Increased Risk of Cutaneous Squamous Cell Carcinoma After Vismodegib Therapy for Basal Cell Carcinoma

Abstract

IMPORTANCE Smoothened inhibitors (SIs) are a new type of targeted therapy for advanced basal cell carcinoma (BCC), and their long-term effects, such as increased risk of subsequent malignancy, are still being explored. OBJECTIVE To evaluate the risk of developing a non-BCC malignancy after SI exposure in patients with BCC. DESIGN, SETTING, AND PARTICIPANTS A case-control study at Stanford Medical Center, an academic hospital. Participants were higher-risk patients with BCC diagnosed from January 1, 1998, to December 31, 2014. The dates of the analysis were January 1 to November 1, 2015. EXPOSURES The exposed participants (cases) comprised patients who had confirmed prior vismodegib treatment, and the nonexposed participants (controls) comprised patients who had never received any SI. Because vismodegib was the first approved SI, only patients exposed to this SI were included. MAIN OUTCOMES AND MEASURES Hazard ratio for non-BCC malignancies after vismodegib exposure, adjusting for covariates. RESULTS The study cohort comprised 180 participants. Their mean (SD) age at BCC diagnosis was 56 (16) years, and 68.9% (n = 124) were male. Fifty-five cases were compared with 125 controls, accounting for age, sex, prior radiation therapy or cisplatin treatment, Charlson Comorbidity Index, clinical follow-up time, immunosuppression, and basal cell nevus syndrome status. Patients exposed to vismodegib had a hazard ratio of 6.37 (95% CI, 3.39-11.96; P < .001), indicating increased risk of developing a non-BCC malignancy. Most non-BCC malignancies were cutaneous squamous cell carcinomas, with a hazard ratio of 8.12 (95% CI, 3.89-16.97; P < .001), accounting for age and basal cell nevus syndrome status. There was no significant increase in other cancers. CONCLUSIONS AND RELEVANCE Increased risk for cutaneous squamous cell carcinomas after vismodegib therapy highlights the importance of continued skin surveillance after initiation of this therapy.

Treatment of Advanced Basal Cell Carcinoma with Sonidegib: Perspective from the 30-Month Update of the BOLT Trial

“…The above phenomenon suggests that the patient's SCC may have evolved from a pre-existing BCC lesion through selective squamatization not suppressed by vismodegib. A single institution case-control study evaluating the risk of developing non-BCC malignancy after HPI exposure found a hazard ratio of 8.12 for the development of cutaneous squamous cell carcinoma in the vismodegib exposure group [40]. One shortcoming of the study was the variability of screening frequency for both the cases and controls.…”

“…Both treatment arms successfully met the primary end point of ORR as assessed by central review at the time of primary analysis (cutoff of 28 June 2013). An objective response was achieved by 20 of 55 patients (36%; 95% CI: 24-50) in the 200 mg treatment group and 39 of 116 patients (34%; 95% CI: [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] in the 800 mg treatment group as assessed by central review. No substantial difference in ORR could be found in different subgroups stratified by geographic location or histologic subtype.…”

A Practical Guide for the Follow-Up of Patients with Advanced Basal Cell Carcinoma During Treatment with Hedgehog Pathway Inhibitors

“…Given the above considerations, and the need of patients with BCC for a full‐body skin examination during follow‐up visits , the importance of a total skin examination is emphasized during HPI treatment, in order to screen for the development of new skin cancers including BCC and SCC (Table ).…”

Spotlight on vismodegib in the treatment of basal cell carcinoma: an evidence-based review of its place in therapy

“…Based on the results of a case–control study, in which an increased risk for SCC in patients treated with vismodegib was recorded, the authors recommended continued skin surveillance after the initiation of vismodegib 28. However, the latter study received harsh criticism concerning its methodology, and its results were strongly disputed 29,30.…”