Sznol Advocates for More Awareness of Immune-Related Toxicities

Mario Sznol, MD

Although value and benefit are derived from immunotherapy in many areas of oncology, immunotherapeutic agents do carry a number of toxicities, according to Mario Sznol, MD, who added that these related events can be swiftly managed with strong communication, awareness, and knowledge.

“One of the biggest challenges with the administration of immunotherapy is the management of the toxicities that arise, such as gastrointestinal toxicities, colitis, enteritis, hepatitis, liver function, and endocrine disorders, along with others,” explained Sznol, a professor of medicine and codirector of Yale SPORE in Skin Cancer at Yale Cancer Center. “Some of the other toxicities include myocarditis, myositis, and myasthenia gravis—all 3 could arise in the same patient. Ultimately, we must stay informed on these toxicities, along with the best ways to manage them, to ensure that our patients derive the most benefit possible from immunotherapy.”

In an interview with OncLive^®, Sznol, who was also cochair of the 5th Annual International Congress on Immunotherapies in Cancer®, a program run by Physicians’ Education Resource®, discussed the critical importance of being aware of the immune-related toxicities that could arise when treating patients, along with the best ways to manage them.

OncLive^®: How do immune-related toxicities vary among the different checkpoint inhibitors?

Sznol: The most common agents used in the community are anti–PD-1 and anti–CTLA-4 agents. The immune-related adverse effects [irAEs] seen with both of these classes of agents are very similar. With anti–PD-1 agents, we see more pneumonitis but fewer cases of diabetes mellitus, for example. However, the general spectrum of toxicities is similar and can affect almost every organ.

Things start to become more complicated when we combine therapies. For example, when you combine an anti–PD-1 agent with an antiCTLA-4 agent, there are more toxicities. In such cases, we need to determine which toxicities came from the immunotherapy and which ones came from the chemotherapy. In addition, there are now new combinations involving VEGF inhibitors and anti–PD-1. If a patient experiences diarrhea, we must determine which therapy caused it. Notably, very few patients receive IL-2 at this time; however, that agent could result in cytokine-related toxicities.

How do you manage these irAEs in your own practice?

We have a lot of experience with their management because we’ve been dealing with them for more than 10 years. It’s important to have well-trained nurses and other health care providers, along with those who are there to quickly answer the phones. The clinical secretaries play a huge role because they know how to route and manage these calls. After all, they are the first line of defense and the ones who do the initial management, particularly supportive care. In general, we tend to keep a close eye on our patients because, for some of these toxicities, they can quickly go from mild to very severe cases. Ultimately, close communication is key.

What other advice can you give regarding the optimal management of irAEs?

We should not be afraid of these agents. Instead, we should be vigilant and informed on all the potential toxicities that may arise. In addition, we should be suspicious about any AE that a patient may experience because it could be an immunerelated toxicity. If we catch these toxicities early on, we can manage them early.

As long as we are monitoring our patients and administering these agents safely, I believe immunotherapy, especially in the skin cancer arena, is incredibly effective. These agents provide value to a large number of patients. As long as we know what toxicities to expect, we are all capable of effectively managing these toxicities.

In melanoma specifically, what are some of your go-to immunotherapy regimens?

For melanoma, we also use the combination of an anti–PD-1 and an anti–CTLA-4 agent in most patients, such as nivolumab [Opdivo] and ipilimumab [Yervoy], although some patients receive nivolumab or pembrolizumab [Keytruda] alone. Whether to use a single-agent or a combination therapy is a lengthy discussion in the space. However, for almost all patients, if we’re going to administer a standard of care, we will use either single-agent antiPD-1 or in combination. Notably, we tend to favor the combination for a variety of reasons, even though combination therapies are associated with more AEs.

Even if we use anti–PD-1 as monotherapy first, the combination of an anti–PD-1 and anti–CTLA-4 inhibitor in the second-line setting still has a very respectable response rate. In the first- and second-line settings, for almost all patients with metastatic melanoma, we will start off with immunotherapy.

In the adjuvant setting, it’s a little different. Although PD-1 inhibitors are approved in the adjuvant setting for melanoma, there is a decision of whether to use targeted therapy or immunotherapy for patients with BRAF mutations. Therefore, this becomes more complicated.

What immunotherapeutics are emerging in the pipeline with some practicechanging potential?

There are many emerging immunotherapy agents that we're excited about. We look forward to hearing more about tumor-infiltrating lymphocytes (TIL) adoptive cell therapy. Regarding melanoma, I don't believe that we're going to see any agents that are nearly as active as anti–PD-1 alone in at least 40% to 50% of patients.

Even so, I believe a number of agents out there will give us meaningful responses in small subsets, probably in combination with anti–PD-1. There could be something such as an anti-CD40 or an anti-LAG3. It could also be one of the many intratumoral therapies or adoptive cell therapy with TIL. The list goes on.

Recently, during the 2020 Society for Immunotherapy of Cancer Annual Meeting, interesting data were presented on the first-in-class, nextgeneration, DuoBody-PD-L1×4-1BB bispecific antibody, GEN1046, in solid tumors. Although I can’t list them all, we’re beginning to see the emergence of more active agents. The challenge is, once we shift over to the resistant/ refractory setting, each agent may be active only in a small subset of patients. We must determine which patients will derive the most benefit from each therapy.

What were some of the big takeaways from this year’s International Congress on Immunotherapies in Cancer®?

I was most excited about the TIL adoptive cell therapies. We invited Amod A. Sarnaik, MD, of Moffitt Cancer Center, who discussed this topic in much greater depth. However, all the presentations were great.

These meetings are critical in the field of oncology because experts are invited to present up-todate information in the areas that they specialize in. These data are then utilized in practice all over [oncology].