Twelve-year continuous therapy with vismodegib for advanced basal cell carcinoma: Tolerability and partial reversibility of adverse events

Introduction

Vismodegib was the first hedgehog (Hh) pathway inhibitor approved by the Food and Drug Administration for treatment of advanced basal cell carcinoma (BCC) in 2012.¹ The treatment course is to be continued indefinitely or until treatment failure, making the management of long-term side effects crucial.² Due to adverse events, most patients require repeated “drug holiday” interruptions and are rarely able to continue therapy beyond 1 to 2 years.^1,3 While it is not clear how long the duration of treatment is required, the shortest case of treatment with histologic cure is 2 weeks.⁴ We successfully treated a patient for more than 10 years with no treatment interruption, which was well tolerated and for which several adverse events appear to be reversible. This extends our understanding of the therapeutic role of this medication.

Case report

A 35-year-old woman with Gorlin syndrome, having previously been affected by over 50 BCCs, presented in 2011 with a locally advanced BCC on the right neck after 2 attempts at excision by head and neck surgeons, including a radical neck dissection and nerve graft placement to reanimate her face, and preceded by radiation for Hodgkin's lymphoma during her adolescence (Fig 1, A and B). Due to the location of the overlying sclerotic skin of the carotid artery and risk of exsanguination, the head and neck surgical team of the regional academic medical center determined that she was not an appropriate candidate for surgery.

Fig 1.

Long-term clinical improvement with vismodegib therapy. A, Patient presented at baseline with multiple BCCs and (B) locally advanced basal cell carcinoma on the right neck. C and D, Following 1 year of continuous therapy, clinical resolution of nearly all BCCs was depicted. BCC, Basal cell carcinoma.

She was started on vismodegib 350 mg daily via the expanded access program prior to the medication becoming Food and Drug Administration-approved. Due to long-term clinical improvement and the patient’s refusal to stop the medication, she remained on vismodegib without a drug holiday for 12 years, with clinical improvement evident (Fig 1, C and D). Her long-term side effects on therapy included amenorrhea, which we previously identified as a blockade at the level of the follicle-stimulating hormone receptor, and also alopecia universalis (Fig 2, A). In addition, she reported a consistent weight decrease. In 2023, she developed a new BCC on the posterior neck while on vismodegib, one of the few tumors in more than a decade.

Fig 2.

Reversal of alopecia upon discontinuation. A, Baseline alopecia universalis at 12 years of continuous therapy. B, Six months after discontinuation, significant hair growth can be appreciated.

The patient entered a clinical trial of intralesional medication (ClinicalTrials.gov ID NCT03889912), which required a washout period from vismodegib. Around 2 months later, her menstrual cycle resumed, as confirmed by a gynecology consultation. She reported diffuse hair regrowth beginning on her scalp and then her eyebrows during this time period as well (Fig 2, B). She resumed vismodegib 6 months after initiating the clinical trial with cessation of menses and return of alopecia.

Discussion

The most frequent adverse events reported with vismodegib therapy include alopecia, muscle spasms, weight loss, and dysgeusia.^5,6 The less common side effect of amenorrhea was reported in 3 of 10 women of reproductive age.⁴ According to previous studies, patients will experience a median number of four adverse effects while on the medication long-term, with 42% of effects resolving after cessation.⁶ With the longevity that is typically associated with vismodegib therapy, physicians must balance between effectiveness, quality of life, adverse events, and adherence. Management strategies have been proposed to continue therapy, such as on-off treatment schedules and dose reductions, which have led to reduced toxicity while still maintaining efficacy in multiple studies.^7,8

Our patient experienced amenorrhea throughout her 12 years of therapy and was managed by gynecology consultation. Our patient demonstrated for the first time that this adverse event can be reversible. However, it is not clear whether other menopause-associated alterations would reverse with permanent discontinuation of vismodegib.

In addition to its role in multiple endocrine pathways, Hh signaling also plays a role in hair follicle development and follicle bulge stem cell maintenance. Our patient had begun to show hair regrowth upon stopping vismodegib therapy, suggesting another adverse effect that is reversible upon cessation of the drug. In addition, she reported some weight gain. Significantly, she did not have the side effects of dysgeusia or ageusia, suggesting that the weight changes might be unrelated to taste changes. It is evident that the Hh pathway is fundamental in the development of multiple processes, and its inhibition can cause a myriad of adverse effects in patients taking Hh inhibitors. The second Food and Drug Administration-approved drug for advanced BCC, sonidegib, is more lipophilic.⁹ While it shares a similar side effect profile, it is possible that, due to different pharmacodynamics, the long-term use might be tolerated differently.

We successfully treated a patient with a 12-year uninterrupted course with clinical improvement accompanied by manageable side effects. As it has been suggested that adverse effects most commonly occur within the first 6 months of treatment with a decreased risk afterward, it is evident that a long-term therapeutic daily dose can be tolerated.⁷

Conflicts of interest

None disclosed.