FDA Approval Summary: Sonidegib for Locally Advanced Basal Cell Carcinoma

Casey, Denise; Demko, Suzanne; Shord, Stacy S.; Zhao, Hong; Chen, Huanyu; He, Kun; Putman, Alexander H.; Helms, Whitney S.; Keegan, Patricia; Pazdur, Richard

doi:10.1158/1078-0432.ccr-16-2051

Cited by 99 publications

(64 citation statements)

References 8 publications

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“…The Smo inhibitors, vismodegib and sonidegib, are currently approved for the treatment of advanced basal cell carcinoma (BCC) and they have demonstrated efficacy in clinical trials of Hh-MB (47–49). Despite the dramatic response to these inhibitors in the initial clinical trails, drug resistance readily arises in both human and animal models as a consequence of mutation in Smo (50), amplification of Gli2 (51) or cyclin D1 (52).…”

Section: Discussionmentioning

confidence: 99%

Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion

et al. 2017

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Astrocytes, the most abundant type of glial cells in the brain, play critical roles in supporting neuronal development and brain function. While astrocytes have been frequently detected in brain tumors, including medulloblastoma (MB), their functions in tumorigenesis are not clear. Here we demonstrate that astrocytes are essential components of the MB tumor microenvironment. Tumor-associated astrocytes (TAA) secreted the ligand sonic hedgehog (Shh), which is required for maintaining MB cell proliferation despite the absence of its primary receptor Patched-1 (Ptch1). Shh drove expression of Nestin in MB cells through a Smoothened-dependent, Gli1-independent mechanism. Ablation of TAA dramatically suppressed Nestin expression and blocked tumor growth. These findings demonstrate an indispensable role for astrocytes in MB tumorigenesis and reveal a novel Ptch1-independent Shh pathway involved in MB progression.

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Section: Discussionmentioning

confidence: 99%

Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion

et al. 2017

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“…The largest part of Hh modulators developed so far act as antagonists of the upstream Smoothened receptor (Smo) [16e20], whereas only a few inhibitors of the downstream effectors Glioma-associated oncogene homologue (Gli) proteins have been disclosed, most of which acting by an unclear or indirect mechanism of action [12,21e24]. Two Smo antagonists, namely Vismodegib and Sonidegib, have been approved by the Food and Drug Administration (FDA) in 2012 and 2015, respectively, for the treatment of metastatic and locally advanced BCC, while a number of additional Smo antagonists are currently undergoing clinical evaluation [19,20,25]. However, the emergence of drug-resistance [15,26e29], and the occurrence of aberrant Hh activation downstream of Smo seriously limited the use of these drugs, and raised some concerns on the efficacy of therapeutic approaches that target Smo.…”

Section: Introductionmentioning

confidence: 99%

Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Berardozzi

Bernardi

Infante

et al. 2018

European Journal of Medicinal Chemistry

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Aberrant activation of the Hedgehog (Hh) pathway is responsible for the onset and progression of several malignancies. Small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector Gli1 have thus emerged recently as valuable anticancer agents. Here, we have designed, synthesized, and tested new Hh inhibitors taking advantage by the highly versatile and privileged isoflavone scaffold. The introduction of specific substitutions on the isoflavone's ring B allowed the identification of molecules targeting preferentially Smo or Gli1. Biological assays coupled with molecular modeling corroborated the design strategy, and provided new insights into the mechanism of action of these molecules. The combined administration of two different isoflavones behaving as Smo and Gli antagonists, respectively, in primary medulloblastoma (MB) cells highlighted the synergistic effects of these agents, thus paving the way to further and innovative strategies for the pharmacological inhibition of Hh signaling.

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“…Approval of sonidegib was based on results of the pivotal phase II BOLT trial [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment; NCT01327053], which examined the efficacy and safety of sonidegib in patients with laBCC and mBCC . At the 6‐month analysis, treatment with sonidegib 200 mg daily demonstrated objective response rates (ORRs) by central review of 43% in patients with laBCC and 15% in patients with mBCC .…”

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confidence: 99%

Long‐term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42‐month analysis of the phase II randomized, double‐blind BOLT study

et al. 2019

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Background Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. Objectives This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib. Methods Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. Results The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0Á2-36) for mBCC in the 200-mg group and 46Á1% (95% CI 37Á2-55Á1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. Final 42-month efficacy and safety results from the BOLT study, R. Dummer et al. 1373Fig 3. Objective response rates by central review across all BOLT (Basal Cell Carcinoma Outcomes with LDE225 Treatment) analyses in patients receiving sonidegib 200 mg daily. 17,19,20 Results are for the intent-to-treat population. BCC, basal cell carcinoma; laBCC, locally advanced BCC; mBCC, metastatic BCC; ORR, objective response rate. Fig 4. Kaplan-Meier plots of duration of response per central review in patients receiving sonidegib 200 mg daily (responders only). BCC, basal cell carcinoma; laBCC, locally advanced BCC; mBCC, metastatic BCC; mo, months. 1374 Final 42-month efficacy and safety results from the BOLT study, R. Dummer et al. The data are presented as n (%). Results are for the safety population. AE, adverse event; BOLT, Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment; SAE, serious AE. Final 42-month efficacy and safety results from the BOLT study, R. Dummer et al. 1375 Fig 6. Adverse events in ≥ 20% of patients treated with sonidegib 200 mg and 800 mg daily CK, creatine kinase.

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FDA Approval Summary: Sonidegib for Locally Advanced Basal Cell Carcinoma

Cited by 99 publications

References 8 publications

Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion

Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion

Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Long‐term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42‐month analysis of the phase II randomized, double‐blind BOLT study

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