Oncology

Locally Advanced Basal Cell Carcinoma

Systemic Therapies for Locally Advanced Basal Cell Carcinoma

clinical topic updates by Nikhil Khushalani, MD

Overview

Systemic therapy plays a vital role in the treatment of patients with locally advanced basal cell carcinoma (laBCC), particularly when surgery or radiation is not feasible. HHIs and immunotherapy have expanded the systemic treatment landscape for laBCC, and work is being done to identify and test novel systemic therapies.

Expert Commentary

“. . . there are 2 HHIs with FDA approval for advanced laBCC: vismodegib and sonidegib. There is also the anti–PD-1 ICI cemiplimab, which is FDA approved for patients with laBCC and metastatic BCC who have previously been treated with an HHI or are not considered appropriate candidates for HHI therapy.”

— Nikhil Khushalani, MD

In cases of laBCC in which we feel that a systemic therapy may be appropriate, there are 2 major classes of drugs that we consider. The first is HHIs, and there are 2 HHIs with US Food and Drug Administration (FDA) approval for advanced laBCC: vismodegib and sonidegib. There is also the anti–PD-1 ICI cemiplimab, which is FDA approved for patients with laBCC and metastatic BCC who have previously been treated with an HHI or are not considered appropriate candidates for HHI therapy.

The rationale for using HHI therapy is that the most sporadic BCCs tend to have mutations in hedgehog signaling pathway genes, especially PTCH1 and SMO. In the absence of hedgehog ligands, the transmembrane receptor PTCH1 suppresses SMO, and the pathway is quiescent. If something disrupts this, either through ligand binding or the development of PTCH1 mutations, the results are the constitutive activation of downstream signaling, the activation of various transcription factors, and, potentially, the development of BCC. Vismodegib and sonidegib bind to and inhibit SMO to abrogate the constitutive activation of the pathway. The toxicity profiles of vismodegib and sonidegib are similar, and there is little difference in terms of their efficacy in laBCC. However, HHIs tend to work slowly, and approximately 50% of patients on these therapies develop refractory disease.

The rationale for using cemiplimab is that BCC tends to have a close etiologic association with UV light damage and has a high tumor mutational burden, which is associated with a favorable response to anti–PD-1 therapy in some cancers. With the efficacy of cemiplimab, people are asking whether other immunotherapeutic drugs can be used. The combination of the PD-1 inhibitor nivolumab and the LAG-3 inhibitor relatlimab is being investigated for the treatment of refractory BCC. Another investigational agent that is being explored in laBCC, silmitasertib, targets CK2, which is important in hedgehog signaling and DNA repair mechanisms. There is interest in understanding molecular pathways in BCC and how to overcome them.

References

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Schenk KM, Deutsch JS, Schollenberger MD, et al. 820P Nivolumab (NIVO) +/- relatlimab (RELA) or ipilimumab (IPI) for patients (pts) with advanced treatment-naïve or -refractory basal cell carcinoma (BCC). Ann Oncol. 2022;33(suppl 7):S922-S923. doi:10.1016/j.annonc.2022.07.946

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