Prophylactic Tocilizumab Reduces Toxicity, Boosts Efficacy in Immune Checkpoint Inhibitor–Treated Melanoma

Interleukin-6 (IL-6) blockade could represent an important approach to managing immunotherapy-related toxicities that arise during melanoma management with immune checkpoint inhibitors, according to Matthew Hadfield, DO.

“I specialize in early-phase clinical trials as well as cutaneous malignancies, and I have a particular interest in immunotherapy toxicities, which unfortunately happen when we give immune checkpoint inhibitors and [other] immunotherapeutics; [these agents] can over-activate the immune system and cause immunotherapy toxicities,” Hadfield said in an interview with OncLive®. “We want to use the immune system to fight cancer, and we want to mitigate toxicities that [are associated] with immunotherapy. We’re still early in the discovery of biomarkers [to determine which patients are] going to develop toxicities and [which are] not. An interesting target is IL-6, which can be blocked by tocilizumab [Actemra], amongst other medications. Preclinical evidence shows that IL-6 overexpression can lead to therapeutic resistance to checkpoint inhibitors, and [IL-6] can also be a major cytokine in the development of toxicities.”

During a poster presentation at the 2024 ASCO Annual Meeting, investigators shared findings from a phase 2 study (NCT03999749) that examined IL-6 blockade with tocilizumab with the goal of reducing immune-related toxicities following treatment with ipilimumab (Yervoy) and nivolumab (Opdivo) in patients with unresectable melanoma. At a median follow-up of 23 months, patients who received prophylactic tocilizumab in combination with ipilimumab and nivolumab followed by nivolumab maintenance (n = 70) achieved a best overall response (BOR) rate of 57% per RECIST 1.1 criteria. The median progression-free survival was 9.1 months, the median duration of response was not yet reached, and the estimated 2-year overall survival rate was 75%.

In the safety population (n = 71), patients experienced grade 1 or 2 immune-related adverse effects (irAEs) at a rate of 71%; grade 3 or 4 irAEs were reported in 22% of patients. The most common grade 1 or 2 irAEs included pruritus (n = 23), skin/rash toxicities (n = 21), and elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels (n = 20). Grade 3 or 4 irAEs included elevated AST/ALT levels (n = 4), diarrhea (n = 4), colitis (n = 2), and lipase/amylase level elevation (n = 2).

In the interview, Hadfield, an assistant professor of medicine with research interests including phase 1 clinical trials and cutaneous malignancies at the Warren Alpert Medical School of Brown University in Providence, Rhode Island, offered his perspective on the significance of the phase 2 study, discussing its rationale, the findings, and the future directions of this type of research.

OncLive: What is the significance of IL-6 as a therapeutic target in melanoma?

Hadfield: IL-6 is an important cytokine that’s been shown in preclinical models to contribute to therapeutic resistance to immune checkpoint inhibitors, particularly in melanoma. It is also an important cytokine that is upregulated during the development of toxicities. We use IL-6–blocking medications, such as tocilizumab, to manage steroid-refractory cases of immunotherapy toxicities. [IL-6 is] an important therapeutic target, both from an efficacy and a toxicity standpoint, and that led to the rationale for this clinical trial.

The standard of care for metastatic untreated melanoma is a combination of immune checkpoint blockade with either ipilimumab and nivolumab or relatlimab and nivolumab [Opdualag]. The concept behind the trial is that by blocking IL-6, you can both decrease therapeutic resistance and potentially [protect] against toxicity.

What were the key findings from the phase 2 trial presented during the 2024 ASCO Annual Meeting?

Forty of 70 patients had a RECIST response, [translating to] a BOR rate of 57%, including 7 patients with a BOR of complete response, 4 with a BOR of stable disease, and 17 with a BOR of [disease] progression, at median follow-up of [23 months]. Approximately 46 patients had a clinical benefit, which was 65% [of the population].

One of the more interesting findings was that there were 16 cases of grade 3 or 4 immunotherapy-[related] toxicities, including 2 episodes of [grade 3 or 4] colitis, out of the 71 patients who were eligible for toxicity evaluation. The expected rate of grade 3 or 4 adverse effects [(AEs) with nivolumab plus ipilimumab in patients with advanced melanoma] is approximately 34% based on [findings from] the [phase 3] CheckMate 511 trial [NCT02714218]; [patients in our phase 2 study had a comparatively] decreased rate of toxicity, which is promising. All grade 3 or 4 irAEs were reversible, and there was no grade 4 toxicity.

There is some correlative work that’s being done [examining] osteopontin IL-6­–positive, CD38-negative classic monocytes, which are associated with response and higher levels of naive CD8 T cells, which is associated with progression. The [phase 2] trial showed that we can [use prophylaxis to] preserve the efficacy [of immunotherapy] seen in previous trials in unresected melanoma and that we can reduce the toxicity rate, which is important. This [finding] is going to serve as a platform for trials in the future, so it’s a big step.

What are the potential clinical implications of these findings?

There’s a twofold effect. [In terms of] patients who have primary resistance to immunotherapy and don’t derive the benefit that that we’re hoping to give, we can see potentially increased efficacy by introducing other novel therapeutic targets, like blocking IL-6 based on past research. However, more promising from this specific set of data is that we can potentially prophylact against toxicities. As we begin to learn more about [which patients are] at higher risk for developing these toxicities, we can possibly start adding these prophylactic regimens early [in the treatment course]; that’s where the correlative work will be important. The goal here is to try to keep patients receiving therapies for as long as possible and [avoid treatment discontinuation because of] grade 3 or 4 AEs. [This phase 2 trial is] a great study and is promising for what the future may hold.

What are the next steps for this research?

The future of cancer management in general, beyond melanoma, is going to be some type of immunotherapeutic approach. Understanding more about what causes therapeutic resistance is going to be important in trying to expand the amount of solid tumor types that are deriving benefit from checkpoint inhibitors. We aren’t going to be able to make much progress treating patients with immunotherapy if we can’t better diagnose and manage the toxicities they develop, and that’s where this trial is important.

This [study] serves as a platform to show that we can preserve [treatment] efficacy, which is the biggest thing we are concerned about. If you start using drugs that may dampen the immune system in some way, [do they] reduce the efficacy of the treatment? What we’re seeing is that there is an uncoupling between efficacy and toxicity, and the more we can tease that out, the more we’ll be able to appropriately treat patients and keep them on therapies longer.

Immunotherapy-[related] toxicities oftentimes can be devastating. They can be life threatening, but they also can take patients who have curable disease and give them chronic conditions. We’re in the early phases of learning about this. This research is important, and it’s important for us to engage with the management of immunotherapy-associated toxicities and be vigilant in diagnosing them, so we can appropriately manage them. As we start bringing in these new therapeutic options, ensuring we’re up to date [with the current research is important] because the field is evolving so quickly. Managing immunotherapy toxicities is a new concept for many oncologists, and this is where the field is going to be for a long time. Embracing this and being well versed in these toxicities is going to be important.

Reference

Weber JS, Puranik A, Mitzutani T, et al. Interleukin-6 receptor blockade with tocilizumab to reduce immune-related toxicity with ipilimumab and nivolumab in metastatic melanoma. J Clin Oncol. 2024;42(suppl 16):9538. doi:10.1200/JCO.2024.42.16_suppl.9538