The incidence of nonmelanoma skin cancer is on the rise in both men and women.1 The treatment of basal cell carcinoma (BCC) can be characterized into 4 major groups, namely surgical (e.g., standard excision, Mohs surgery), destructive (e.g., cryotherapy, lasers), topical (e.g., 5-fluorouracil, imiquimod), and systemic therapy. As to systemic therapy, it includes chemotherapy, retinoids, targeted therapy, or relatively new immunotherapy.¹

Before determining a treatment option, it is very important to define if BCC is at a high or low risk. Advanced BCC develops when a lesion cannot be treated by surgery or radiation, categorized as locally advanced (la) BCC, or when the tumor spreads to distal sites, it is called metastatic (m) BCC.¹ High recurrence risk advanced requiring tumor board recommendation for radiation therapy, hedgehog inhibitors (HHI), clinical study, or immune checkpoint inhibitor (ICI) therapy.¹ BCC indications for systemic therapies include mBCC, inoperable tumor, recurrent BCC after 2 or more surgeries, Gorlin-Goltz and other genetic syndromes, or if surgery in an operable tumor leads to unacceptable functional or aesthetic deformity, or if surgery is contraindicated.¹

The National Comprehensive Cancer Network (NCCN) guidelines 2022.2 recommend HHIs like vismodegib and sonidegib should be tried first, if systemic therapy route is chosen.¹ Vismodegib was found to be safe and efficacy in 2 well-known clinical trials.¹ Dr. Željko Mijušković from Military Medical Academy, Belgrade, Serbia, presented cases of 4 advanced BCC patients who were administered vismodegib and showed very good results within 6-10 months, with alopecia being the only adverse event (AE) in 1 patient.¹ He recommended HHI for mBCC, laBCC, but also in some syndromes (e.g., Gorlin, xeroderma pigmentosum), multiple BCC, and as neoadjuvant therapy.¹ However, Dr. Mijuškovi noticed some issues with the HHI use relating to primary resistance, acquired resistance, and squamous cell carcinoma (SCC), since a patient who had alopecia developed a recurrent BCC in the right eye.¹ Of SCC, he also presented a case of a patient who developed undifferentiated pleomorphic sarcoma on the back after treatment with HHI vismodegib, who can be a good candidate for immunotherapy.¹

According to the treatment algorithm, immune checkpoint inhibitor (ICI) therapy is recommended in patients with refractory or recurrent advanced BCC, despite the use of HHI.¹ Blocking immune checkpoints programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte associated protein 4 (CTLA-4) allows T-cell to kill tumor cells.¹ Skin BCC, melanoma and SCC have high tumor mutation burden, and hence are candidates for immunotherapy. Immunotherapy was first introduced in melanoma in 2014, followed by other cancers.¹ The NCCN guidelines recommend cemiplimab-rwlc, an anti-PD-1 antibody, for laBCC or mBCC patients in which an HHI was not effective or not appropriate.1 Cemiplimab was found to be safe and efficacious in mBCC (nodal and distant) and unresectable laBCC in clinical trials.¹ Progression-free survival (PFS) in advanced BCC was found to be 19.3 months, the estimated 12-month probability of survival was 92.3%, and the overall response rate (ORR) was 31%.¹ The objective ORR in mBCC patients was 21.4%, and the disease control rate was almost 68%.¹

Dr. Mijuškovi then presented data on the efficacy of pembrolizumab, which is also an anti-PD-1 antibody, with or without vismodegib for advanced BCC, showing that ORR of pembrolizumab alone was higher at 44% vs. pembrolizumab + vismodegib, which had an ORR of 29%.1

Lastly, when discussing the AEs of ICI therapy, a study showed that skin rash was the first manifestation of an AE, while another study showed that when analyzing survival with or without toxicity, patients who had skin toxicity had better overall survival (OS).¹ Dr. Mijuškovi mentioned a paper by Apalla Z. et al. on European recommendations for managing dermatological AEs associated with ICI use.1 He cautioned that cutaneous immune-related AEs are strongly associated with ICI therapy and patient survival.¹

Dr. Mijuškovi concluded by saying that “Immunotherapy impacts the prognosis of BCC”.1 He speculated that CTLA-4 and PD-1 combination therapy, or neoadjuvant or some other novel options could be introduced in the near future for laBCC and mBCC.¹ Future research may improve the understanding of the efficacy and appropriate indications of immunotherapy.¹