Systemic Targeted Treatments for Basal Cell Carcinoma

Adverse Effects of Systemic Treatments

The 2 approved SHH inhibitors—vismodegib and sonidegib—appear to have similar side-effect profiles, with the most common adverse effects being muscle spasms, dysgeusia, alopecia, nausea, vomiting, diarrhea, weight loss, and fatigue.^20,21,27 These side effects occur at high frequencies (>40%) for both SHH inhibitors and often lead to discontinuation of the medication.²¹ Rates of treatment discontinuation range from 15% to 50% on average.^12-14,18 Fortunately, the majority of these adverse effects do not appear to increase in severity or frequency with prolonged use of these medications.^14,16,28

Various conservative and pharmacologic measures can be implemented to help manage side effects. For muscle spasms, which are the most commonly reported adverse effect, supplementation with magnesium, transcutaneous electrical nerve stimulation, acupuncture, massages, stretching, and thermal compresses can potentially be beneficial.²⁹ Calcium channel blockers also may be effective, as one small prospective cohort study reported a reduction in the frequency of muscle cramps with amlodipine 10 mg daily.³⁰ For alopecia, which typically is reversible and caused by SHH inhibition of the normal hair cycle, minoxidil theoretically can help, as it reduces telogen arrest and extends the anagen growth phase.^31,32 Although usually mild and self-limiting, management of dysgeusia, weight loss, and gastrointestinal upset often can be managed with dietary changes, such as smaller, more frequent meals.^33,34 Finally, alternative dosing strategies and drug holidays have been employed to mitigate these side effects and increase drug tolerability.^35,36 These are discussed in the Alternative Dosing section.

Given the essential role of the SHH pathway in embryologic development, SHH inhibitors carry a black box warning of embryofetal teratogenicity and are contraindicated in females who are pregnant or breastfeeding. For females of reproductive potential, verification of pregnancy status should be performed prior to initiating treatment with an SHH inhibitor. These patients should be counseled on the use of contraception during treatment and for at least 24 months and 20 months after cessation of vismodegib and sonidegib, respectively.^27,37,38 Male patients, even after a vasectomy, should use barrier contraception during treatment and for at least 3 months and 8 months after the final dose of vismodegib and sonidegib, respectively.^37,38

Laboratory abnormalities commonly associated with SHH inhibitors include elevated hepatic enzymes, particularly with vismodegib, and elevated creatine kinase levels, particularly with sonidegib.^28,39 Other laboratory abnormalities that can occur include hypercholesterolemia, hypercreatininemia, hyperglycemia, and increased serum lipase levels.^19,28 Although these laboratory abnormalities usually are asymptomatic and self-limiting, regular monitoring should be performed.

There also is concern that SHH inhibitors may induce the development of cSCC. A case-control study of 55 cases and 125 control patients found an increased risk for cSCC in those previously treated with vismodegib, with a hazard ratio of 8.12.⁴⁰ However, a subsequent retrospective cohort study of 1675 patients with BCC failed to find any association with cSCC among those treated with vismodegib compared to those who received standard surgical therapy.⁴¹ Clinical data for sonidegib are lacking, but the BOLT trial found that cSCC occurred in 3 patients receiving treatment with the SHH inhibitor.¹⁸ Thus, further studies are needed to more thoroughly assess this concern. Close monitoring for cSCC may be warranted in patients prescribed SHH inhibitors at this time.

Cemiplimab has demonstrated an acceptable safety profile and is generally well tolerated. In the phase 2 trial of cemiplimab for cSCC, approximately 5% of patients discontinued treatment because of adverse effects. The most commonly reported side effects of cemiplimab were diarrhea (27%), fatigue (24%), nausea (17%), constipation (15%), and rash (15%).²³ In the phase 2 trial for laBCC, grade 3 or 4 adverse events occurred in 48% of patients, with hypertension (5%) being the most common.²⁶ Although rare, immune-mediated adverse reactions also can occur, given the mechanism of action of ICIs. These side effects, ranging in severity from mild to fatal, include pneumonitis, colitis, hepatitis, nephritis, myocarditis, and hypophysitis. Therefore, close monitoring for these immune-mediated reactions is critical, but most can be managed with corticosteroids or treatment interruption if they occur.^42,43

No absolute contraindications exist for cemiplimab; however, extreme caution should be taken in immunosuppressed individuals, such as solid organ transplant recipients and those with chronic lymphocytic leukemia (CLL), as safety data are limited in these patients.^44,45 Although small retrospective studies have reported reasonable tolerability in solid organ transplant recipients treated with ICIs, an allograft rejection rate of 41% was found in a meta-analysis of 64 patients.^46-48 In CLL patients with keratinocyte carcinomas, ICIs have been safely used and have even demonstrated efficacy for CLL in some cases.^49-52