Use of Hedgehog Pathway Inhibitors in Combination Therapy for Basal Cell Carcinoma: A Review and Narrative Synthesis

Hedgehog pathway inhibitors (HHIs) target aberrant Hedgehog signaling as a treatment of basal cell carcinomas (BCCs) but are limited by poorly tolerated adverse events (AEs) and development of resistance. To address these challenges, combination regimens have been investigated to improve tumor clearance while mitigating toxicity.

To investigate the landscape and mechanisms behind combination therapies involving HHIs for locally advanced BCC and identify patient populations most likely to benefit from each combination regimen.

Comprehensive PubMed and ClinicalTrials.gov searches were conducted for BCC combination therapies involving HHIs. Literature was analyzed following PRISMA guidelines and reviewed independently by 2 reviewers, with a third resolving conflicts. Nine studies were included, involving either vismodegib or sonidegib with concomitant itraconazole, radiation therapy, photodynamic therapy (PDT), pembrolizumab, intratumoral immunotherapy, or surgical debulking. Outcomes from combination therapies were compared to respective monotherapy outcomes from the ERIVANCE and STEVIE trials for vismodegib and the BOLT trial for sonidegib.

Of studies reviewed, 89% demonstrated superior outcomes measured in objective response ratio (ORR) compared to monotherapy. The highest mean ORR of 100% was demonstrated in the combination therapies of sonidegib with radiation and vismodegib with PDT. The regimen with the worst efficacy was vismodegib with pembrolizumab, with an ORR of 29%, which was worse than the respective monotherapies. Additionally, 71% of combination studies revealed a smaller percentage of patients lost to AE when compared to the respective monotherapy trials. Most tolerable combinations included sonidegib with itraconazole, sonidegib with radiation, and vismodegib with intratumoral immunotherapy. Lastly, 75% of combination therapy studies reported a better tolerability profile when compared to monotherapy.

Limitations included the low number of studies in the literature on HHI combination therapies, small study population sizes, lack of heterogeneity of regimens, and study designs involving case reports and series.

Combination strategies for HHI therapy represent a promising avenue to optimize efficacy, improve tolerability, and expand therapeutic options for patients with BCC.