Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial

Basset-Séguin, Nicole; Hauschild, Axel; Grob, Jean-Jacques; Kunstfeld, Rainer; Dréno, Brigitte; Mortier, Laurent; Ascierto, Paolo A.; Licitra, Lisa; Dutriaux, Caroline; Thomas, Luc; Jouary, Thomas; Meyer, Nicolas; Guillot, B.; Dummer, Reinhard; Fife, Kate; Ernst, D. Scott; Williams, Sarah; Fittipaldo, A.; Xynos, Ioannis; Hansson, Johan

doi:10.1016/s1470-2045(15)70198-1

Cited by 219 publications

(221 citation statements)

References 24 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: 78%

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

172

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: 78%

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

172

183

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“…Beyond exacerbation of preexisting disease, it is possible that treatment with Hh antagonists may actually increase the risk of contracting IBD. Indeed diarrhea (28% of patients) and weight loss (44% of patients) are common side effects of long-term systemic vismodegib treatment (32). Although the underlying cause of these effects was not reported, our results suggest that development of IBD certainly should be considered as a possibility.…”

Section: Discussionmentioning

confidence: 64%

Control of inflammation by stromal Hedgehog pathway activation restrains colitis

Lee

Rothenberg

Seeley

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4+Foxp3+ regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.

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“…Similar findings were reported in the Safety Events in Vismodegib (STEVIE) trial, in which an overall response rate of 37.9% was found among 29 patients with metastatic BCC. 109 Oral vismodegib has been approved by the US Food and Drug Administration as the first systemic therapy for metastatic BCC.…”

Section: Managing Patients With Metastatic and Advanced Basal Cell Camentioning

confidence: 99%

“…Higher response rates among 453 patients with locally advanced BCC were reported in the STEVIE trial, with an overall response rate of 66.7%. 109 Notably, 180 of 499 patients in the STEVIE trial (36%) discontinued treatment because of adverse events, 108 (22%) were recorded as having serious adverse events, and among 31 deaths during the trial, 21 were the result of adverse events. Routine adverse events that patients find troublesome include muscle spasms and arthralgias, alopecia, and dysgeusia often culminating in weight loss.…”

Section: Managing Patients With Metastatic and Advanced Basal Cell Camentioning

confidence: 99%

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Guidelines of care for the management of basal cell carcinoma

Baum¹,

Bordeaux²,

Brown³

et al. 2018

Journal of the American Academy of Dermatology

326

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 in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial

Cited by 219 publications

References 24 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

Control of inflammation by stromal Hedgehog pathway activation restrains colitis

Guidelines of care for the management of basal cell carcinoma

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