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.
Alternative Dosing
The side effects of SHH inhibitors have led to alternative dosing strategies to prevent medication discontinuation and improve adherence. In patients with basal cell nevus syndrome, multimonth drug holidays have been shown to increase drug tolerability without compromising efficacy.35,36 Weekly intermittent dosing regimens of vismodegib ranging from 1 week on followed by 1 to 3 weeks off demonstrated efficacy in a retrospective study of 7 patients with advanced BCC.53 All 7 patients experienced improvement in their BCCs, with 3 patients experiencing CR. Importantly, treatment-related adverse effects were mild and well tolerated, with no patients terminating the medication.53 Two other retrospective case series of patients with advanced BCC treated with vismodegib reported similar findings for those placed on an intermittent dosing schedule ranging from once every other day to once per week.54,55
In the large phase 2 randomized trial known as MIKIE, 2 different intermittent dosing regimens of 150 mg vismodegib daily for patients with multiple BCCs were found to have good activity and tolerability.56 The first group (n=116) received vismodegib for 12 weeks, then 3 rounds of 8 weeks of placebo, followed by 12 weeks of vismodegib; there was a 63% reduction in clinically evident BCCs after 73 weeks. The second group (n=113) received the medication for 24 weeks, then 3 rounds of 8 weeks of placebo, followed by 8 weeks of vismodegib; there was a 54% reduction at the end of 73 weeks.56 Subsequent analyses found improvements in health-related quality-of-life outcomes that were similar for both groups.57
Consequently, alternative dosing schedules appear to be a viable option for patients at risk of discontinuing treatment because of adverse effects, and current data support the recently approved recommendations of dose interruptions of up to 8 weeks to manage adverse effects in patients with laBCC or mBCC.58 Nevertheless, further clinical studies are required to determine the optimal intermittent dosing regimen for patients treated with SHH inhibitors.
Neoadjuvant Administration
Recently, vismodegib has been studied as a neoadjuvant therapy for BCC with promising results. Several small retrospective studies and case reports have documented successful treatment of both operable and inoperable periocular laBCC, with preservation of the eye in all patients.59-61 An open-label trial of 15 patients with advanced BCC who received neoadjuvant vismodegib for 3 to 6 months prior to surgical excision reported a mean reduction of 35% in the final surgical defect size, with no recurrence at 22 months.62,63 The latest and largest study performed was a phase 2 open-label trial known as VISMONEO, where 44 of 55 laBCC patients (80%) receiving neoadjuvant vismodegib for a mean duration of 6 months (range, 4–10 months) achieved the primary end point of tumor surgical downstaging.64 Of the 44 patients who had tumor downstaging, 27 (61%) experienced histologically proven CRs. Additionally, a 66% reduction in the average target lesion size was reported in this group compared to29% in the 11 patients who did not have tumor downstaging (P=.0002).64 Thus, SHH inhibitors may hold an important neoadjuvant role in the treatment of BCC by decreasing surgical defect size and allowing for surgical management of previously inoperable cases.
Synergism With Radiation
Preliminary data suggest SHH inhibitors may help potentiate the effects of radiation therapy for the treatment of BCC. Currently, the evidence primarily is limited to case studies, with several reports describing complete remission in patients with advanced BCCs who were considered unsuitable candidates for surgery. In these cases, vismodegib was administered either prior to or concurrently with radiation treatment.65-69 An in vitro study also documented the radiation-sensitizing effects of vismodegib in a BCC cell line.70 Recently, a phase 2 trial (ClinicalTrials.gov identifier NCT01835626) evaluating the concurrent use of vismodegib and radiotherapy for patients with advanced BCC was completed, but data has yet to be published.
Synergism With and Benefit of Antifungal Therapy
The antifungal drug itraconazole is a potent inhibitor of the SHH pathway and may have an adjunctive role in the treatment of BCC. Similar to vismodegib and sonidegib, itraconazole acts as a direct antagonist of SMO. However, it is thought to bind to a distinct site on SMO.71,72 An open-label, exploratory phase 2 trial of 19 patients with BCC found that oral itraconazole 200 to 400 mg daily decreased tumor proliferative index by 45% (P=.04), as measured by Ki-67; SHH activity by 65% (P=.03), as measured by GLI1 messenger RNA; and mean tumor area by 24%.73 In a case series of 5 patients with mBCC refractory to conventional SHH inhibitor therapy, combined treatment with itraconazole and arsenic trioxide resulted in stable disease and a 75% reduction in SHH activity (P<.001).74 One case report documented tumor regression leading to stable disease for 15 months in a patient with laBCC treated with itraconazole monotherapy due to being unable to afford vismodegib or sonidegib. However, within 2 months of treatment discontinuation, the lesion progressed considerably.75 The efficacy of a topical formulation of itraconazole also has been tested in an open-label, placebo-controlled phase 2 trial, but no benefit was observed.76
Posaconazole is a second-generation antifungal agent that may serve as a potential alternative to itraconazole.77 Although clinical data are lacking, a basic science study found that posaconazole could inhibit the growth of SHH-dependent BCC in vivo (in mice).78 Furthermore, posaconazole has demonstrated a better safety profile with fewer and more mild side effects than itraconazole and does not require dose adjustment for those with hepatic or renal failure.79,80 Thus, posaconazole may be a safer alternative to itraconazole for the treatment of BCC. Further clinical studies are needed to elucidate the potential synergistic effects of these antifungal agents with the 2 currently approved SHH inhibitors for the treatment of advanced BCC.
