Systemic Targeted Treatments for Basal Cell Carcinoma
The sonic hedgehog (SHH) inhibitors vismodegib and sonidegib are the only 2 first-line systemic medications approved for the treatment of locally aggressive basal cell carcinoma (BCC). Vismodegib is the only SHH inhibitor approved for metastatic BCC. Cemiplimab, an immune checkpoint inhibitor (ICI), is now an approved second-line therapy for locally advanced or metastatic BCC. Efficacy and adverse effect profiles of vismodegib and sonidegib appear comparable, although head-to-head clinical trials have not been conducted. Despite the remarkable efficacy demonstrated by the 2 SHH inhibitors, adverse effects are common and often lead to treatment discontinuation. Alternative dosing schedules may help to manage these side effects, with recent approval of dose interruptions of up to 8 weeks. Given the high rate of recurrence and emerging concern regarding drug resistance, maintenance dosing regimens and potential synergism with other treatment modalities, such as radiotherapy or antifungal therapy, should be further explored. The use of SHH inhibitors in the neoadjuvant setting also is warranted, as it may allow for surgical management of previously inoperable cases of BCC.
Practice Points
- The sonic hedgehog (SHH) inhibitors vismodegib and sonidegib currently are the only 2 oral medications approved by the US Food and Drug Administration for the first-line treatment of locally advanced basal cell carcinoma (BCC). Vismodegib also is approved for metastatic BCC.
- Cemiplimab, a programmed cell death protein 1 inhibitor, is now an approved treatment for patients with advanced BCC refractory or intolerant to SHH inhibitor therapy.
- Adverse effects of SHH inhibitors, most commonly muscle spasms, often lead to treatment discontinuation, but intermittent dosing regimens can be used to increase tolerability and adherence.
- Combining SHH inhibitors with radiotherapy or antifungal therapy as well as maintenance dosing strategies may help reduce the risk of recurrence.
- Neoadjuvant administration of a SHH inhibitor may enable surgical excision of previously inoperable cases through tumor shrinkage.
Drug Resistance
Treatment resistance to SHH inhibitors, though uncommon, is a growing concern. Acquired mutations in the SMO binding site or downstream mediators of the SHH pathway have been shown to confer resistance to vismodegib and sonidegib.72,81-83 In addition, it appears that there may be shared resistance among the drugs in this class. One study assessing the efficacy of sonidegib in 9 patients with laBCC resistant to vismodegib found that these patients also did not respond to sonidegib.84 Interestingly, 1 case report documented tumor regression of an intracranial BCC in a patient treated with sonidegib and itraconazole after failure with vismodegib.85 An in vitro study also found that itraconazole maintained SHH inhibitory activity for all drug-resistant SMO mutations that have been reported.72 Therefore, itraconazole monotherapy or combination therapy with a canonical SHH inhibitor may be considered for patients with recalcitrant BCC and warrants further investigation.
Taladegib is a newly developed SMO inhibitor that may serve as another promising alternative for patients who develop resistance to vismodegib or sonidegib. A phase 1 trial of taladegib for advanced BCC found an ORR of 69% (11/16) in the SHH inhibitor–naïve group and an ORR of 36% (11/32) in the group previously treated with a SHH inhibitor.86 Additionally, the safety profile and frequency of adverse effects appear to be similar to those associated with vismodegib and sonidegib.86,87 Unfortunately, no clinical trials evaluating taladegib for BCC are ongoing or in development at this time.
Recurrence
There appears to be a relatively high rate of recurrence for BCC patients who achieve a CR to SHH inhibitors. In a retrospective study of 116 laBCC patients who experienced a CR after vismodegib therapy, 54 patients (47%) relapsed at 36 months. Among the 54 patients that relapsed, 27 were re-treated with vismodegib, which resulted in an ORR of 85% (23/27), a CR rate of 37% (10/27), and a PR rate of 48% (13/27).88 Another retrospective study of 35 laBCC patients who relapsed after vismodegib treatment reported a 31% (11/35) clinical recurrence rate at 6-month follow-up.89 An observational retrospective study also assessed the efficacy of SHH inhibitor maintenance therapy for advanced BCC patients who achieved a CR.90 In the study, 27 (64%) patients received a maintenance dose of 150 mg vismodegib once per week for 1 year, while 15 (36%) patients decided not to take a maintenance dose following CR of their BCC. All patients who took the maintenance therapy did not experience clinical recurrence at 1-year follow-up, whereas 26% of patients not on the maintenance dose relapsed.90 Consequently, these results indicate that BCC recurrence is frequent after SHH inhibitor therapy and highlights the importance of close surveillance after CR is attained. Nevertheless, most patients still respond to treatment with SHH inhibitors after relapsing, and intermittent maintenance doses may be an effective means to reduce risk of recurrence.
Conclusion
Vismodegib and sonidegib are SHH inhibitors approved for the treatment of laBCC and mBCC. Cemiplimab is now also approved for patients who do not respond to SHH inhibitors or for whom SHH inhibitors are not tolerable. Although these systemic targeted therapies can lead to notable tumor shrinkage and even complete regression in some patients, recurrence is common, and adverse effects may limit their use. Drug resistance is an emerging issue that requires additional examination. Further clinical studies are needed to determine which patients are likely to respond to these targeted treatments.
Various intermittent and maintenance drug regimens should be evaluated for their potential to mitigate adverse effects and reduce risk of recurrence, respectively. The synergistic effects of these medications with other therapies as well as their neoadjuvant and adjuvant roles should be further investigated. For example, administration of an SHH inhibitor prior to surgical excision of a BCC may allow for a smaller surgical defect size, thereby improving cosmetic and functional outcomes. Moreover, these systemic targeted medications may allow for previously inoperable tumors to become amenable to surgical treatment.
Although SHH inhibitors and PD-1 inhibitors represent a major advancement in the field of oncodermatology, real-world efficacy and safety data in the upcoming years will be important for elucidating their true benefit for patients with BCC.
