IRAK-4 Inhibitor CA-4948 May Enhance Immunotherapeutic Outcomes in Melanoma With Brain Metastases

Bently Doonan, MD

Promising preclinical findings have demonstrated that IRAK-4 is a viable target to increase the efficacy of immunotherapy in patients with melanoma who have brain metastases. The development of the oral, IRAK-4 inhibitor, CA-4948, showed enhanced antitumor activity and efforts are underway to evaluate the agent in combination with pembrolizumab (Keytruda) in a first in-human clinical trial (NCT05669352), according to Bently Doonan, MD.¹

“We’re starting to gather more information about the tumor microenvironment,” Doonan explained. “Understanding how we can manipulate or effect the tumor microenvironment to make immunotherapies work better is going to be vital to expanding their scope, efficacy, and impact [of these agents]. We [hypothesize] that the IRAK-4 inflammatory mitosomal pathway and the ability to inhibit it with drugs [such as] CA-4948 has the potential to open those doors.”

According to murine data published in Clinical Cancer Research in February 2023, high-dose CA-4948 monotherapy (100 mg/kg) vs CA-4948 vehicle in specimens harboring B16F10 central nervous system (CNS) melanoma tumors improved the mean overall survival by 35%. The median survival was 17.0 days for mice receiving the therapy compared with 12.6 days for mice receiving vehicle. Investigators also noted that there was markedly reduced tumor burden observed in brain tissue isolated on day 7 of treatment.²

In an interview with OncLive^®, Doonan, an assistant professor at the University of Florida in the Division of Hematology & Oncology, discussed how an agent can penetrate the blood-brain barrier, interacting with the tumor microenvironment and how this approach may open doors for patients with brain metastases.

What was the rationale for investigating CA-4948?

What we’re focusing on is a novel, small molecule inhibitor called CA-4948 or emavusertib. This is an agent that targets a unique intracytoplasmic molecule called IRAK4 [which] has a role in many cancers often as a mutation-driven cancer. Most lymphomas possess a mutation in [the] driver function inside of it, the inflammatory mitosome that’s driven by this combination of proteins that are the response of the cell to external stimulus of inflammation, [for example] Toll-like receptors or IL-1. What we [know] is that cancer cells use what’s supposed to be a defense mechanism for their own benefit.

Initially we were studying emavusertib in the CNS lymphoma space but pivoted toward melanoma when we found that we were also seeing changes in the tumor microenvironment. This was an area that we wanted to expand to, and we looked at the overall expression of [IRAK4] in melanoma patients and looked for the highest risk patients who have melanoma—those who have brain metastases. Unfortunately, it’s an incredibly common occurrence, approximately 40% to 60% [of patients and] it’s likely higher [for] the total number of individuals who are going to be affected by brain metastases.

For those patients we have things [such as] immunotherapy and targeted therapy, but unfortunately, they often fall short. We can add…focused radiation therapy, [for example], but it still limits the overall scope of effect that we can have in these patients lives, and [brain metastases are] still a major driver of their mortality.

We first looked to see [if] this agent [could] get into the brain because we know that most drugs can’t. It’s a good defense mechanism that our body has that less than 2% of all drugs actively effectively get into the brain, especially through a therapeutic concentration.

Outside of the more straightforward mechanism [of using IRAK4 as a target for] CA-4948 in lymphomas, we found that we were affecting the tumor microenvironment [with the drug]. [Therefore], we wanted to look at a cancer that had an integral tumor microenvironment [and] we shifted our focus to metastatic melanoma.

We weren’t the first to look at this potential inflammatory marker in melanoma, we found a lot of literature to support that melanoma cells upregulate IRAK4 as well. However, they’re not doing it through mutation, they’re doing it in response to inflammation.

We often think of melanoma as being this incredibly inflammatory cancer, which we think is a good thing because that’s why immunotherapies have such a strong foothold in that disease. Ultimately, half of patients with melanoma don’t benefit from immunotherapy. Partially that’s because inflammation can be good, but too [much] inflammation is bad, and we’re noticing that inflammation leads to suppression.

When we added [CA-4948], we found that it turns down that inflammation in a very unique way and that it affects how the cells use that inflammation for growth. It slows their growth, but more importantly, it seems like it’s regulating the tumor microenvironment to then when we add the traditional therapies for melanoma on top of it, like a checkpoint inhibitor, it has an improved effect. In these aggressive resistant mouse models of metastatic melanoma, ones that traditionally don’t even respond to checkpoint therapy, we can improve the survival of these mice by adding the 2 agents together.

Was there anything surprising within these findings?

One of the most interesting components is this field are the tumor-associated macrophages and the myeloid compartments. The myeloid cells are this representative pool of cells that are called from the bone marrow or endogenous loci in these target areas that are regulating and affecting how the body’s immune system is interacting with the tumor.

Now, we often want them to be [working] in our favor, but in response to injuries, inflammation, trauma, or to cancers, oftentimes the reflexive ability of the cells calls a whole bunch of [other] cells to the area that are not going to do the functions that we want—they’re going to lead to further suppression and they diminish the effects of traditional immunotherapy.

Even though the body’s response to inflammation is to turn off the inflammation, it goes overboard and so in turn it’s recruiting the cells from the rest of the body, namely from the bone marrow, that are immature and don’t perform their job well. When they get to that tumor site, they get converted to the protumor cause, what we consider as myeloid differentiated suppressor cells or tumor-associated macrophages.

One of the most interesting findings that we’re seeing is that when you add the IRAK4 inhibitor, [there was] a decrease in the recruitment of immature myeloid cells…. We think this is the linchpin of why this is having a combination effect that benefits the underlying checkpoint therapy.

Interestingly, by removing these [cells] and by decreasing that inflammation, we have T cells that perform better. The T cells are more effective [and] we have more of those cells present that are supposed to be functionally trying to kill the tumor even though we’re technically suppressing the drive to inflammation in the environment.

What next steps would you like to take with this research?

We’re positing an approach on 2 fronts and designing and developing some of the preclinical basis and backing and to understand what’s going on. We have some experiments that are ongoing right now to explore more of the mechanistic effects of myeloid differentiation vs suppression of how these cells migrate, but that’s not good enough for patients who have brain metastases.

Through some support from our industry partners, [such as] Merck and Curis Inc, we’re moving this rapidly into a first-in-human clinical trial, with a goal of opening the [enrollment] specifically for patients with melanoma brain metastases. Because it’s already been tested in patients with other diseases, we have a good safety and toxicity [data] backing this. We give a single-agent checkpoint inhibitor to almost every single patient with melanoma, so we know the safety and the parameters. It’s a marriage that we think is going to meet a lot of the standards to potentially benefit a lot of patients and we’re really excited to open that later [in 2023].

If results continue to be positive, how are you hoping that this will affect the way patients are treated in the future?

One of the big things [that] has been lacking in [oncology] is an approach for patients who have solid tumors that metastasize to the brain at the start of [their] journey. For too long, these patients have been kept out of clinical trials or therapeutic [indications] haven’t been designed for them. They’ve been an additional player or have been allowed into studies through very strict rules. This has led to a lack of understanding about how we should manage these diseases.

The goal of having a trial that’s specifically designed for these patients and recruiting solely patients with brain metastases is that we can show that this is an area where patients need help [because this] is a key driver of mortality.

If we can show an effect and prevent the subsequent recurrences of brain metastases in these patients, the next steps would be can we prevent them before they even begin? Would this drug have efficacy at preventing brain metastases in a population where we know more than half of them are going to face that at some point during their life?

We also know that the effect of emavusertib in combination with [other] checkpoint inhibitors isn’t unique to melanoma. It’s a space that we think we can manipulate in multiple cancers where the same effect is happening—where the myeloid compartment in the tumor microenvironment is leading to some over suppression that limits the capacity of checkpoint inhibitors from having improved success. The applications to other disease types, particularly those that have [incidence of] brain metastases or those where a checkpoint inhibitor is a central part of the treatment paradigm, is going to open an area to improve upon something that is almost adapted as a major part of the standard of care.

The main takeaway is that we’ve barely scratched the surface of our true understanding of how we’re using the immune system and immunotherapies. It’s a very delicate tightrope to walk of inducing specific tumor killing through the immune system without [inducing] toxicity or abandoning immunotherapies with the lack of efficacy where we blame it on multiple factors.

References

1. Von Roemeling CA, Doonan BP, Russell RA, et al. Targeted inhibition of IRAK-4 with CA-4948 (emavusertib) sensitizes metastatic brain melanoma to anti-PD-1 immune checkpoint blockade. Cancer Res. 2023;83(suppl 8):LB203. doi:10.1158/1538-7445.AM2023-LB203
2. Von Roemeling CA, Doonan BP, Klippel K, et al. Oral IRAK-4 inhibitor CA-4948 is blood-brain barrier penetrant and has single-agent activity against CNS lymphoma and melanoma brain metastases. Published online February 7, 2023. Clin Cancer Res. 2023;29(9):1751-1762. doi:10.1158/1078-0432.CCR-22-1682