Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib

Chang, Anne Lynn S.; Solomon, James A.; Hainsworth, John D.; Goldberg, Leonard Harry; McKenna, Edward; Day, Bann Mo; Chen, Diana M.; Weiss, Glen J.

doi:10.1016/j.jaad.2013.09.012

Cited by 170 publications

(138 citation statements)

References 23 publications

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“…Lower incidences of grade 3/4 AEs, SAEs and AEs leading to discontinuation were observed with 200 mg vs. 800 mg. The majority of the most common AEs were generally grade 1 or 2 and were similar to those reported with other HPIs10, 11, 12, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39; muscle‐related AEs and the increase in CK that can accompany these AEs are thought to be a class effect of HPIs 11, 12, 30, 31, 35, 39. Muscle‐related AEs were effectively managed with dose adjustments or interruptions.…”

Section: Discussionsupporting

confidence: 79%

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Lear

Migden

Lewis

et al. 2017

Acad Dermatol Venereol

165

183

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BackgroundPatients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult‐to‐treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial.ObjectiveTo evaluate long‐term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18‐ and 30‐month analyses.MethodsBOLT (NCT01327053, ClinicalTrials.gov), a double‐blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI‐treatment–naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review.ResultsWith 30 months of follow‐up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200‐mg arm died. Median overall survival was not reached in either population; 2‐year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non‐aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%).ConclusionSonidegib continued to demonstrate long‐term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

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Section: Discussionsupporting

confidence: 79%

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Lear

Migden

Lewis

et al. 2017

Acad Dermatol Venereol

165

183

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“…The recommendations for the treatment of metastatic BCC are shown in Table XI, and the level of evidence/ strength of the recommendations are in Table XII. [106][107][108][109][110][111][113][114][115] …”

Section: Managing Patients With Metastatic and Advanced Basal Cell Camentioning

confidence: 99%

Guidelines of care for the management of basal cell carcinoma

Baum¹,

Bordeaux²,

Brown³

et al. 2018

Journal of the American Academy of Dermatology

310

219

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Basal cell carcinoma (BCC) is the most common form of human cancer, with a continually increasing annual incidence in the United States. When diagnosed early, the majority of BCCs are readily treated with office-based therapy, which is highly curative. In these evidence-based guidelines of care, we provide recommendations for the management of patients with BCC, as well as an in-depth review of the best available literature in support of these recommendations. We discuss biopsy techniques for a clinically suspicious lesion and offer recommendations for the histopathologic interpretation of BCC. In the absence of a formal staging system, the best available stratification based on risk for recurrence is reviewed. With regard to treatment, we provide recommendations on treatment modalities along a broad therapeutic spectrum, ranging from topical agents and superficially destructive modalities to surgical techniques and systemic therapy. Finally, we review the available literature and provide recommendations on prevention and the most appropriate follow-up for patients in whom BCC has been diagnosed. ( J Am Acad Dermatol

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“…Vismodegib was made available for compassionate use through an expanded access program in the United States and the recently published results also confirmed the antitumor efficacy of vismodegib (50). In this small number of cases, responses appeared to be negatively associated with prior systemic therapy (n ¼ 9) such as other Hh inhibitors (n ¼ 5) or cisplatin in patients with laBCC, suggesting that these patients have either more aggressive tumors, or that vismodegib is more effective as a primary treatment.…”

Section: Preclinical Efficacy Modelsmentioning

confidence: 76%

“…50). Forty-one patients were randomized (2:1) to receive oral vismodegib 150 mg daily or placebo for a planned treatment period of 18 months.…”

Section: Preclinical Efficacy Modelsmentioning

confidence: 99%

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Basset-Séguin

Sharpe

Sauvage

2015

Molecular Cancer Therapeutics

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Basal cell carcinoma (BCC) is the most commonly diagnosed cancer. While most BCCs are amenable to surgery, some tumors can reach a more advanced stage or metastasize, and become ineligible for surgical resection or radiotherapy. Abnormal activation of the Hedgehog (Hh) pathway is a key driver in BCC pathophysiology. Consequently, inhibitors of the Hh pathway have been developed. Molecules that inhibit the receptor protein Smoothened (SMO) are the most advanced in clinical development. Vismodegib is the first-in-class SMO inhibitor and has been approved in a number of countries for the treatment of metastatic or locally advanced BCC. Several molecules have demonstrated antitumoral activity, but treatment may be limited in duration by a number of side effects, and it is not yet established whether these agents are truly curative or whether continued treatment will be required. Resistance to SMO inhibition has been reported in the clinic for which incidence and mechanisms must be elucidated to inform future therapeutic strategies. Intermittent dosing regimens to improve tolerability, as well as neoadjuvant use of Hh pathway inhibitors, are currently under investigation. Here, we review the most recent outcomes obtained with Hh inhibitors under clinical investigation in BCC.

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Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib

Abstract: This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.

Cited by 170 publications

References 23 publications

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Guidelines of care for the management of basal cell carcinoma

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

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