Annika Belzer,Jolanta Pach,Ryland D. Mortlock,James Clune,Kelly Olino,Mario Sznol,Aarti Bhatia,Barbara Burtness,Sean Christensen,Jonathan S. Leventhal
Evaluating the medical management of locally advanced and metastatic basal cell carcinoma: A single institutional retrospective analysis investigating efficacy, safety, and tolerability
aBCC,advanced basal cell carcinoma,basal cell carcinoma,checkpoint inhibitor,cutaneous oncology,hedgehog pathway inhibitor,HPI,ICI,immunotherapy
Evaluating the medical management of locally advanced and metastatic basal cell carcinoma: A single institutional retrospective analysis investigating efficacy, safety, and tolerability

To the Editor: Basal cell carcinoma (BCC) is the most common malignancy globally. Surgery is the first-line treatment. Advanced basal cell carcinoma (aBCC) encompasses metastatic and locally advanced (including large, deep, or aggressive) disease. Metastatic and a subset of locally advanced disease carry a poor prognosis and are generally not amenable to surgery or radiation therapy. Systemic therapy for aBCC includes hedgehog pathway inhibitors (HPIs), with response rates of 60% but poor tolerability, and immune checkpoint inhibitors (ICIs) (40% response rates)., aBCC is uncommon and medical management varies because of the absence of a clear consensus. To investigate our institutional experience treating aBCC, after institutional review board approval we performed a retrospective review of the Yale Hospital electronic medical record (2012-2022). Patients with aBCC treated with vismodegib, sonidegib, nivolumab, ipilimumab, cemiplimab, and/or pembrolizumab were included. Patients with BCC nevus syndrome were excluded. Twenty-three patients (11 metastatic, 12 locally advanced cases) met inclusion criteria (Table I). Prior to systemic treatment, 5 received radiation therapy and 12 had surgery. Thirteen received HPIs (56.5%), 2 received ICIs (8.7%), and 8 received ICIs after HPIs (34.8%). Objective response was determined by oncologic documentation according to Response Evaluation Criteria in Solid Tumors criteria, including partial response and complete response. Within the ICI cohort, the objective response rate was 50.0% (20.0% partial response, 30.0% complete response). Objective responses were observed in 52.4% of the HPI cohort (47.6% partial response, 4.8% complete response) (Table II). Of those on systemic treatment alone, 3 of 9 (33.3%) responded to HPIs and 4 of 6 (66.7%) responded to ICIs. Only 23.8% on HPIs and 20.0% on ICIs achieved sustained response after 1 year. Response was not associated with baseline tumor bulk or prior radiation therapy or lymphadenectomy. Patients with metastatic disease were more likely to progress despite treatment (61.1% metastatic, 30.8% locally advanced). At recent follow-up (median time from diagnosis 36.8 months, range 7 to 100 months), disease-specific survival was 72.7% for patients with metastatic and 100% for locally advanced disease. Adverse events (AEs) frequently impacted therapy. Common AEs of HPIs were muscle cramps, dysgeusia, weight loss, and alopecia. Fatigue, diarrhea, and dermatologic toxicities were common with ICIs. Similarly to previous reports,, Grade 3 to 4 AEs resulted in treatment interruption in 38.1% and discontinuation in 33.3% of patients on HPIs (fatigue, muscle cramps, dysgeusia, anorexia), and interruption in 30.0% and discontinuation in 20.0% of patients on ICIs (fatigue, colitis, myocarditis, thyroiditis, adrenal insufficiency). Limitations of our study include its retrospective nature, data from a single institution, small sample size, and variable treatment latency. Nevertheless, we found that overall response rates were in line with previous reports and similar between patients with aBCC who received HPIs and ICIs. The discontinuation rate secondary to AEs of ICIs appeared slightly favorable compared to HPIs. Most patients treated with ICIs first received an HPI. Given that aBCC is rare, a national registry would facilitate further clinical investigation.

Dr Leventhal serves on the advisory boards of La Roche-Posay and Sanofi and Regeneron Pharmaceuticals. Dr Burtness served as a consultant for Astra Zeneca, Cue BioPharma, Macrogenics, Vaccinex, ALX Oncology, Arvinas, Nektar, Celgene, Merck, Merck KgA, and Debio Pharm. Dr Christensen has served as a consultant to Sanofi, Regeneron, and LEO pharmaceuticals.