Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study

Basal cell carcinoma (BCC), the most common human malignancy [ 1, 2], presents a significant public health burden [ 3]. Although BCC can be treated with surgery or radiation therapy in the majority of cases, disease may progress to become locally advanced (laBCC) or, rarely, metastatic (mBCC) [ 4]. It is estimated that up to one-third of giant BCCs occur in the setting of delay in diagnosis and treatment [ 5]. Such patients may no longer be responsive to conventional therapy [ 6– 8] and face limited options. The majority of BCC tumors, including laBCC and mBCC, harbor genetic alterations in the Hedgehog signaling pathway, leading to abnormal pathway activation and uncontrolled cellular proliferation [ 9, 10]. As the principal driver in BCC pathogenesis and progression, the Hedgehog pathway represents a key therapeutic target. Vismodegib, a first-in-class small molecule inhibitor of Hedgehog pathway signaling [ 11– 13], was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of adults with mBCC or with laBCC that has recurred after surgery or who are not candidates for surgery or radiation [ 14, 15]. Vismodegib is currently approved in more than 60 countries worldwide. More recently, a second Hedgehog pathway inhibitor (HPI) (sonidegib) has been approved for laBCC based on the results from the BOLT study [ 16].

Primary analysis of the pivotal phase II ERIVANCE BCC trial of vismodegib [ 17] met its primary end point, with an independent review facility (IRF)–assessed response rate of 30% in patients with mBCC and 43% in patients with laBCC and an investigator-assessed median duration of response (DOR) of 12.9 and 7.6 months, respectively. The primary analysis was conducted 9 months after completion of accrual. As vismodegib is the first HPI in wide clinical use, and because some patients with advanced BCC, including patients with Gorlin syndrome (also known as basal cell carcinoma nevus syndrome [BCCNS]), may require prolonged vismodegib treatment, it is particularly important to understand the safety and efficacy of long-term vismodegib therapy. Here, we report final data from ERIVANCE BCC, with 39 months of follow-up after the completion of accrual, that confirms and extends the long-term safety and durability of response associated with vismodegib and further evaluates efficacy across relevant patient subgroups and tumor histologic subtypes.

Patients with advanced BCC represent a population with significant unmet medical need, particularly those for whom standard treatments (surgery or radiation) are ineffective or would result in unacceptable disfigurement or morbidity from surgery. Vismodegib, an oral, selective HPI, is the first FDA- and EMA-approved HPI and the first drug to be approved for the treatment of advanced BCC. Long-term efficacy and safety of vismodegib are therefore of particular clinical interest.

The results of this study significantly expand upon previous analyses [ 17, 20] and support the efficacy and durability of response with long-term vismodegib therapy. Clinically relevant data include efficacy demonstrated by investigator-assessed ORR across a range of patient subgroups, not reported previously, including aggressive histologic subtypes (eg, infiltrative BCC). Importantly, efficacy did not appear to be substantially influenced by missed doses of vismodegib. The observation that effectiveness persists in the face of missed doses is important, as some patients do require treatment breaks during long-term treatment to manage AEs and avoid permanent discontinuation. Overall, median duration of treatment on vismodegib was 12.9 months, with some patients continuing on treatment with vismodegib for more than 3 years. Longer treatment duration allows patients to achieve higher total dosing. An exploratory analysis of the STEVIE study also demonstrated that increased treatment interruption was associated with increased median treatment duration and overall response rate [ 21]. This, along with other factors (such as slight baseline heterogeneity between patients) may, in turn, contribute to the slightly increased response rate observed in laBCC patients who missed up to 33% of doses compared to those who did not miss any doses. Estimated median DOR more than tripled in the laBCC cohort compared with the primary analysis, from 7.6 to 26.2 months, primarily because of prolonged responses over the longer-term follow-up. Interestingly, a number of responders experienced substantial treatment-free intervals after treatment discontinuation. The median OS of 33.4 months in the vismodegib-treated mBCC cohort is particularly significant when compared with the median OS of 24 months in a historical cohort of patients before the availability of vismodegib [ 22] and a median OS of 8 months in a review of 5 patient cases and 170 published patient cases [ 23].

The safety profile of vismodegib remained consistent with that reported in the primary analysis. The most common AEs were muscle spasm, dysgeusia, and alopecia, which appear to be class effects associated with on-target inhibition of the Hedgehog signaling pathway [ 24]. The incidence of these AEs generally increased with longer durations of exposure to vismodegib, with muscle spasms and alopecia occurring in most (>80%) patients who received vismodegib for ≥12 months. There were no additional occurrences of SCC since the primary analysis report, and the incidence of SCC did not differ according to duration of treatment exposure (≥12 months vs <12 months). The percentage of patients who discontinued treatment because of an AE was 21.2% ( n = 22). Muscle spasms were reported in 5 patients (4.8%) and weight decreased and dysgeusia were each reported in 2 patients (1.9%); all other AEs leading to discontinuation of study drug were reported in 1 patient each. AEs associated with vismodegib treatment are typically grade 1 to 2 in severity; however, the cumulative and chronic nature of these AEs may result in patient discontinuation. A comparable safety profile was observed when vismodegib was assessed in a setting representative of routine clinical practice (STEVIE) where, in an interim analysis, the most common AEs included muscle spasms (64%), alopecia (62%), dysgeusia (54%), and weight loss (33%), with most AEs being grade 1 or 2 in severity [ 25]. Strategies to manage AEs during long-term vismodegib treatment are essential in order to enable patients to stay on treatment and consequently receive its full benefit. While such management strategies are used in clinical practice (eg, calcium channel blockade or cyclobenzaprine to manage muscle spasms [ 26]), treatment interruption is a commonly used strategy that allows patients to remain on treatment, without appearing to substantially affect efficacy [ 21]. Based on the AE analysis per patient–years of vismodegib exposure, which indicates that the risk of a new AE is higher during the first year of treatment, such management strategies are particularly important during this period.

In conclusion, this long-term study of vismodegib involving 39 months of observation after the completion of accrual in the ERIVANCE BCC trial reinforces the clinical usefulness of vismodegib in patients with advanced BCC for whom treatment options are limited, and demonstrates the durability of response and long-term safety of vismodegib.