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©2016 MFMER | 3539966-1 ©2016 MFMER | 3539966-1
Mayo School of Continuous Professional Development
Targeted Therapy Comes to BCC: Hedgehog Inhibitors
Scott W. Fosko, M.D. Chair, Department of Dermatology Mayo Clinic Florida Jacksonville, Florida
©2016 MFMER | 3539966-2
Disclosures
• Genentech: • Prior
• Consultant, Speaker’s Bureau, & Advisory Board • Industry sponsored clinical trials
• Planning • Completion at Mayo Clinic Florida, Investigator
initiated vismodegib research support via Saint Louis University, funding via Genentech,
• I am a Mohs Surgeon and routinely manage BCCs surgically.
©2016 MFMER | 3539966-3
Outline: • Part I: History of Drug Development & January 2012 FDA
Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse Events
• Part II: Since 2012, what have we learned. • Neo adjuvant, alternate dosing regimens, drug
resistance, cSCCs emerge during tx, long term safety • Part III: Sonidegib FDA approval 2015 for laBCC • Part IV: Case Presentations
©2016 MFMER | 3539966-4
©2016 MFMER | 3539966-5
©2016 MFMER | 3539966-6
HHIs and BCC • Hedgehog inhibitor, binds to smoothened, blocking cell proliferation
• FDA approved vismodegib January 2012 for locally advanced BCC (laBCC) and metastatic BCC (mBCC), sonidegib in 2015 for laBCC
• It works, at times impressively, but not always
• Durability of response is unknown
• Embryotoxic and teratogenic
• Side effects are very common, muscle cramps (70%), altered or loss of taste (50%)and hair loss (50%)
• Drug resistance can develop & SCCs can emerge during treatment
• Neoadjuvant role reported, modest improvement (30%) reduced Mohs surgery wound’s surgical size
• Ideal dosing and duration of therapy is being studied (MIKIE Trial)
• Other Hedge Hog Inhibitors in the pipeline
• For some patients, impactful, a game changer…laBCC and BCNS
• Any questions?
©2016 MFMER | 3539966-7
Outline: • Part I: History of Drug Development & January 2012
FDA Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse Events
• Part II: Since 2012, what have we learned. • Neo adjuvant, alternate dosing regimens, drug
resistance, cSCCs emerge during tx, long term safety • Part III: Sonidegib FDA approval 2015 for laBCC • Part IV: Case Presentations
©2016 MFMER | 3539966-8
1950s: Idaho
1970s: Drosophila labs
Corn lilies: cyclopamine cyclops
Hedgehohg pathway/Embryogenesis
©2016 MFMER | 3539966-9
Hedgehog Pathway (Hh)
• Important regulator of growth & development in embryogenesis
• Dormant during adulthood (Ptch=tumor suppressor)
• Inappropriate activation in many cancers: BCC, medulloblastoma, pancreatic, prostate, ovarian, colon, sarcomas, etc.
Clin Ther. 2012;34:2039-50.
©2016 MFMER | 3539966-10
Mechanism of Action
©2016 MFMER | 3539966-11
Justilien V and Fields AP. Clin Cancer Res 2015;21:505-13. (Mayo Florida)
©2016 MFMER | 3539966-12
Dreier J et al Expert Opin Emerging Drugs 2014
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Sekulic et al. N Engl J Med. 2012 Jun 7;366(23):2171-9.
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Erivance: Pivotal Phase 2 Study • International, single-arm, open label
• 2 cohorts (n=104): • mBCC (n=33) • laBCC (n=71) (recurrent tumors, non-surgical or XRT candidates)
• Median Age: 62 years • Male: 61%, Female 39% • 21% of patients = Basal Cell Nevus Syndrome (BCNS/Gorlins) • Vismodegib 150mg PO QD
• Treated until disease progression (+20% size, new ulceration, new lesions), unacceptable toxicities, or end of study
Sekulic, N Engl J Med. 2012 Jun 7;366(23):2171-9.
©2016 MFMER | 3539966-15
Erivance Phase 2 Study
• 1° end-point: objective response rate (ORR) • mBCC: RECIST guidelines (Response Evaluation Criteria in Solid
Tumors), ↓ 30% radiographically SLD (Sum Longest Diameter) • laBCC: ↓ 30% visible tumor or resolution of ulceration
• Complete Response: ORR and Negative Biopsy • laBCC 21%, 0% mBCC
• Partial Response: ORR and Positive Biopsy • laBCC 22%, 30% mBCC
Sekulic, N Engl J Med. 2012 Jun 7;366(23):2171-9.
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Maximum Tumor Shrinkage in the Two Cohorts.
Sekulic, N Engl J Med. 2012 Jun 7;366(23):2171-9.
©2016 MFMER | 3539966-17
Erivance
Sekulic, N Engl J Med. 2012 Jun 7;366(23):2171-9.
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Erivance Phase 2 Study
• Median duration of therapy: 9.7 months
• Median duration of response: 7.6 months
• Adverse Events: Majority Grade 1/2 • Muscle cramps 68% • Alopecia 63% • Dysgeusia 51%
Sekulic, N Engl J Med. 2012 Jun 7;366(23):2171-9.
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Serious Adverse Events (n=26, 25%)
• 7 fatal (mBCC=1, laBCC=6) • Patients with multiple comorbidities • Relationship to drug unknown
Sekulic, N Engl J Med. 2012 Jun 7;366(23):2171-9.
©2016 MFMER | 3539966-20
Vismodegib • January 2012 FDA approved for:
1. Adults, metastatic BCC (mBCC) 2. Adults, locally advanced BCC (laBCC)
• >1 cm that recurred following surgery • or who are not candidates for surgery • & who are not candidates for radiation
Sekulic et al N Engl J Med. 2012 Jun 7;366(23):2171-9.
©2016 MFMER | 3539966-21
Black Box Warning: Embryotoxic and Teratogenic • Women:
• Verify pregnancy status within 7 days prior to starting therapy • Effective contraception (2 forms, barrier and highly effective
method), during and 9 months after last dose
• Men • Secreted in semen • Condom use recommended, even after vasectomy • During and 3 months after last dose; avoid sperm donation
• Lactation: unknown risk, advise patient • Blood donation: 9 months after last dose
©2016 MFMER | 3539966-22
Inhibiting the Hh Pathway in Patients w/ Basal-Cell Nevus (Gorlin) Syndrome
• 2nd Phase 2 trial, n=41 • Randomized, double-blind,
placebo-controlled • Vismo 150mg vs placebo • Significant clinical benefit found & placebo arm stopped New BCCs: 2 vs 25/year Decreased size -77% vs -22%
Tang et al N Engl J Med. 2012 Jun 7;366(23):2180-8.
©2016 MFMER | 3539966-23
Inhibiting the Hh Pathway in Patients w/ Basal-Cell Nevus (Gorlin) Syndrome
• 54% (14/26) of patients discontinued drug due to adverse events
• Majority Grade 1/2
• Upon ceasing drug • Dysgesia & muscle cramps ceased at 1 month • Hair regrowth noted at 3 months
Tang et al N Engl J Med. 2012 Jun 7;366(23):2180-8.
©2016 MFMER | 3539966-24
Outline: • Part I: History of Drug Development & January 2012 FDA
Approval of vismodegib for “laBCC and mBCC”. • Efficacy and Adverse Events
• Part II: Since 2012, what have we learned: • Neo adjuvant, drug resistance, cSCCs emerge during
tx, long term safety, alternate dosing regimens • Part III: Sonidegib FDA approval 2015 for laBCC • Part IV: Case Presentations
©2016 MFMER | 3539966-25
Literature
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Poulalhoun et al, Dermatology, m2015;230:101-4. (France)
Vismodegib and SCC
©2016 MFMER | 3539966-27
Orouji,A et al BJD 2014 Jan 21
Vismodegib and SCC
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Vismodegib and Keratoacanthomas
JAMA Dermatol 2013;149:242-3
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1. Collision tumor, delayed detection after BCC regresses
2. Dedifferentiation of BCC later in course of therapy
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SCC Initial Presence or Emergence • Thoroughly evaluate your patient at the time of
presentation. Biopsy lesions! • Ideally manage SCCs prior to tx • Monitor closely during treatment. • Repeat biopsy for areas of non-response or
progression during treatment.
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BCC Tumor Regrowth While On Drug: Resistance can Develop
Chang AL, Oro AE Arch Dermatolo 2012;148:1324-5
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BCCs: New or Regrowth during or after tx: • New during tx: 21% (6/28) of patients developed new BCCs
while on vismo
• Regrowth after tx: overall 5% (36/690) • Avg time: 55-62 weeks
Chang AL, Oro AE Arch Dermatolo 2012;148:1324-5
©2016 MFMER | 3539966-33
Fertility and Sterility; 2014, May 30.
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Other Adverse Events • Elevated INR, on Coumadin, 3 wks after tx • Hypersensitivity reaction, 3wks after tx, psoriasis
(ustekinumab) and other agents • Cholestatic injury, concomitant aspirin and naproxen use
©2016 MFMER | 3539966-35
Neoadjuvant + Surgery
Chang et al. JAMA Dermatol 2013;149:639-41.
©2016 MFMER | 3539966-36
Neoadjuvant +Mohs Surgery
• Reduced surgical defect: 31%
• If used at least 3 months
Ally et al J Am Acad Dermatol. 2014 Nov;71(5):904-911
©2016 MFMER | 3539966-37
Neoadjuvant + XRT
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Br J Dermatol. 2015 Feb 21. doi: 10.1111/bjd.13748. [Epub ahead of print]
Neoadjuvant + XRT
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Gathings RM, Orscheln CS, Huang WW. Letter: JAAD April 2014
Neoadjuvant + XRT
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Cusack et al JAMA Dermatol 2015;151:70-2. (Drexel University)
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Sofen et al Epub J Am Acad Dermatol. 2015 Apr 24.
©2016 MFMER | 3539966-43
42%
16%
44%
Complete histologic clearance
©2016 MFMER | 3539966-44
Sekulic et al. J am Acad Dermatol 2015;Jun;72:1021-1026.
©2016 MFMER | 3539966-45
Sekulic et al. J am Acad Dermatol 2015;Jun;72:1021-1026.
©2016 MFMER | 3539966-46
STEVIE Trial: Long-term Safety and Efficacy
Basset-Seguin N et al. Lancet Oncol 2015;16:729-35.
©2016 MFMER | 3539966-47
STEVIE Trial: Long-term Safety and Efficacy
Basset-Seguin N et al. Lancet Oncol 2015;16:729-35.
©2016 MFMER | 3539966-48
STEVIE Trial: Long-term Safety and Efficacy
Basset-Seguin N et al. Lancet Oncol 2015;16:729-35.
©2016 MFMER | 3539966-49
Basset-Seguin N et al. Lancet Oncol 2015;16:729-35.
©2016 MFMER | 3539966-50
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MIKIE Trial: Rogers et al. Poster 9509 at ASCO June 2016
©2016 MFMER | 3539966-52
MIKIE Trial: Rogers et al. Poster 9509 at ASCO June 2016
©2016 MFMER | 3539966-53
MIKIE Trial: Rogers et al. Poster 9509 at ASCO June 2016
©2016 MFMER | 3539966-54
MIKIE Trial: Rogers et al. Poster 9509 at ASCO June 2016
©2016 MFMER | 3539966-55
Outline: • Part I: History of Drug Development & January 2012 FDA
Approval of vismodegib for “laBCC and mBCC”. • Efficacy and Adverse Events
• Part II: Since 2012, what have we learned. • Neo adjuvant, alternate dosing regimens, drug
resistance, cSCCs emerge during tx, long term safety • Part III: Sonidegib FDA approval 2015 for laBCC • Part IV: Case Presentations
©2016 MFMER | 3539966-56
Migden MR et al. Lancet Oncology 2015:16;716-28.
©2016 MFMER | 3539966-57
200 mg qd 800 mg qd
©2016 MFMER | 3539966-58
Dummer R et al. J Am Acad Dermatol 2016;75:113-125
©2016 MFMER | 3539966-59
• Dummer R et al. J Am Acad Dermatol 2016;75:113-125
• Dummer R et al. J Am Acad Dermatol 2016;75:113-125
Dummer R et al. J Am Acad Dermatol 2016;75:113-125
©2016 MFMER | 3539966-60
Dummer R et al. J Am Acad Dermatol 2016;75:113-125
©2016 MFMER | 3539966-61
Dummer R et al. J Am Acad Dermatol 2016;75:113-125
A: Partial Response B: Stable Disease
C: Partial Response D: Partial Response
©2016 MFMER | 3539966-62
Dummer R et al. J Am Acad Dermatol 2016;75:113-125
©2016 MFMER | 3539966-63
Dummer R et al. J Am Acad Dermatol 2016;75:113-125
©2016 MFMER | 3539966-64
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Lacouture M et al. The Oncologist August 2016
©2016 MFMER | 3539966-66
Lacouture M et al. The Oncologist August 2016
©2016 MFMER | 3539966-67
Outline: • Part I: History of Drug Development & January 2012 FDA
Approval of vismodegib for “laBCC and mBCC”. • Efficacy and Adverse Events
• Part II: Since 2012, what have we learned. • Neo adjuvant, alternate dosing regimens, drug
resistance, cSCCs emerge during tx, long term safety • Part III: Sonidegib FDA approval 2015 for laBCC • Part IV: Case Presentations
©2016 MFMER | 3539966-68
Summary: HHIs and BCC • Hedgehog inhibitor, binds to Smo, blocking cell proliferation
• Vismodegib: FDA approved 2012 for locally advanced BCC (laBCC) and metastatic BCC (mBCC), Sonidegib: 2015 laBCC
• Embryotoxic and teratogenic
• It works, at times impressively, but not always.
• Durability is unknown and unpredictable.
• Side effects are common, muscle cramps, altered or loss of taste and hair loss
• Resistance can develop & SCCs can emerge during treatment
• Neoadjuvant role reported, Surgery and XRT
• Ideal dosing and duration of therapy is being studied further
• For some and select patients, quite impactful…
©2016 MFMER | 3539966-69
Justilien V and Fields AP. Clin Cancer Res 2015;21:505-13.
©2016 MFMER | 3539966-70
Non-Surgical Treatment Modalities
©2016 MFMER | 3539966-71
Acknowledgements: Research Team at Saint Louis University (SLU) • Rosemary King, PA-C
• Dr. Yadira Hurley
• Research Fellows • Dr. Melinda Chu • Dr. Timur Galperin • Dr. Geoff Potts
• Mohs Fellows • Dr. Jordan Slutsky
• Biostatistician • Eric Armbrecht, Ph.D.