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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

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Page 1: Targeted Therapy Comes to BCC: Hedgehog Inhibitors · Part I: History of Drug Development & January 2012 FDA Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse

©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

Presenter
Presentation Notes
Good morning I am Scott Fosko from Saint Louis University and I want to thank Dr. Agarwal and Marghoob for the invitation to speak with you this morning about imiquimod
Page 2: Targeted Therapy Comes to BCC: Hedgehog Inhibitors · Part I: History of Drug Development & January 2012 FDA Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse

©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.

Page 3: Targeted Therapy Comes to BCC: Hedgehog Inhibitors · Part I: History of Drug Development & January 2012 FDA Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse

©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

Page 4: Targeted Therapy Comes to BCC: Hedgehog Inhibitors · Part I: History of Drug Development & January 2012 FDA Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse

©2016 MFMER | 3539966-4

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©2016 MFMER | 3539966-5

Page 6: Targeted Therapy Comes to BCC: Hedgehog Inhibitors · Part I: History of Drug Development & January 2012 FDA Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse

©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?

Page 7: Targeted Therapy Comes to BCC: Hedgehog Inhibitors · Part I: History of Drug Development & January 2012 FDA Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse

©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

Page 8: Targeted Therapy Comes to BCC: Hedgehog Inhibitors · Part I: History of Drug Development & January 2012 FDA Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse

©2016 MFMER | 3539966-8

1950s: Idaho

1970s: Drosophila labs

Corn lilies: cyclopamine cyclops

Hedgehohg pathway/Embryogenesis

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©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.

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Mechanism of Action

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©2016 MFMER | 3539966-11

Justilien V and Fields AP. Clin Cancer Res 2015;21:505-13. (Mayo Florida)

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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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©2016 MFMER | 3539966-14

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.

Presenter
Presentation Notes
laBCC= 1) inoperable; 2) sx not recommended (>1cm; >2 recurrences) 3)sx w/ substantial morbidity
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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.

Presenter
Presentation Notes
laBCC= 1) inoperable; 2) sx not recommended (>1cm; >2 recurrences) 3)sx w/ substantial morbidity
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Maximum Tumor Shrinkage in the Two Cohorts.

Sekulic, N Engl J Med. 2012 Jun 7;366(23):2171-9.

Presenter
Presentation Notes
Figure 1 Maximum Tumor Shrinkage in the Two Cohorts. Panel A shows a waterfall plot of maximum tumor shrinkage (the sum of the longest diameters, as compared with baseline), according to the independent review before progression, in the group of 33 patients with metastatic basal-cell carcinoma. Each bar represents a patient; 3 had a best percentage change of 0 in the sum of the longest diameters, accounting for the gap in the bars. Three patients did not have measurements, and 1 could not be evaluated for assessment of best confirmed response; data from these 4 patients were excluded from this figure. Panel B shows a waterfall plot of maximum tumor shrinkage before progression, as assessed by independent review, in the 63 patients with locally advanced basal-cell carcinoma who were included in the efficacy analysis. For patients with target lesions that were assessed only by measuring the externally visible dimension, the maximum tumor shrinkage shown is based on the externally visible dimension. For patients who also underwent radiographic assessment, the waterfall plot shows the assessment approach yielding the greater percent reduction (either radiographic assessment or measurement of the externally visible dimension). Four patients did not have lesion measurements; data from these patients were not included in this figure. The asterisk denotes a patient with tumor shrinkage of less than 30% and a response assessed on the basis of the complete resolution of ulceration. In both panels, the dashed line represents a 30% decrease in the sum of the longest diameters.
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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.

Presenter
Presentation Notes
laBCC= 1) inoperable; 2) sx not recommended (>1cm; >2 recurrences) 3)sx w/ substantial morbidity
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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.

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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.

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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

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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.

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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.

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©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

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Literature

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Poulalhoun et al, Dermatology, m2015;230:101-4. (France)

Vismodegib and SCC

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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

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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

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Neoadjuvant + Surgery

Chang et al. JAMA Dermatol 2013;149:639-41.

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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

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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.

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42%

16%

44%

Complete histologic clearance

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Sekulic et al. J am Acad Dermatol 2015;Jun;72:1021-1026.

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Sekulic et al. J am Acad Dermatol 2015;Jun;72:1021-1026.

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STEVIE Trial: Long-term Safety and Efficacy

Basset-Seguin N et al. Lancet Oncol 2015;16:729-35.

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STEVIE Trial: Long-term Safety and Efficacy

Basset-Seguin N et al. Lancet Oncol 2015;16:729-35.

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STEVIE Trial: Long-term Safety and Efficacy

Basset-Seguin N et al. Lancet Oncol 2015;16:729-35.

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Basset-Seguin N et al. Lancet Oncol 2015;16:729-35.

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MIKIE Trial: Rogers et al. Poster 9509 at ASCO June 2016

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MIKIE Trial: Rogers et al. Poster 9509 at ASCO June 2016

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MIKIE Trial: Rogers et al. Poster 9509 at ASCO June 2016

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MIKIE Trial: Rogers et al. Poster 9509 at ASCO June 2016

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©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

Page 56: Targeted Therapy Comes to BCC: Hedgehog Inhibitors · Part I: History of Drug Development & January 2012 FDA Approval of vismodegib for “laBCC” and mBCC. • Efficacy and Adverse

©2016 MFMER | 3539966-56

Migden MR et al. Lancet Oncology 2015:16;716-28.

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200 mg qd 800 mg qd

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Dummer R et al. J Am Acad Dermatol 2016;75:113-125

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• 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

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Dummer R et al. J Am Acad Dermatol 2016;75:113-125

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Dummer R et al. J Am Acad Dermatol 2016;75:113-125

A: Partial Response B: Stable Disease

C: Partial Response D: Partial Response

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Dummer R et al. J Am Acad Dermatol 2016;75:113-125

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Dummer R et al. J Am Acad Dermatol 2016;75:113-125

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Lacouture M et al. The Oncologist August 2016

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Lacouture M et al. The Oncologist August 2016

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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

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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…

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Justilien V and Fields AP. Clin Cancer Res 2015;21:505-13.

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Non-Surgical Treatment Modalities

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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.


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