. The promising response rates are driving us to do this randomized trial. Response rates seen in a phase 1 or phase 2 trial are generally not reliable enough for us to make this a standard of care. [Investigators of] the phase 3 trial will [evaluate] the active compound itolizumab or placebo given in conjunction with corticosteroids, which are the mainstay of therapy still.

Were there any safety concerns noted with itolizumab?

Safety as reported in the phase 1b/2 trial was actually quite good. We have to understand that these are investigator-reported and investigator-attributed safety events. But there were very few dose-limiting adverse events [AEs]. In fact, there was only 1 dose-limiting AE that was reported in the EQUATE trial. These are [ill] patients and there are lots of AEs on study [and] that is not unexpected. As we can tell, at the moment, the drug appears to be safe when administered with corticosteroids.

Turning to the phase 3 EQUATOR trial, which is about to be initiated, what are the key objectives and what findings from EQUATE influenced the design of the EQUATOR trial?

The randomized trial is really 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.

The phase 1b/2 trial tested 3 dose levels—0.4, 0.8, and 1.6 mg/kg. 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. The 0.8-mg/kg dose [was determined to] be pursued in the randomized phase 3 trial.

The patients who will be enrolled in the phase 3 trial are those with either grade 3 or 4 aGVHD, or those with grade 2 aGVHD who have lower gastrointestinal involvement, which signals a higher risk group of patients. [Enrolled patients will receive] an induction dose [of 1.6 mg/kg] followed by maintenance dosing [every 2 weeks], at the 0.8-mg/kg dose level.

What will itolizumab provide to the treatment landscape for aGVHD?

I think we all really want to find new agents that are more effective as frontline therapy for [patients with] aGVHD. This is a promising compound. We have explored CD6 depletion as a way of preventing GVHD as early as the 1990s at Dana-Farber [Cancer Institute]. This is coming full circle for with us testing an agent that targets CD6 in the treatment of aGVHD. We’re excited to participate in the trial [and] are hoping for positive results, [so] we will see how the drug performs in a formal blinded randomized clinical trial.

We certainly can consider whether this drug has a role in chronic GVHD as well as acute. However, we're focusing our efforts on aGVHD space.

References

1. 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. Abstract OS10-04. Accessed March 29, 2022. https://ebmt2022.abstractserver.com/program/#/details/presentations/638
2. 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. Abstract OS10-04. Accessed March 29, 2022. https://ebmt2022.abstractserver.com/program/#/details/presentations/637