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Immunotherapy in NMSCs

CE / CME

Immunotherapy Advances in the Management of Nonmelanoma Skin Cancers

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: May 09, 2023

Expiration: May 08, 2024

CME/CE Information

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Basal Cell Carcinoma

Zeynep Eroglu, MD:
BCC is the most common skin cancer, and the annual incidence is rising.1,2 Most BCC cases are localized to the skin and can be cured with surgical excision, either by a dermatologist or a surgeon via the use of the Mohs micrographic surgery or a wide excision. The rate of metastatic BCC (mBCC) is very low with a rate of <0.5% based on most studies. However, patients with BCC and tumors ≥2 cm have a higher risk of metastasis.

There are several risk factors associated with BCC. UV radiation exposure from the sun is critical in the development of BCCs. Also, patients who are chronically immunosuppressed from medications or other cancers are at a higher risk of developing BCC and in particular advanced BCC (aBCC).

Patients with aBCC are the rare subset of patients for whom surgery or radiation are no longer options. They may have had those treatments before and their BCC has come back, or they have unresectable metastatic disease.

Hedgehog Pathway Inhibitors in Advanced Basal Cell Carcinoma

Zeynep Eroglu, MD:
The first-line treatment for aBCC remains HHIs such as vismodegib or sonidegib. This table shows some of the trial data of HHIs in aBCC.3-6 The overall response rates (ORRs) with these drugs range from 50% to 70% in laBCC and are a little lower in mBCC. The median duration of response (DoR) usually ranges up to a couple of years and median progression-free survival (PFS) can be 1-2 years with the use of HHIs in BCC.

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ERIVANCE BCC: Toxicity With Vismodegib

Zeynep Eroglu, MD:
HHIs can be difficult to tolerate for many patients. These safety data are from the phase II ERIVANCE trial of vismodegib in laBCC and mBCC.3 In this trial, nearly 60% of patients experienced grade 3 toxicities. Common adverse events (AEs) with vismodegib are muscle cramps or spasms that can be quite debilitating for some patients. Patients also may experience a lack of taste or a change in taste, where food tastes very metallic or salty. This can be a significant issue that leads to weight loss. Not surprisingly, prolonged use of HHIs can become difficult to tolerate for quite a few patients.

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Phase II Trial of Anti–PD-1 Antibody Cemiplimab in Advanced BCC

Zeynep Eroglu, MD:
Given their association with UV radiation exposure, BCCs have a high tumor mutational burden.7 As a result, there has been a lot of interest in the use of anti–PD-1 therapies for aBCC.

This phase II clinical trial led to the approval of the anti–PD-1 antibody, cemiplimab, for aBCC in 2021.8,9 The prerequisite for study entry was prior HHI treatment (vismodegib or sonidegib) with the resulting progression of disease or inability to tolerate HHI treatment or lack of an objective response after 9 months of treatment. In addition, patients had to be ineligible for any surgical or radiation approaches. Patients received cemiplimab at the fixed dose of 350 mg IV every 3 weeks.

There were 2 groups of patients in this trial. One group included patients with laBCC (n = 84), and the second group (n = 54) included patients with mBCC.

The primary endpoint was ORR. Of note, in some NMSC trials, including this one, response can be measured by not only the RECIST 1.1 criteria but also the modified WHO criteria. The latter allows for direct measurement of skin lesions that can be incorporated into combined response criteria.

Key secondary endpoints included DoR, PFS, overall survival (OS), complete response (CR), and safety.

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Response Rates With Cemiplimab in laBCC

Zeynep Eroglu, MD:
The ORR with cemiplimab in laBCC was 32% with 7% of patients having a CR. The median duration of follow-up for this cohort of 84 patients was 16 months, and the median time to response was approximately 4 months.

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Survival With Cemiplimab in laBCC

Zeynep Eroglu, MD:
The median PFS for patients with laBCC was 16.5 months, and the median OS had not yet been reached at the time of this analysis. The estimated 2-year OS rate was 80%.

There was also an exploratory biomarker analysis in this cohort to measure any association of response with markers such as PD-L1 expression and tumor mutation burden, and there were no clinically significant associations found. This suggests that cemiplimab can be used for patients with BCC regardless of PD-L1 expression or other related markers.

Based on these results, cemiplimab was approved for the treatment of patients with laBCC previously treated with an HHI or for whom HHI is not appropriate.10

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Survival With Cemiplimab in mBCC

Zeynep Eroglu, MD:
Now, let us look at the efficacy of cemiplimab in patients with mBCC. Not surprisingly, PFS and OS rates in the mBCC cohorts were lower.11 The median PFS was 8.3 months. The median OS was not reached, and the 12-month OS was 84%.

Based on these data, cemiplimab was also approved by the FDA for patients with mBCC previously treated with an HHI or for whom an HHI is not appropriate.10

In general, we use anti–PD-1 antibodies for patients with aBCC if they have had disease progression on HHI therapy or are not able to tolerate it. However, the response rate with anti–PD-1 therapy tends to be lower in BCC than what we see in cSCC and MCC. Even so, it is still great to have anti–PD-1 therapy as an option for those patients with BCC who are refractory to HHI therapy.

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Cemiplimab Safety in laBCC or mBCC

Zeynep Eroglu, MD:
There were no new safety signals noted in this trial. Most (99%) patients experienced a treatment-emergent AE (TEAE). TEAEs included some of the common AEs associated with immunotherapy. In the laBCC and mBCC groups, respectively, approximately 30% and 43% of patients experienced fatigue; 24% and 37% had diarrhea; 22% and 15% had pruritus; and 19% and 17% experienced arthralgia. Approximately 10% of patients discontinued the drug because of an AE. Grade 3 TEAEs occurred in 52% of patients, but there were no deaths. Overall, it was a relatively well-tolerated drug.

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Select Studies With PD-1 Inhibitors Alone or in Combination With Other Therapeutics in Advanced BCC

Zeynep Eroglu, MD:
There are ongoing studies in aBCC evaluating immunotherapy in combination with another immunotherapy or with HHIs. For example, there is a study looking at cemiplimab with pulsed dosing of the HHI sonidegib to see if there may be a benefit in combining HHIs and anti–PD-1 therapy.12 Another study is evaluating the combination of the anti–PD-1 antibody nivolumab and the anti–CTLA-4 antibody ipilimumab or the LAG-3 antibody relatlimab in aBCC.13 Preliminary data from this study were presented at ESMO 2022. Of the 6 patients receiving the nivolumab plus relatlimab combination, 1 had a partial response. Hopefully, we will see more data in the upcoming years about these combination approaches in BCC, for both locally advanced and metastatic disease.

BCC Key Takeaways

  • Cemiplimab is approved by the FDA for the treatment of patients with laBCC previously treated with an HHI or for whom HHI is not appropriate.
  • Ongoing trials in aBCC are evaluating the use of immunotherapy-based combinations, immunotherapies with oncolytic viruses, and in the neoadjuvant setting.

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A 73-year-old man was diagnosed with BCC on the right side of his nose and underwent Mohs surgery to remove the lesion. After 8 years, he presents with a lesion in the same area, and the workup reveals a 2.5-cm lesion with poorly defined borders. He is given vismodegib 150 mg/day for 33 months but discontinues treatment because of muscle spasms, loss of taste, and anorexia.

Which of the following would be the most appropriate next step for managing this patient’s BCC?

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