Emerging Data May Provide More Options for Systemic Treatment of Basal Cell Carcinoma, Says In

Gino K. In, MD, MPH

During a Targeted Oncology Case Based Peer Perspective event, Gino K. In, MD, MPH, assistant professor of Clinical Medicine, Oncology, assistant professor of Dermatology, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California in Los Angeles, CA, assessed the risk status of an 88-year-old patient with basal cell carcinoma and discussed treatment options.

Targeted Oncology™: How would you characterize this patient’s risk status?

IN: The NCCN [National Comprehensive Cancer Network] provides guidelines on assessing BCCs [that] are at high risk for recurrence or metastases. Some of these features are similar to what we see with CSCC [cutaneous squamous cell carcinoma]. There are both clinical and pathological risk factors. Tumors greater than 2 cm in diameter or slightly smaller ones on either the mass or high-risk areas would be considered high risk. Poorly defined borders, recurrent tumors, a history of immune suppression, and tumors in areas where they’ve had prior radiation, perineural invasion, and also some other pathological features could help you identify which of these patients will be at high risk.¹

Would you consider a Hedgehog pathway inhibitor for this patient specifically?

This 88-year-old patient with ulcerating BCC on the right side of the nose doesn’t qualify for surgery or radiation. We’ve had a few people say that they’ve had some positive experiences [with these agents]. Hedgehog pathway inhibitors are the only systemic therapy approved [for] BCC. This is a relevant pathway for this cancer type. They can be fairly effective and are probably the treatment that you would want to go with first, if you were going to truly go with something systemic.

How long would you treat him?

Some of these patients will tolerate these therapies well without much toxicity. However, some of them will develop a number of different adverse effects such as appetite [suppression], dysgeusia, changes in…taste, fatigue, and alopecia. It can be tricky, and I think it’s all about finding that right balance.

Do you think this was the correct choice of therapy?

There are 2 different Hedgehog pathway inhibitors that are currently approved. One is vismodegib, and the other one is sonidegib [Odomzo].

Vismodegib came out several years earlier than sonidegib, so there [are] more data for vismodegib. There are no studies, and there probably never will be, because of how pharmaceutical companies do things, to compare the 2 drugs. In my own practice, I’ve treated patients with both. I have seen some patients who tolerated one better than the other. In my opinion, in terms of efficacy, there’s not too much difference. Tolerability might be one reason you would consider one versus the other. Their toxicity profiles are similar, so don’t put too much emphasis on that.

There were data to look at vismodegib both in the locally advanced and metastatic settings, and it’s given with or without food. Sonidegib is the newer drug only studied in locally advanced disease in prospective trials. It had similar dosing and drug interactions [to vismodegib].

What data support the use of these therapies in patients with BCC?

Response rates are a bit higher in the locally advanced setting, at about 45% [with both agents].^2,3 [Responses to vismodegib are] a bit lower in the metastatic setting [30%],² which shouldn’t be too surprising. Remember, the majority of patients who present with advanced BCC requiring systemic therapy are probably going to have locally advanced disease more often than metastatic.

Some of these patients can have nice responses [with vismodegib], and it’s not uncommon to see complete responders [among] the locally advanced group. But with almost all these patients, you will see negative change in their tumor diameter. Even though not all these patients are responding, a lot of them do have disease control where the tumors are at least stable or shrinking to a certain extent. Few patients are just progressing directly through the treatment.

Can you discuss the adverse effects of Hedgehog pathway inhibitors?

There are significant toxicities that we do need to watch out for. I talked about dysgeusia and anorexia; both of those may warrant nutrition consults. Alopecia is common. I think that for some of my patients who are men, maybe they don’t care so much. But for our patients who are women, this is something that they do ask about and do have concerns about. Muscle spasms [are] also something that you should be aware of. Sometimes these patients will have elevated CK [creatinine kinase] levels and so they may require…amlodipine. Sometimes, I also will give patients either dose reductions or dose holidays, as well, to help offset that.

What options would you consider after a hedgehog inhibitor if the patient progresses with BCC?

Historically, there have been patients who have been treated with cytotoxic [chemotherapy], platinum, and anthracyclines. We’ll see small case series or case reports that show some efficacy. In my practice, we’ve treated a handful of patients with that approach.

One clue that may trigger you to consider a therapy rather than just a typical infiltrative or nodular BCC [is a] a histologic subtype that is basal squamous or anaplastic or carcinomatous. Some of those subtypes [that] are a bit more aggressive may be more likely to respond to some of these traditional cytotoxics, which are designed to kill fast-growing cells. That is one situation where you might think about something like that.

When it comes to the immune checkpoint inhibitors, it’s the early days in terms of those data being [available for BCC]. There are case reports in some patients that [show a] benefit, and there are a couple of small phase 2 studies looking at that.

Cemiplimab [Libtayo] has recently had data released to suggest that in patients whose [disease] failed on Hedgehog inhibitors, cemiplimab has a response rate of about 30%. That is something that’s going to be pursued in larger studies and is potentially something to keep your eye on. You’re not going to be able to get it on label unless maybe patients have mismatch repair–deficient [tumors] or high TMB [tumor mutational burden].

IL-2 has mostly been used as intralesional therapy or local therapy for BCC and not something I’d recommend if it weren’t metastatic. The same thing is true with TIL [tumor-infiltrating lymphocyte] infusions. There are phase 2 level data looking at itraconazole, which is a fungal agent, and that has shown some benefit as well.⁴

How has coronavirus disease 2019 (COVID-19) affected your practice?

We’re reducing unnecessary visits and minimizing exposures. It’s important to our patients. If anyone has not yet reviewed the data that [were] released at the ASCO [American Society of Clinical Oncology] Annual Meeting regarding COVID-19 [among] patients with cancer, I would encourage you to look at that. They delineated which patients are at highest risk for complications from COVID-19, both [among] the cohort of patients with lung cancer and also all patients with cancer. [Factors examined included] older age, male gender, multiple comorbidities, active cancer versus remission, and cancer that is progressing versus responding. Those were considered important risk factors.

The timing of FDA adjustments to labeling of pembrolizumab [Keytruda] to be dosed every 6 weeks is incredibly important for our health care system in general, let alone for our patients with cancer.⁵ I think that was a game changer. I’m trying to switch my patients over to 6-week dosing after I’ve seen that they’ve already had a good response. Patients who have low volume of disease and patients who are getting adjuvant pembrolizumab for melanoma—those might be patients for whom I just go directly to dosing [every 6 weeks].

My understanding is that the manufacturer [of cemiplimab will be] requesting a less frequent dosing interval. I wouldn’t be surprised if many checkpoint inhibitors start using less frequent dosing.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Basal cell skin cancer, version 1.2020. Accessed September 16, 2020. https://bit.ly/38HAZT4}

_{2. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171-2179. doi:10.1056/ NEJMoa1113713}

_{3. Migden MR, Guminski A, Gutzmer R, et al. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial. Lancet Oncol. 2015;16(6):716- 728. doi:10.1016/S1470-2045(15)70100-2}

_{4. Sohn GK, Kwon GP, Bailey-Healy I, et al. Topical itraconazole for the treatment of basal cell carcinoma in patients with basal cell nevus syndrome or high-frequency basal cell carcinomas: a phase 2, open-label, placebo-controlled trial. JAMA Dermatol. 2019;155(9):1078-1080. doi:10.1001/jamadermatol.2019.1541}

_{5. FDA approves new dosing regimen for pembrolizumab. FDA. April 28, 2020. Accessed September 16, 2020. https://bit.ly/3kBx2o3}