Systemic Therapy for CSCC and its Related Toxicities

Michael R. Migden, MD:Well, both pseudoprogression and immune-related adverse events are interesting because they’re both things that have to be dealt with whenever you’re prescribing immunotherapy. But, interestingly, they both have been associated with a potential better overall response, so patients that either have pseudoprogression—and I’ll get into in a minute what that is—or immune-related adverse events, may actually have a more durable or complete response to immunotherapy. You can think of it the way I think of it—more sensitivity to the treatment to the point where there’s some issue developing.

So, let’s talk about first the pseudoprogression. Pseudoprogression, as the name says, would be something that’s not true progression, but it may be perceived as progression. This is where a tumor starts looking angrier, has more erythema, possibly erosion, and it may be increasing in size. And it’s important to recognize that it may be actual progression where the tumor is actually growing, or it may just be that it’s the dramatic influx of activated T-cells—tumor infiltrated lymphocytes that are producing this apparent change that is alarming. When I first saw pseudoprogression in one of my patients, I was very concerned. “Wow, maybe this isn’t working, maybe the tumor is just growing tremendously.” But, actually, within a couple more infusions, that patient turned around completely and went from this much more angry, eroded lesion to a substantially smaller lesion and one that looked a lot calmer.

So, knowing that pseudoprogression can occur is a big part of dealing with it because one of the main things is, do you really want to stop treatment, or do you want to give people more time to see if they actually respond. If you give them more time and it responds, great. If you give them more time and it looks like it’s heading in the wrong direction, still you can consider doing additional biopsies outside the original surface area of the lesion. And, if those biopsies where you knew there wasn’t tumor before are now coming back as tumor, then that’s pretty definitive for it’s not pseudoprogression, it’s progression.

But the flip side of that of thinking that it’s progression and taking people off when they may not have a viable alternative, is not a good thing for the patient. Think about it—they may have no other real option and you’re taking the one option that may work for them. And it may actually work for them better because if they’re having pseudoprogression, as I said, they may actually have a better response. So, it’s very important to recognize and consider these things before you take the patient off.

As far as immune-related adverse events, these patients on the systemic therapies—anti—PD-1s—typically day by day, have a very high tolerability. In other words, it’s very well tolerated. I have had some patients’ spouses say, “Hey, can you give them something?” And I’d say, “What do you mean?” And they said, “Oh, my spouse has too much energy. They’re bouncing off the wall. They’re more active than they have been before, it’s irritating me. Can you slow them down?” And this just speaks to the patient feeling better and being more active, having less pain.

Unfortunately, there are some other immune-related adverse events, or just nonspecific inflammation. You can think of it as a nonspecific attack by the body’s own immune system of normal tissue or organs. And the vast majority of these are lower in grade and are easily treatable if detected early—usually with systemic corticosteroids, and depending on the grade of events, a range of either 0.5 to 10 mg per kg per day of prednisone, or if it’s a higher grade, 1 to 2 mgs per kg per day, or equivalent of prednisone as the tool.

This is really well spelled out in both the ASCO [American Society of Clinical Oncology] guidelines for treatment of immune-related adverse events and there are several other organizations that have guidelines for treating this. And, depending on which organ is involved, you can tailor that. The most important thing though about immune-related adverse events is to get started with treatment early, which is again, something to suppress that immune response, but to be evaluated, for the patient to show up in the emergency department early.

So I tell all of my patients, if you have a new mild cough, a new diarrhea, something doesn’t seem right, you’re going in and you’re getting evaluated, and you need to tell that doctor in the emergency [department], “Hey, I’m on immunotherapy and I need you to do the laboratories and the imaging to find out where is the problem.” And once that initial therapy is given, enlisting the specialists of interest, in other words, depending on what organ system tissue is involved, if it’s gastrointestinal, you need to get a gastrointestinal doctor, if it’s pneumonitis, you need to get a pulmonologist. So, having that high-end specialist then take over the rest of the management of that patient is critical. And, with that proper early addressing at the start of immune-related adverse events, giving the therapy and then transitioning into the specialist managing the rest, they’re very treatable. Fortunately, the vast majority of immune-related adverse events are lower grade and are treated early.

There is a possibility of death if you have immune-related adverse events, especially ones that aren’t addressed, thus the importance and thus the long conversation I have with all my immunotherapy patients about being seen for literally anything. Because if you think of all the things that end in -itis—a thyroiditis, a pneumonitis, a colitis—and then even others like skin blistering and rashes, it really could be literally any part of the body that’s involved.

Transcript edited for clarity.