Mayo School of Continuous Professional Development. Scott W. Fosko, M.D. Chair, Department of Dermatology Mayo Clinic Florida Jacksonville, Florida

Transcription

1 Targeted Therapy Comes to BCC: Hedgehog Inhibitors Mayo School of Continuous Professional Development Scott W. Fosko, M.D. Chair, Department of Dermatology Mayo Clinic Florida Jacksonville, Florida 2016 MFMER

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 MFMER

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

4 2016 MFMER

5 2016 MFMER

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

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

8 1950s: Idaho cyclops Corn lilies: cyclopamine 1970s: Drosophila labs Hedgehohg pathway/embryogenesis 2016 MFMER

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: MFMER

10 Mechanism of Action 2016 MFMER

11 Justilien V and Fields AP. Clin Cancer Res 2015;21: (Mayo Florida) 2016 MFMER

12 Dreier J et al Expert Opin Emerging Drugs MFMER

13 Sekulic et al. N Engl J Med Jun 7;366(23): MFMER

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 Jun 7;366(23): MFMER

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 Jun 7;366(23): MFMER

16 Maximum Tumor Shrinkage in the Two Cohorts. Sekulic, N Engl J Med Jun 7;366(23): MFMER

17 Erivance Sekulic, N Engl J Med Jun 7;366(23): MFMER

18 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 Jun 7;366(23): MFMER

19 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 Jun 7;366(23): MFMER

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 Jun 7;366(23): MFMER

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

22 Inhibiting the Hh Pathway in Patients w/ Basal-Cell Nevus (Gorlin) Syndrome 2 nd 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 Jun 7;366(23): MFMER

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 Jun 7;366(23): MFMER

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

25 Literature 2016 MFMER

26 Vismodegib and SCC Poulalhoun et al, Dermatology, m2015;230: (France) 2016 MFMER

27 Vismodegib and SCC Orouji,A et al BJD 2014 Jan MFMER

28 Vismodegib and Keratoacanthomas JAMA Dermatol 2013;149: MFMER

29 1. Collision tumor, delayed detection after BCC regresses 2. Dedifferentiation of BCC later in course of therapy 2016 MFMER

30 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 MFMER

31 BCC Tumor Regrowth While On Drug: Resistance can Develop Chang AL, Oro AE Arch Dermatolo 2012;148: MFMER

32 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: weeks Chang AL, Oro AE Arch Dermatolo 2012;148: MFMER

33 Fertility and Sterility; 2014, May MFMER

34 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

35 Neoadjuvant + Surgery Chang et al. JAMA Dermatol 2013;149: MFMER

36 Neoadjuvant +Mohs Surgery Reduced surgical defect: 31% If used at least 3 months Ally et al J Am Acad Dermatol Nov;71(5): MFMER

37 Neoadjuvant + XRT 2016 MFMER

38 Neoadjuvant + XRT Br J Dermatol Feb 21. doi: /bjd [Epub ahead of print] 2016 MFMER

39 Neoadjuvant + XRT Gathings RM, Orscheln CS, Huang WW. Letter: JAAD April MFMER

40 2016 MFMER

41 Cusack et al JAMA Dermatol 2015;151:70-2. (Drexel University) 2016 MFMER

42 Sofen et al Epub J Am Acad Dermatol Apr MFMER

43 Complete histologic clearance 42% 16% 44% 2016 MFMER

44 Sekulic et al. J am Acad Dermatol 2015;Jun;72: MFMER

45 Sekulic et al. J am Acad Dermatol 2015;Jun;72: MFMER

46 STEVIE Trial: Long-term Safety and Efficacy Basset-Seguin N et al. Lancet Oncol 2015;16: MFMER

47 STEVIE Trial: Long-term Safety and Efficacy Basset-Seguin N et al. Lancet Oncol 2015;16: MFMER

48 STEVIE Trial: Long-term Safety and Efficacy Basset-Seguin N et al. Lancet Oncol 2015;16: MFMER

49 Basset-Seguin N et al. Lancet Oncol 2015;16: MFMER

50 2016 MFMER

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

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

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

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

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

56 Migden MR et al. Lancet Oncology 2015:16; MFMER

57 200 mg qd 800 mg qd 2016 MFMER

58 Dummer R et al. J Am Acad Dermatol 2016;75: MFMER

59 Dummer R et al. J Am Acad Dermatol 2016;75: Dummer R et al. J Am Acad Dermatol 2016;75: Dummer R et al. J Am Acad Dermatol 2016;75: MFMER

60 Dummer R et al. J Am Acad Dermatol 2016;75: MFMER

61 A: Partial Response B: Stable Disease C: Partial Response D: Partial Response Dummer R et al. J Am Acad Dermatol 2016;75: MFMER

62 Dummer R et al. J Am Acad Dermatol 2016;75: MFMER

63 Dummer R et al. J Am Acad Dermatol 2016;75: MFMER

64 2016 MFMER

65 Lacouture M et al. The Oncologist August MFMER

66 Lacouture M et al. The Oncologist August MFMER

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

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

69 Justilien V and Fields AP. Clin Cancer Res 2015;21: MFMER

70 Non-Surgical Treatment Modalities 2016 MFMER

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 MFMER