Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and affects more than 3 million individuals per year in the United States.1 Approximately 40% of patients diagnosed with BCC will develop another BCC within 5 years of the initial diagnosis.2 Most cases are successfully treated with surgical excision and occasionally topical therapy or radiotherapy. Despite the high cure rate with conventional treatments, BCC can recur and can cause substantial destruction of the surrounding tissue if left untreated.3-5 In some instances, BCC can even metastasize and lead to death.6 For patients who are poor candidates for surgical or topical treatment modalities because of locally advanced BCC (laBCC) or metastatic BCC (mBCC), systemic treatment may be indicated. Vismodegib, sonidegib, and cemiplimab are the only systemic medications approved by the US Food and Drug Administration (FDA) for the treatment of laBCC and/or mBCC. Vismodegib and sonidegib target the sonic hedgehog (SHH) signaling pathway that is abnormally activated in more than 90% of BCCs.7 Cemiplimab is an immune checkpoint inhibitor (ICI) that targets the programmed cell death protein 1 (PD-1) receptor.8 Herein, we review the clinical utility of these medications and their evolving roles in the treatment of BCC.
SHH Pathway Inhibitors
The SHH pathway is a key regulator of cell proliferation and differentiation during embryogenesis.7 During adulthood, SHH signaling decreases but still plays an important role in stem cell activation and in regulation of the hair follicle growth cycle.9,10 However, de novo mutations in the genes that comprise the SHH pathway can result in aberrant constitutive activation, leading to unrestricted cell proliferation. Genetic mutations resulting in activation of Smoothened (SMO), a G-protein–coupled receptor involved in the signal transduction and propagation of the SHH pathway, have been implicated in the pathogenesis of BCC. Inactivating mutations also are commonly observed in patched homolog 1, an upstream cell-surface protein that inhibits SMO.7 The mechanism by which vismodegib and sonidegib, 2 of the FDA-approved oral medications for the treatment of advanced BCC, block the SHH pathway is through the selective inhibition of SMO.7,11
Vismodegib first received FDA approval in 2012 for the treatment of laBCC and mBCC after initial results from the pivotal ERIVANCE phase 2 trial demonstrated an objective response rate (ORR) of 43% (27/63) and 30% (10/33) in patients with locally advanced and metastatic disease, respectively. In this single-arm study, all enrolled patients (63 with laBCC and 33 with mBCC) received 150 mg of oral vismodegib daily.12 Updated results at 39 months demonstrated improved ORRs of 60% (38/63) and 48% (16/33) for the laBCC and mBCC groups, respectively. A complete response (CR) and partial response (PR) were observed in 32% (n=20) and 29% (n=18) of patients with laBCC, respectively.13 These results have been confirmed in subsequent studies, including the large international open-label trial known as STEVIE, with ORRs of 68.5% for 1119 cases of laBCC and 37% for 96 cases of mBCC.14-17 The CR and PR rates were 33% and 35%, respectively, for the laBCC group. The CR and PR rates for the mBCC group were 5% and 32%, respectively.14
The FDA approval of sonidegib for laBCC—but not mBCC—occurred in 2015 after the pivotal BOLT randomized phase 2 trial demonstrated an initial ORR of 43% (18/42) for laBCC and 15% (2/13) for mBCC after administration of 200 mg of sonidegib daily.18 A final follow-up analysis at 42 months resulted in ORRs of 56% (37/66) and 8% (1/13) for the laBCC and mBCC groups, respectively.19 Additionally, improved efficacy was not observed in the 151 patients who were randomized to receive treatment with the higher 800-mg dose; however, they did experience a higher incidence of adverse events.18,19
Currently, the true clinical differences between vismodegib and sonidegib remain uncertain, as no head-to-head trials have been conducted. Moreover, direct comparison of the data from the ERIVANCE and BOLT trials is challenging owing to fundamental differences in methodologic design, including the criteria used to assess BCC severity. The ERIVANCE trial utilized the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while BOLT used the rigorous modified RECIST. However, an expert consensus study attempted to compare the 2 trials by modifying the outcomes from BOLT with the former RECIST criteria. The expert group found that the 2 SHH inhibitors had comparable efficacy and adverse event profiles.20 Nevertheless, a recent meta-analysis found that although ORRs for laBCC were similar between the 2 drugs, the CR rate for vismodegib was 31% compared with 3% for sonidegib. Additionally, for mBCC, they reported the ORR of vismodegib to be 2.7 times higher than that of sonidegib (39% vs 15%).21
Immune Checkpoint Inhibitors
Immune checkpoint inhibitors have successfully been utilized in the treatment of cutaneous squamous cell carcinoma (cSCC); however, their use for treating BCC has been limited until recently.22-25 In February 2021, cemiplimab became the first and only ICI approved for the treatment of laBCC and mBCC in patients who did not respond to or were intolerant to prior SHH inhibitor therapy.26 Cemiplimab—a human monoclonal antibody against the PD-1 receptor expressed on T cells—blocks its interaction with programmed cell death ligand 1 and programmed cell death ligand 2 present on tumor cells. The blockade of the PD-1 pathway releases the inhibition of the antitumor immune response and enables appropriate cytotoxic T-cell activity to occur.8
The FDA approval of cemiplimab for the treatment of advanced BCC was based on an open-label, multicenter, single-arm phase 2 trial (NCT03132636) evaluating 84 patients with laBCC refractory or intolerant to SHH inhibitor therapy.26 Patients received an intravenous infusion of cemiplimab 350 mg every 3 weeks for up to 93 weeks or until disease progression or unacceptable toxicity. An ORR of 31% (26/84) was observed with a CR and PR of 6% (5/84) and 25% (21/84), respectively. The median duration of follow-up was 15 months.26 Given the clinically meaningful results of this trial, investigating the efficacy of other PD-1 inhibitors, such as pembrolizumab and nivolumab, for treatment of advanced BCC may prove worthwhile.