The addition of itolizumab to standard-of-care corticosteroids vs placebo will be evaluated in patients with acute graft-versus-host disease, as part of the phase 3 EQUATOR trial.
John Koreth, MBBS, DPhil
The addition of itolizumab to standard-of-care (SOC) corticosteroids vs placebo will be evaluated in patients with acute graft-versus-host disease (aGVHD), as part of the phase 3 EQUATOR trial (NCT05263999), according to John Koreth, MBBS, DPhil, who added that if the data prove to be positive, this approach possesses the potential to become a fill an unmet need and move the needle forward for this population.
Previously, results from the phase 1/2 EQUATE trial (NCT03763318) showed that among 25 patients with high-risk aGVHD, itolizumab produced a complete response (CR) rate of 52% and an overall response rate (ORR) of 64% at day 29, across all dose cohorts examined. In a subset of patients (n = 18) who received itolizumab treatment within 3 days of their first corticosteroid administration, the CR rate and ORR were 61% and 67%, respectively.
The randomized, double-blind, phase 3 trial will evaluate the safety and efficacy of itolizumab compared with placebo in combination with corticosteroids in the first-line treatment of patients with aGVHD.1-3 The primary objectives of the trial are to achieve early disease response, to evaluate the durability of response, corticosteroid use, survival outcomes, and the incidence of chronic GVHD in these patients, according to Koreth.
“Patients with higher-risk grades of aGVHD are a population of patients in need. The SOC of corticosteroids alone has been around for multiple decades with very middling outcomes at best. I entirely endorse the idea that we should all, as transplanters, be looking to see what can be done to advance the SOC for these patients,” Koreth, a senior physician at Dana-Farber Cancer Institute, said. “[I believe the] answer to this is: clinical trial participation. I hope itolizumab is 1 of those agents that people are [considering to have potential] benefit [in these patients] and [to be] worthy of [further] evaluation in a robust trial such as [EQUATOR].”
In an interview with OncLive®, Koreth, who is also the director of Translation Research and Stem Cell Transplantation, as well as a professor of medicine at Harvard Medical School, discussed the potential of itolizumab in patients with high-risk aGVHD, prior findings from the EQUATE trial, the key objectives of the phase 3 EQUATOR trial, and the hope for this agent in this patient population.
Koreth: For several decades, at the Dana-Farber Cancer Institute, we have been interested in molecules that can potentially target the CD6 protein on the surface of immune effector cells. In previous work, we had shown that when we could selectively deplete immune cells carrying CD6 from the donor graft [in transplant patients], we were able to reduce the rates of GVHD [and have] impressive survival.
However, that therapeutic [that we tested] has not gotten to the market for a variety of nonscientific and nonbiologic reasons. Therefore, when Equillium came to us and said they had a different, but similar monoclonal antibody called itolizumab, which also targets CD6 and could be considered for GVHD treatment, we were interested.
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. 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, which is a serious deal for our transplant patients.
This was the initial study that [we had] partnered with Equillium [to conduct]; it was done in a multi-institutional setting, and it selected for patients [with] high-risk aGVHD. These are the patients who we are concerned would not be likely to achieve a good response to the SOC, which is corticosteroids alone. No FDA-approved therapies [are available] for this indication, but we do have patients who are routinely treated with steroids across the world.
In this study of 25 patients with high-risk aGVHD, itolizumab was added to corticosteroids [and was explored at] several different dose levels. Responses were impressive. First off, the drug did what we expected it to do in that the levels of CD6 on the surface of immune cells went down substantially, especially at the 2 higher dose levels [examined. CD6 levels] remained depressed for several weeks, which was the interval between [doses]. Indeed, those cells appeared to switch more to a regulatory [T-cell] phenotype. As such, the regulatory T-cell ratios appeared to go in the direction we wanted with the treatment.
Secondly, the CR rate and ORR by day 29 were [52%] and [64%], respectively, across every dose, [although we should recognize] that certain doses may be less optimal than others. 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. [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.
[It should also be noted that these] responses were very rapid, generally more rapid than I had expected. Many of these CRs were in patients who had responded within 15 days, or within 2 weeks, of the onset of treatment. Although the initial response readout was for day 29, seeing these early responses by day 15 was heartening, as were the fact that they were durable.
[Seventy-nine percent of day 29 responders maintained a response through day 169], recognizing that treatment did not continue for 6 months. Even coming off the treatment, there was a durable impact [with this agent]. This is coupled with the fact that we were able to significantly [reduce] doses of corticosteroids, which is another way to determine [whether patients] are deriving benefit. All of this was promising, and suggested that this should be explored further in a pivotal trial.
First, I want to underscore that this is a sick population; these are inpatients with acute involvement, typically of the lower intestinal tract. They have ulceration of the intestinal epithelium, risk of bleeding, diarrhea, and cannot [receive] anything by mouth. The barrier to bacteria, particularly within the intestinal tract, is now reduced [in these patients]. As such, infections are a major complication, [and they stem from] this inflammatory process. When you add additional therapy, it becomes difficult at times to separate what is [happening] due to drug vs the disease. 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. Impressively, the patients who responded to treatment had better survival than those who did not, suggesting that it was not a case where we were winning the battle, but losing the war. You could imagine a scenario where you come in with an agent that is so immunosuppressive that it completely ablates the immune system, and thereby destroys GVHD. However, at the same time, it destroys the patient's ability to withstand infections. In that setting, [patients] could have no benefit from such therapy.
In this case, we did not see that. What we saw was that the patients who responded to treatment were also the ones who had a survival benefit vs those who did not respond. 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.
This is a trial that is very focused on the patients who are relatively high risk. We are looking at [those with] stage 3/4 aGVHD, [which are] the most severe types of aGVHD. We are also looking at patients who have milder involvement but still have lower intestinal tract involvement. We believe that is a relatively high-risk population.
This is a multi-institutional phase 3 trial, [where patients will receive] itolizumab vs placebo as first-line therapy [in combination with corticosteroids]. This is up front, [which means we are evaluating this approach as something we can give] before patients run into problems. [This is for] patients who are aged 12 years and above, have this complication, and are within 3 days of starting their steroids.
The idea is to achieve early disease response [with itolizumab]. The major primary end point [of the trial] is the rate of CR at day 29. The key secondary end points include confirmed ORR, to see how durable those responses are, and to see how much you can taper [treatment with] corticosteroids for patients who are or who are not on the study drug. [Additionally, the trial will look at] survival within that first year after the start of treatment for [rates of] chronic GVHD.
The trial is [currently open to enrollment. This study follows patients for 1 year to evaluate long-term outcomes]. It is not enough, in my mind, to just have a day 29 readout, declare success at 1 month, and then [potentially] find in the long run that [this approach] failed to be beneficial [for the patients].
This could be a potential game changer. 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 SOC for these patients, who, at this point, have a very significant unmet medical need.
There is a lot of ‘ifs’ there, but this is the way to do it. You do a randomized pivotal trial in a multi-institutional setting and in a multi-regulatory environment across different countries. That 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.
Patients with intestinal involvement and higher grades of aGVHD are medically underserved by the current SOC, which is corticosteroids alone. Any clinical trial in this space, be it [EQUATOR] or another trial, should be prioritized by any transplant center that has an academic inclination or an inclination toward moving the SOC in a better direction.
We do have high-quality data in patients with high-risk aGVHD that were gathered prospectively in a multi-institutional setting and showed both tolerable safety and promising efficacy with this agent. It does sound like an interesting agent worthy of discussion.