Lewis Discusses Options for a Patient With Basal Cell Carcinoma

Karl D. Lewis, MD

Karl D. Lewis, MD, the professor of Medicine in the Cutaneous Oncology Program at University of Colorado in Aurora, CO, discussed the case of a 88-year-old patient with Basel cell carcinoma.

Targeted Oncology^TM: Can you describe the Hedgehog pathway and how Hedgehog pathway inhibitors (HHIs) work in basal cell carcinoma?

LEWIS: Activation and alteration of the Hedgehog signaling pathway is associated with several cancers, including BCC.^1,2 [The pathway is] a series of proteins where the PTCH1 [PATCHED1] protein on the primary cilium has an inhibitory effect on the SMO [smoothened receptor].¹ And, in the presence of Hedgehog ligand, PTCH1 disengages from SMO, and now SMO is activated and affects downstream proteins, including the GLI1 [transcription factor], leading to gene transcription and cell division. And so, the Hedgehog inhibitors are SMO inhibitors; they have direct effects on the SMO protein. Most BCCs have mutations in the PTCH1 protein,^1-3 so they lose that inhibitory effect on SMO. [It becomes] activated, [and] that’s where the HHIs work.

What are the HHIs on the market today, their treatment regimens, and challenges in terms of adverse events (AEs)?

The FDA-approved HHIs are vismodegib [Erivedge] and sonidegib [Odomzo].3 Vismodegib is for locally advanced and metastatic BCC, and sonidegib is for locally advanced BCC only. There’s no starting dose [for vismodegib], the [dose is 150 mg orally once daily] and there’s no dose reductions.⁴ If there’s toxicity, you need to hold the dose [or] stop. The dose for vismodegib is 150 mg daily, and for sonidegib it’s 200 mg daily.^4,5 Some people are doing every other day dosing or differing schedules.^6,7 You can take the vismodegib with or without food. There are some food issues with sonidegib, not as many drug interactions. But the adverse effects [with these agents] are predictable. Patients get muscle cramps, they lose their hair, and they lose their taste. And, as a result of losing their taste, they don’t want to eat, and they lose weight. The first Hedgehog inhibitor was discovered incidentally back in the 1960s, when there was a number of lambs who were being born cyclopic. [When it] was investigated, [they] found [that] pregnant lambs were eating corn lily plants. There was a certain compound in that corn lily plant that they ended up terming “cyclopamine” because of the effects it had on the lambs. So the Hedgehog pathway is very important in embryogenesis and polarity. These agents can be very dangerous if somebody becomes pregnant on them, there’s great risk of birth defects.^3,4

The response rates [with HHI are] impressive. Like targeted therapies, if that cancer is dependent on [a] pathway that is driving tumorigenesis, if you can block it, there will be robust responses. With vismodegib, the ORR [overall response rate] in the locally advanced cohort was 43% [95% CI, 30-56; P < .001], and with sonidegib in the locally advanced, about 43% [95% CI, 27.7-59.0].^8,9 We were involved in these clinical studies, and I think some of the response rates are actually kind of an underestimation, because many of these patients with locally advanced disease have a lot of scarring. If you’re measuring that scarring, the visible tumor is gone, but they still have a defect there and they could be listed as stable disease. Even though that 43% in my mind is still impressive, I do think it’s potentially an underestimation of what the benefit of these agents can be in this population.

Can you describe the data that support the use of vismodegib in a patient like this?

The phase 2 ERIVANCE study [NCT00833417] assessed vismodegib for advanced BCC in 2 cohorts of patients: a metastatic cohort of 33 patients; and a locally advanced cohort of 71 patients.8 They all received vismodegib 150 mg daily, until disease progression or intolerable toxicity. The primary end point was objective response rate by independent review. So independently assessed overall response for the metastatic cohort was 30%, and all of those were partial responses [95% CI, 16%-48%; P = .001]. [The response rate was] 43% for locally advanced BCC and about 21% of those patients had complete response [95% CI, 30-56; P < .001]. Those were biopsy-proven complete responses and vast majority of patients had [a] decrease in their tumor burden. There were very few patients that had progression as their best response, and so this [demonstrates] the point that these tumors are driven by these PTCH mutations in the hedgehog pathway.

What were the common AEs that occurred in the ERIVANCE study, and how do you manage the toxicities with vismodegib?

[As I mentioned before], the toxicity profile is predictable: It’s hair loss, taste loss, and muscle cramping, and almost all the patients I treat with vismodegib have some degree of those 3 AEs.^4,8 Now, it does vary, but everybody, in my experience, has some degree of those toxicities. We’ll get to the grades of the side effects, but most of them are low grade. They’re just persistent, and so that’s a problem when you have a drug like this that you’re planning to treat [patients with]. As long as it’s working, you want to keep them on drug, but if they’re having persistent low-grade toxicities that [are] affecting their quality of life, it’s challenging to keep them on [the] drug long term. Generally, the recommendation in terms of managing toxicity is drug holidays.^10,11 You just give them a break from therapy for a couple of weeks, let things reset, and then rechallenge them. I tend to just treat them until tolerability again, I don’t have a plan, “We’ll treat you for 6 weeks, give you a 2 week break” sort of thing. I treat to tolerability, give them a break; once they’re feeling better, I restart treatment.

Instead of a treatment holiday, do you ever consider every-other-day dosing or dose reduction for vismodegib?

Well, there’s no dose reduction, it’s 150 mg daily, [and the 150-mg capsule is] the only strength [vismodegib] comes in.⁴ Some people talk about every-other-day dosing.^4,6 The problem with that, in my mind, is if you look at the phase 1 study of vismodegib, this drug is highly protein-bound.4 You must saturate the protein to have adequate concentration of drug. So if you’re doing a schedule where you’re not saturating that, there is concern that you’re not getting therapeutic drug levels. So, that’s why I haven’t gone to these alternative dosing schedules. I do the drug holidays.

Considering the side effects, what’s the longest that you’ve had a patient on vismodegib?

I’ve had patients on [the] drug for over a year. It gets tough, but there is a spectrum [to patients’ experiences with the] side effects, and some are on the better end of that spectrum and can maintain it for longer periods of time. But some patients can tolerate it for years, [though that is] the exception rather than the rule.

Do you ever switch from one to the other to see if they might tolerate a different HHI better?

I haven’t really gone to switching agents for tolerability issues. I don’t know that there’s enough difference that there would really be a major impact on how patients would tolerate it.

What is your advice for counseling patients on managing the AEs with vismodegib?

It’s important to counsel the patients that these AEs are going to come and [to do] anything that they can find that helps. So if somebody struggles with muscle cramps, they [should] make lifestyle changes.¹² For example, they don’t stretch first thing in the morning, which we all want to do when we get out of bed, which can then trigger muscle cramping. They lose their taste, they’re not eating, they’re starting to lose weight, [then counseling them on] trying to increase their calories in terms of small volumes of food, just [to] try to keep the weight on as best they can [can be helpful]. And then, the [hair loss] issue is really a cosmetic thing.

You mentioned that most of the toxicities with vismodegib are low grade, yet tolerability still seems to be an issue. Can you expand on that?

The data show that most of the toxicities are grades 1 and 2.⁴ If you look at all grades [that occurred in 10% or more of patients there was]: 30% nausea, 40% fatigue, 45% weight loss, 72% muscle spasms, but only 3.6% of the muscle spasms are grade 3. About 7% of the weight loss is grade 3. Change of taste or loss of taste [occurred] in 66% of the patients, but no grade 3 [occurrences]. So, they’re all low-grade toxicities. Some may say, “Oh, it’s a well-tolerated therapy.” And yes, if you look at just CTCAE [common terminology criteria for adverse events] grading, it’s mild to moderate.¹³ But, [if] you try to live with loss of taste for months on end, it gets to be a major quality-of-life issue. So toxicities are low grade, but they’re persistent.

It’s different than BRAF/MEK agents, where those toxicities are top-heavy. If you can get those patients through the early months of targeted therapy with BRAF/MEK for metastatic melanoma, they often then start to tolerate the drug much better. There is a tolerance that develops. With HHI, that tolerance really doesn’t develop.

What are the data for medications to mitigate AEs of HHI such as muscle cramping?

[There are] some data, more anecdotal than anything, that calcium channel blockers may mitigate some of the muscle cramps, although giving elderly patients blood pressure medicine like that gets to be a separate issue.^11,12,14 There’s case reports of looking at L-carnitine as an aid for muscle cramping.¹⁴ Amlodipine [can be used], but again, with patients like this patient, who is 88 years old, you’ve got to be careful with blood pressure. ^11,12,14 So, there are not a whole lot of good [data for medications or supplements to address] these toxicities.

What do you think of these responses to the poll?

One vote was hold vismodegib and I think that’s very reasonable, although the patient’s saying he doesn’t want to reinitiate; that’s another thing. But the response that this patient had was impressive. So I think that would be very reasonable, just to see how he does. But this case aside, if patients are really intolerant to these drugs, and there’s additional disease, and they need response, then cemiplimab [Libtayo] would be the next drug of choice.

Given that attempts to mitigate this patient’s adverse effects are not working, what would your next step in treatment be?

If he doesn’t want to continue with the HHI, then [the next step is] observation or cemiplimab.¹⁰ Now, if it looked like [the patient] had a complete response, I don’t think it would be unreasonable to do some scouting biopsies to see if there’s residual BCC there. [We could] watch and see what happens, in terms of that tumor. You could do a drug holiday, see how that is; if it gets better, rechallenge him with the HHI and watch him. Or if he clearly has disease or [he is] progressing, [then cemiplimab, an antibody to PD-1, would be the next drug of choice]. It is now approved as a second-line therapy in patients who are intolerant to HHI.^10,15,16

What data support the efficacy of cemiplimab for a patient like this?

[Cemiplimab was studied in locally advanced BCC after HHI therapy (NCT03132636) in an open-label, multicenter, single-arm, phase 2 trial.^17,18] It was presented at ESMO [European Society for Medical Oncology Annual Congress], and then recently published in Lancet Oncology. [Those data] led to the approval of cemiplimab as second line for patients with locally advanced and metastatic BCC.^15,16 [It was a 2] cohort study [of patients who had disease progression while receiving HHI therapy or who were intolerant to HHIs, no better than stable disease after 9 months of HHI therapy, measurable disease, and good performance status]: group 1 was [patients with] metastatic BCC, and group 2 was [patients with] locally advanced [BCC].^17,18 [Both cohorts] were treated with cemiplimab 350 mg [intravenously] every 3 weeks [for up to 93 weeks or until progression or unacceptable toxicity.] The primary end point was ORR by independent central review.

In the locally advanced cohort [there were] 84 patients, median age of 70 years, predominantly male [56%], and they had good performance status, ECOG grade 0 or 1.^17,18 The primary site of tumor was predominantly the head and neck [89%]. The reason for discontinuation of HHI therapy [was as follows]: 71% were listed as having disease progression and 38% were listed as intolerant. So there could be multiple reasons why they came off the HHI. Only about 8% had no better than stable disease after 9 months.

[There was a] 31% ORR, with a 6% complete response rate.^17,18 Partial response [was observed in] 25% [of patients], 49% patients had stable disease, and only 11% of patients had progressive disease as the best response. Very encouragingly, like other immunotherapies, the median duration of response was not reached. At 6 months, 91% of the patients maintained response; at 12 months, 85% of the patients maintained response. And, importantly, baseline PD-L1 expression was not associated with efficacy.

At the time of first assessment [at 56 days], only a few patients had a response.^17,18 As you get to the time of second assessment [at 182 days], more patients who are responders started to show the response. But there are some patients who didn’t respond until month 8. Unlike cutaneous squamous cell carcinoma, where responses can be very quick with [antibodies to PD-1], with BCC the responses tend to be delayed, probably because there’s a different immunologic infiltration and response to immunotherapy. So you really do have to stick with these patients. Treat them, get [the] first assessment; [if] they’re not responding but they’re tolerating it, keep going, even after that second assessment, because you clearly can see late responders. I’m interested to see, as we move forward in terms of follow-up with this study, [if] we’ll start to see more of patients who are late responders to cemiplimab. We’ve seen that in cutaneous squamous cell carcinoma. With longer follow-up, that response rate is improving, and I’m interested to see if BCC is the same way.

What are the safety concerns with cemiplimab?

[Cemiplimab is] a PD-1 antibody, and the toxicity profile is really not much different than any other PD-1.¹⁶ There really were no safety signals that were unexpected. [The most common AEs were musculoskeletal pain, fatigue, rash, and diarrhea.] [There were] some grade 3 toxicities, including colitis and adrenal insufficiency, just as you see with other PD-1 agents. Most toxicities [were] low grade; a few grade 3 and 4 toxicities [were reported, primarily lab abnormalities such as lymphopenia, hyponatremia, hypophosphatemia, increased aspartate aminotransferase, anemia, and hyperkalemia.]

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