Atlas Examines Tolerability of Hedgehog Pathway Inhibitors and Transition to IO in mBCC

Jennifer L. Atlas, MD

Hematologist/Oncologist

Atrium Health Levine Cancer Institute

Charlotte, NC

Peers & Perspectives in Oncology: What is the indication for cemiplimab-rwlc in patients with BCC?

Atlas: This is the labeling for cemiplimab in basal cell carcinoma¹: for locally advanced BCC previously treated with a hedgehog pathway inhibitor [HHI] or for whom HHI is not appropriate , or metastatic BCC [mBCC] previously treated with HHI, or for whom an HHI is not appropriate. For metastatic BCC, the indication is approved under accelerated approval based on tumor response rates and durability of response that were noted in a trial [Study 1620; NCT03132636].

Do medical oncologists often initiate treatment or continue treatment initiated by dermatology?

[Whether] medical oncologists initiate treatment or continue treatment that’s been initiated by dermatology…or these patients are being sent to you because they’re having toxicity…is an interesting regional question, because depending on where you’re practicing in the country, I think in the Southeast and over in the Texas area, our dermatologists feel very comfortable initiating HHI, but you will find that if you have the same conversation in other parts of the country, that’s very different. When you have a patient referred by dermatology…typically the reason for the referral is usually because of progression.

What patient-specific factors lead you to consider patients inappropriate for HHI?

I don’t think [there are] that many people who are ineligible, from a medical oncologist standpoint. Some patients tolerate it, and [others] don’t. I think if someone has cachexia or issues like that, where weight loss is going to be a problem, or they already are having peripheral vascular disease, and a lot of pain in their legs already, maybe that’s someone who might not do well with the muscle spasms or cramps. I’ve had some female patients who outright refuse for alopecia to be on the table, and that has been a reason why we have not given an HHI. Those are some examples I can think of in my clinical practice.

How long do patients typically continue HHI, and when do you discontinue?

Looking through some of the data for hedgehog pathway inhibitors, vismodegib [Erivedge] and sonidegib [Odomzo]… for patients with locally advanced BCC, I tell my patients that [over] two-thirds of them are going to have some response, and it’s pretty quick.^2,3 I tell most patients, give me 8 to 12 weeks; if we’re not having a response, this is not the drug for you, and we shouldn’t treat you to [the point of intolerable] toxicity. The response rates go down when we’re looking at regional nodal involvement or metastatic disease [36.9% for vismodegib, 46.1% for sonidegib].

[In terms of] adverse events [AEs], there are gastrointestinal [GI] AEs reported: nausea, vomiting, diarrhea, and constipation [Table 1⁴]. We’re pretty good at treating that in medical oncology in our other disease subsets, so I feel confident we can manage those. The ones that I find to be the most prohibitive are sometimes the fatigue, [particularly in] older patients, the taste changes, and the weight loss; these are the things that, over time, can become difficult. The muscle spasms and arthralgias are one of the most common reasons that patients ultimately come off these drugs.

How was cemiplimab investigated in this population?

[The phase 2] Study 1620 supported the use of immunotherapy [IO] in advanced BCC. They separated these patients into 2 groups. Group 1 had adult patients with metastatic [nodal or distant metastasis], and group 2 had patients with locally advanced BCC. Initially, they went on 350 mg of cemiplimab every 3 weeks with a flat dosing with tumor assessments initially every 9 weeks, then spaced out further. The primary end point was overall response rate [ORR] by independent central review [ICR], and there were key secondary end points looked at like duration of response, progression-free survival [PFS], overall survival [OS], and safety and tolerability.

The reason for discontinuing hedgehog inhibitor prior to coming on was progression of disease for 71% of the patients.⁵ So these were people who had progression, and there was overlap because 38% of those patients were intolerant of HHIs, so some of those patients had both: they were progressing and having intolerance. As far as key inclusion criteria, I always explain this in depth to patients before I talk with them about HHIs vs IO, because there’s such a craze for IO right now. We have a lot of patients sent to us who maybe aren’t the right candidates to go on IO without trying an HHI first.

These were patients who had a diagnosis of invasive BCC. They either had to have prior progression or intolerance to an HHI, or no better than stable disease after 9 months of [HHI] therapy— which is hard for a lot of patients to stay on to begin with—at least 1 measurable baseline lesion and ECOG performance status of 0 to 1. Exclusion criteria were very similar to many of our other IO studies: patients with ongoing autoimmune diseases requiring immune suppression, prior PD-1 or PD-L1 therapy, or concurrent malignancy other than basal cell carcinoma or another nonmelanoma skin cancer.

What were the outcomes of this trial?

Looking at the response rates by ICR, [ORR was 22%] and the ORR was 26% for the investigator assessment.6 Circling in on the complete responses and partial responses, I will say in my clinical practice, I have seen most of these patients on IO have either partial responses or stable disease. The disease control rate is [over] 30%. I always point out time to response to patients and providers. We see quick responses in cutaneous squamous cell carcinomas, but don’t give up on the drug quite yet [because] the responses take longer to happen for BCC, and that tends to average somewhere between 3 and 4 months. I will tell patients: Don’t give up if you’re tolerating it OK; we usually have to wait a little longer for these.

Looking at our advanced target lesion changes overall, there was a clinical benefit rate of approximately 80%, with many patients having either stable disease or partial responses. Median PFS was 10 months, and the 12-month OS rate is 83%.

Looking at our [treatment-emergent] AEs, similar to many of our other trials looking at IO [Table 2⁶], fatigue is a big issue. GI AEs are a bigger issue here with IO therapy, [especially] in older patients with diarrhea and constipation. One thing that I thought was interesting because this is not something we necessarily talk a lot about in IO, at least in other trials for cutaneous malignancies, was hypertension. The rate of grade 3 hypertension was 11%; that caught me when I was looking through this [vs] all the IO trials I look at in cutaneous malignancies. But outside of that it falls along lines with other trials that we see with IO toxicity.

CASE UPDATE

• At the time, he was started on vismodegib.
• After 2 months of therapy, he is experiencing painful joints and muscle spasms; he has lost 10 lb since treatment initiation .
• His muscle pain does not significantly improve with nutritional/ hydration counseling, physical therapy, or amlodipine.
• Additionally, he is experiencing dysgeusia.

Is holding HHI for 2 weeks usually enough to make those AEs go away?

I tend to see these linger longer than that, so in my clinical practice, I wouldn’t normally expect significant change in that time frame. But some strategies can be used; for alopecia we rely on our dermatology partners in rare situations. Most of my patients will not pursue treatment for that. There are agents [such as amlodipine and L-carnitine] to help with muscle spasms. There’s really not anything good to help with the [dysgeusia]. It’s a lot of aggressive support with nutritional consultations. I think setting expectations and counseling the patients ahead of time for this particular AE [is needed], and the taste changes and weight loss go hand in hand.

CASE UPDATE

• Vismodegib was held for 2 weeks.
• Symptoms returned after reinitiation.
• The patient has expressed reservations about continuing therapy.

This is a frequent reason for patients to get sent to me because I’m told they’re refractory or intolerant to HHI, and I’ll institute some of those things to try to help see whether it’s a possibility. How long toxicities persist after discontinuation depends on the toxicity. The muscle spasms and cramps usually get better pretty quickly. A lot of the other things take weeks to months to see an improvement, which can be hard in an older patient subset. Many of us work at larger cancer centers, so, thankfully, we have dietitians and big supportive teams that dermatology clinics don’t have, so sometimes their patients come off HHIs quicker.

REFERENCES:

1. Libtayo. Prescribing information. Regeneron; 2024. Accessed September 20, 2024. https://tinyurl.com/mrt2p653

2. Basset-Séguin N, Hauschild A, Kunstfeld R, et al. Vismodegib in patients with advanced basal cell carcinoma: primary analysis of STEVIE, an international, open-label trial. Eur J Cancer. 2017;86:334-348. doi:10.1016/j.ejca.2017.08.022

3. Villani A, Fabbrocini G, Costa C, Scalvenzi M. Sonidegib: safety and efficacy in treatment of advanced basal cell carcinoma. Dermatol Ther (Heidelb). 2020;10(3):401-412. doi:10.1007/s13555-020-00378-8

4. Erivedge. Prescribing information. Genentech Inc; 2023. Accessed September 20, 2024. https://tinyurl.com/3tcsbfx3

5. Stratigos AJ, Sekulic A, Peris K, et al. Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):848-857. doi:10.1016/S1470-2045(21)00126-1

6. Lewis KD, Peris K, Sekulic A, et al. Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors. Ann Oncol. 2024;35(2):221-228. doi:10.1016/j.annonc.2023.10.123