Roundtable Discussion: Adverse Events and Treatment Breaks for Hedgehog Pathway Inhibition in BCC

Jason Luke, MD (Comoderator)

Associate Professor of Medicine

Division of Hematology/Oncology

Director, Cancer Immunotherapeutics Center

UPMC Hillman Cancer Immunology and Immunotherapy Program

UPMC Hillman Cancer Center

Pittsburgh, PA

Laura K. Ferris, MD, PhD (Comoderator)

Professor, Dermatology

Director, Dermatology Clinical Trials

UPMC Hillman Cancer Center

Pittsburgh, PA

LUKE: This is an unresectable case, so let’s reflect on how we think about unresectable BCC. The NCCN guidelines considerations for BCC stratification [help] determine the options in terms of how to manage patients.¹

The low- and high-risk categories can be dictated by factors such as the location and size, so truncal lesions that are small are lower risk. If the border is well defined, that’s a good thing, relatively speaking. If it’s a primary lesion, that’s better than a recurrent lesion. If it’s not associated with immunosuppression, a site of prior radiation, or perineural involvement, those are all important features that predict better outcomes. The subtype, in terms of nodular or superficial, is in a lower-risk category.

Contrast that with the [high-risk group], where lesions on the extremities or on the trunk that are greater than 2 cm, or lesions located on the cheeks, forehead, scalp, neck, and tibia, or head, neck, hands—basically not the trunk— are higher risk. That often [speaks] to the ability to resect these lesions. If the borders are poorly defined, or it’s a recurrent lesion, that’s not good. If there’s associated immunosuppression, prior radiation, or perineural involvement, those are bad features as well. Then the subtype with an aggressive growth pattern is something that is not great, that we don’t want to see.

Dr Ferris, as you think about stratifying a case like this, are there any in particular of these factors that would sway you more than any others? I think our case is a little generic in this regard, but when you think about these things, which of these are the most impressive to you?

FERRIS: For this lesion, [I think about] the size and the location close to important anatomic structures—thinking about getting the appropriate margin on that, or clearing that, knowing that you’re right up against the nasal ala, and thinking about the closeness to the lower [eyelid] as well.

When we look at these, we’re thinking not just how do I get that tumor cleared, but how do I reconstruct that? Where am I going to get tissue, to bring that in? Those are all important features. And then the subtype, superficial basal cells, nodular basal cells tend to be a bit less aggressive and a little easier to clear. But some of those subtypes, like morpheaform or an atypical basal cell, can be harder to clear, too.

LUKE: Yes. When you think about the potential to do a Mohs procedure on the face vs a resection, which might take off part of the nose, how do you think about those kinds of considerations? What’s the point where dermatologic management might need to transition to a full surgical approach?

FERRIS: I would [definitely] clear this with Mohs surgery. This is the classic case where the borders are poorly defined. You want to have complete margin assessment. I think, sometimes, Mohs surgery is seen as “less surgery,” but we think of it as surgery that lets you evaluate every single margin.

If you just do a typical elliptical excision, and bread loaf through that tissue, the pathologist sees about 2% of the actual margin, so there are going to be big areas that aren’t evaluated. With Mohs, because of the way the tissue is processed, you can see the deep and peripheral margins. So for clearing it, [I would use] Mohs. If you’re going to plan to surgically clear, this is where multidisciplinary care comes in, with thinking about reconstruction. Oftentimes, these kinds of reconstructions can be done by most surgeons; however, if this was taking up half the scalp, you would want to think about a different closure reconstruction option.

LUKE: We talked about surgical approaches here and we’re describing this as unresectable, but we want to consider that in the context of a multidisciplinary team, because that determination is often quite complicated. Diagnosing someone as unresectable is a big deal because that sets them down a certain trajectory in terms of eventual outcome.

FERRIS: Patients with unresectable, locally advanced BCC oftentimes have other medical comorbidities. They might be significantly older. While sometimes very aggressive surgery might be an option for them if you only looked at the tumor, when you look at the patient, that patient may not be able to tolerate it. They may be on anticoagulants and have a lot of other issues that would make it hard.

In terms of unmet needs, we were excited when the HHIs came out because it was finally a systemic option for these patients. However, they’re not easy for all patients to tolerate. So I think an unmet need is having something for those patients who try an HHI and say, “I can’t tolerate this.”

When we have very young patients, we tend to think, Is this going to be a good option? What do we do here? This person is young; we’re committing them to long-term therapy with something that is going to have some adverse events [AEs].

EFIOM-EKAHA: I’ve used vismodegib [Erivedge] before, and it’s not the easiest thing to tolerate. The taste issues and all the other toxicities are pretty prominent and tough [Table²]. My questions would be, for that patient for whom either the surgeon or the patient is [wary] of chopping off [the lesion]: What is the best option? How do we select it? Is there a preferred sequence, HHI vs PD-1–directed therapy? We all use immunotherapy in several tumor types and we’re [aware] of managing it but, again, drugs like this are not the easiest to tolerate.

LUKE: Absolutely. Anyone else have experience or want to give their opinion about how you might sequence things?

BEED: I’ve used an HHI in an older woman who came in and she had an unresectable tumor in the corner of her eye, in the inner canthus. She had put a Band-Aid over that, and she came in for something else. We treated her with [an HHI for the tumor] and she could tolerate it for maybe 6 months, then I’d take her off, put her back on, take her off. I have not changed it because it’s worked for her, and she’s now in her 90s. I would certainly use the other HHI as well. The other one is intravenous…and sometimes people can’t afford the [oral medication]. So that’s always a consideration, too.

LUKE: I think in clinical practice that relevance of intravenous vs oral is a big deal.

MALHOTRA: I had a patient at the VA [Veterans Health Administration] who I tried on cemiplimab [Libtayo] immunotherapy. There was a big lesion on his face, close to his eye, and he had stable disease for a long time.

MISBAH: I was almost able to use it, but I didn’t have the opportunity to use an HHI.

AKBAR: I have used an HHI in the past and the biggest trouble I had with that particular patient was bad muscle spasms, despite using the muscle relaxants. That was the reason we ended up discontinuing.

LUKE: You are raising important points on this. In terms of the pros and cons here—I think on a high level, is that the tolerability, generally speaking, of HHIs gets pretty tough after 3 months. I’m even surprised to hear that the 1 patient made it 6 months because most patients by about 3 months are having a tough time.

There are a lot of ongoing trials now, trying to look at pulsatile dosing, shortening the duration, taking breaks, and options like that. But it’s very interesting to think about when to use immunotherapy because if you determine that the patient would not tolerate an HHI, you can go to immunotherapy. The question is: When is that? Is that right away? Is that after you’ve tried it for a while? I think there is an intentional flexibility there that comes down to your clinical decision-making. But it is important to emphasize that Hedgehog inhibition can be quite powerful, in terms of controlling these lesions, and figuring out how to use it the best you can is an important consideration.

CHOWDHARY: I haven’t used vismodegib or sonidegib [Odomzo]. I see a lot of solid tumors, such as lung cancer; a lot of our patients with skin cancers go to the main campus. But I wanted to know, how do you differentiate between using one or the other? If I ever have a patient [in whom] I’m going to go for an HHI, how are you making the decision between vismodegib vs sonidegib?

LUKE: There are no head-to-head data so it’s going to be something about your familiarity, and probably your formulary considerations, in terms of which drug you can get more easily for a patient. I don’t think that there’s clear evidence that one is a lot better than the other. Whichever one you have familiarity with, or can get at a reasonable cost, is probably the way to go, in terms of choosing the in-class agents.

LUKE: Dr Beed, you mentioned your patient with whom you did 6-month treatment intervals on that therapy, and that sounded like that was dictated by the tolerability. Would you have preferred to continuously dose, or do you think that that model of treatment breaks would be something that’s broadly applicable?

BEED: I think it worked well for her. She lost weight, didn’t have any sense of smell and taste, was weak, and had alopecia; we’d stop it and then she’d be all good. Then when it started growing, I’d start it [again]. This has happened about 4 or 5 times now. I’d certainly change her [treatment], but she’s much older, and I thought to put her on intravenous therapy would be a bit much. But she’s amenable to starting something. What do you do when this stops working?

LUKE: That’s the hard question. In the context of other tumor types, and with targeted therapy, my experience is that I often find a utility in treating until what appears to be best response, and then assessing tolerability at that moment. That can, for some patients, be a month of therapy, or 3 months; it depends. But I have a lower threshold for discontinuing if the patient is having a good treatment effect. Whereas, with some other targeted therapies, a resistance doesn’t arise quite so quickly to HHIs. It’s a therapy that we can commonly go back to. So I try not to drag the patient through the painful toxicity, and try to get to that response, and then try to take a break.

What is your experience in terms of intermittent dosing? Were you able to take breaks, or did you notice resistance?

EFIOM-EKAHA: My patient was metastatic so we kept going and, unfortunately, quality of life wasn’t that great.

FERRIS: When it was our only drug, taking breaks—people have studied different sequences of 8 weeks; go 6 months, 8 weeks on, 8 weeks off vs 8 weeks off, 12 weeks on. In reality, the protocols probably get tailored to what the patient is able to tolerate. I think that those breaks give patients the ability to stick with it a little bit longer.

As we have more options, I’m curious: Do you end up ever cycling back and forth—having somebody on an HHI, going to cemiplimab, and going back? Or would you see it as a break or a transition? “We’ve really maxed this out; now let’s move on to cemiplimab.”

LUKE: It all depends on the patient in front of us. I think that would be very reasonable. I haven’t personally done that yet, but I probably haven’t had the chance to. That emphasizes this question of when does intolerance come in? Because if you can transition over without having to document progression, this question of can you go back to it is a good one later on if you’re not getting the response.

I probably wouldn’t give anti–PD-1 more than once. But in terms of targeted therapy, I would definitely be willing to go back to the well multiple times. If there’s been a reasonable period of time, you can often get a second response. So I think that’s an important consideration also, that with these patients, owing to comorbidities and advanced age, we try to keep things on the rails over time. It’s not exactly the same thing as your 40-year-old patient who is looking for a “cure.”

FERRIS: There are some data for using L-carnitine supplementation for the myalgias. Do you ever end up trying that? There’s evidence for some of the things we use in dermatology for hair loss. It seems like, in general, what people don’t tolerate is the muscle cramping more than anything. Just curious if you feel like things like L-carnitine supplementation help or even get you that extra few months to see that response before you would want to transition them.

LUKE: Yes, it’s a good point. I haven’t seen it make a big difference, but I think it’s probably anecdotal experience. But what you raise is an important consideration, which is if you’re starting patients on HHI, get the patient set up with palliative care and with your nutritional support at your cancer center. That can go a long way toward allowing them to stay on drug for longer periods of time.

Some other [factors] we think of, as it’s targeted therapy, is it’s going to be well tolerated. This is not exactly that, and the more help you can get for the patient early on—especially if they’re someone who may not have the level of capacity that they might have had when they were younger.

Depending on their family involvement, these kinds of things can make a big difference in terms of maintaining area under the curve on exposure for patients. In other words, can they keep taking the drug? All of those are important considerations, emphasizing the multidisciplinary care of the patient.

LUKE: One other note that can help with some of these patients with the muscle pains is the use of amlodipine.

How long did it take once you stopped the HHI to see some of the symptoms improve?

BEED: About a month to 6 weeks. She would say, “Christmas is coming; I want to feel good,” so we’d stop it. We’d do it around her holidays and vacations, what she felt was important.

LUKE: Yes, that’s an insightful comment. When we’re giving these palliative therapies—because in reality that’s what we’re talking about here—taking into account the patient’s real life, and what’s going to be meaningful to them, can be a very important thing.

My experience is similar. When patients get sick enough that they want to stop these drugs, it’s usually about 3 to 4 weeks that it takes before the symptoms start to get better. It’s probably going to be dependent, to some extent, on how robust your patient is in the first place. It sounds like your 90-year-old patient was quite the go-getter. It’s probably pretty variable, in terms of what their motivation is, in terms of trying to stay on the medicine. We emphasized [counseling the patients who are receiving HHIs]. Trying to get them set up with nutritional support and palliative care, to make sure that they’ll get all the resources that they might be able to have, in order to help manage through the AEs that they are experiencing, is an important aspect to all of this.

The other thing that I’m going to note, in this context— the obvious outlier here is that many patients with BCC are going to be those associated with solid organ transplant or some other form of immunosuppression. In those scenarios, this question about immunotherapy becomes much more nuanced. There is no evidence from the clinical trial that you could give immunotherapy in that setting. In reality, there’s probably a reason they’re on immunosuppression.

So if you give them anti–PD-1 therapy, you’re probably running a pretty big risk that you’re going to do something bad. That’s another consideration here, and why it’s important to understand how to use HHIs, because anti–PD-1 therapy is not this panacea for all patients. Unfortunately, in skin cancer especially, you’re in a tough spot when thinking about that.

LUKE: In our patient, what would we do next? What are the triggers for thinking about switching over from an HHI to anti–PD-1 therapy? We’ve alluded to a lot of them. Even those who haven’t used these drugs, how would you think about this?

MISBAH: I haven’t used an HHI but I’ve used PD-L1 therapy in other cancers and I would feel comfortable switching, or if it was referred from the dermatologist, to start them on a PD-L1 therapy, taking into consideration those things. You’re right; the patients who get BCC are on immunosuppressives in the first place. But in the case that they could be eligible for a PD-L1 therapy, I feel comfortable using them in other cancers. I haven’t used them often in BCC. I would be OK using it in BCC as well.

LUKE: Dr Malhotra, how would you think about this? The label is fairly vague; it says, “or intolerant,” so what constitutes intolerance? You have a lot of experience at the VA. The people at the VA often have a lot of comorbidities. How might you think about trying to sequence things, or use them optimally?

MALHOTRA: I was trying to think what treatment I would give to my patient—he was an older man with multiple comorbidities. He was cachectic, had lost a lot of weight, had significant bone pains and joint pains, and wasn’t ambulating well at home.

We did not wish to significantly affect his quality of life, and that was the way we decided we were going to stay away from the HHIs. But I think if patients are losing weight, and it has significantly affected quality of life, then that would be a trigger for me to switch at that time if I had started him on an HHI.

LUKE: Dr Beed, you had mentioned before wanting to avoid intravenous treatment in an older patient; that can make sense. Any other thoughts about a slightly different patient where that would be less of a concern?

BEED: I’ve treated a patient with a PD-L1 inhibitor, too. We get surgeons who say, “We can’t do anything; take these patients.” It was fine; it worked well. Both of these [treatments] have worked great. [The lesion] was on his ear and the side of his face, but he was much older and had multiple comorbidities, and he went on to die of something else. I’ve used each of these a few times, and they seem to be very good.

I’m at a small hospital. We have 1 palliative care [unit], which is more like a hospice. So we have to do all this, and spend the time—my nurse practitioner and I—to get them through these AEs, go over everything, and get to know them. It’s a small town, so if I don’t know them, somebody knows them, or their grandmother knows them. You get to give very personalized medicine that way.

LUKE: I’m also quite comfortable giving anti–PD-1 therapy in the context of other cutaneous malignancies. I would be thinking about it from the perspective of disease control. If it’s a lesion that isn’t otherwise out of control, I might be leaning toward anti–PD-1 relatively earlier than later, because if it’s not urgent, you might get 1 of those patients who can go a very long time benefiting from that. However, if their lesion’s quite gnarly [in terms of] putting the anatomic structures in place, I’m probably going to try to treat at least until maximum treatment response, if the patient can tolerate that, and go as long as we can before we think about switching over.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Basal cell skin cancer, version 2.2022. Accessed May 17, 2022. https://bit.ly/3aQgHfR}

_{2. Lacouture ME, Dréno B, Ascierto PA, et al. Characterization and management of Hedgehog pathway inhibitor-related adverse events in patients with advanced basal cell carcinoma. Oncologist. 2016;21(10):1218-1229. doi:10.1634/theoncologist.2016-0186}