Download pptx - Gorlin Group Talk Nov 2012

Transcript
Page 1: Gorlin Group Talk Nov 2012

BCC – Management and Treatment Options

Dr JT Lear,

Dermatology CentreManchester Royal Infirmary &

Dermatology CentreHope Hospital, Manchester

Page 2: Gorlin Group Talk Nov 2012

2

BASAL CELL CARCINOMA

Management and Treatment OptionsNovember 2012

Dr John LearConsultant Dermatologist,

Central Manchester Hospitals

Page 3: Gorlin Group Talk Nov 2012

3

Page 4: Gorlin Group Talk Nov 2012

4

Page 5: Gorlin Group Talk Nov 2012

5

Page 6: Gorlin Group Talk Nov 2012

6

Page 7: Gorlin Group Talk Nov 2012

7

Page 8: Gorlin Group Talk Nov 2012

Results in nBCC:Lesion response & cosmesis (PP) 3- month follow-up

Rhodes et al; Arch Dermatol 2004; 140:17–23

9198

0

10

20

30

40

50

60

70

80

90

100

Complete response

MAL-PDT Surgery

82

33

0

10

20

30

40

50

60

70

80

90

100

Cosmetic outcomes

MAL-PDT Surgery

Page 9: Gorlin Group Talk Nov 2012

nBCC: 5 year recurrence rates MAL-PDT vs. surgery

9198

4 010

0

14

2

144

144

0102030405060708090

100

3mthCRR

12mthRR

24mthRR

36mthRR

48mthRR

60mthRR

MAL-PDT

Excision

Page 10: Gorlin Group Talk Nov 2012

nBCC: 5 year recurrence rates MAL-PDT

• MAL-PDT has now shown long term recurrence rates: - higher (14%) than surgery (4%)– at least equivalent to recurrence rates of standard

alternative treatments to surgery

• PDT offers the benefit of non invasiveness, rapid healing and better cosmetic outcome than surgery

Page 11: Gorlin Group Talk Nov 2012

Long term outcomes MAL-PDT:superficial basal cell carcinoma

(sBCC)

Page 12: Gorlin Group Talk Nov 2012

sBCC: 5 year recurrence rates MAL-PDT vs cryotherapy

97 95

9 1317 19 2219 22

19 2220

0102030405060708090

100

3mthCRR

12mthRR

24mthRR

36mthRR

48mthRR

60mthRR

MAL-PDT

Cryotherapy

Page 13: Gorlin Group Talk Nov 2012

sBCC: 5 year recurrence rates MAL-PDT

• No new recurrences after 36 months• Long term recurrence rates similar to recurrence

rates of standard cryotherapy (22% vs 20%)• PDT offers non invasive, rapid healing and

better cosmetic outcome than cryotherapy• Should be considered as a standard therapy for

sBCC

Page 14: Gorlin Group Talk Nov 2012

Long term outcomes MAL-PDT: Difficult-to-treat basal cell carcinoma BCC

Page 15: Gorlin Group Talk Nov 2012

Why PDT for ‘difficult-to-treat’ BCC?• Surgery, may be inappropriate in a number

of situations – Large or many lesions, poor ability to heal, poor

vasculature, co-morbidities such as immunosuppression, diabetes, anticoagulant medication

– risk of keloid scarring

Page 16: Gorlin Group Talk Nov 2012

Study design

• Open studies in difficult-to-treat sBCC and nBCC

• 94 patients, 123 lesions in European study• 102 patients, 187 lesions in Australian study• 2 MAL-PDT treatment sessions (160 mg/g, 3

hr); cycle repeated in the absence of CR• Assessed clinical and histological response,

recurrence, cosmetic outcome, safety

Page 17: Gorlin Group Talk Nov 2012

Definition of ‘difficult-to-treat’

• Definition of ‘difficult-to-treat’– large BCC:

• largest diameter >15 mm on extremities; >20 mm on trunk; >15 mm on face

– BCC lesion located in H-zone • as described by Swanson (mid-face, temple or ear)

– patient at high risk of surgical complications • bleeding abnormalities, anticoagulant medication and/or

cardiac

– recurrent lesions– Lesions in severely sun-damaged skin

Page 18: Gorlin Group Talk Nov 2012

Long term recurrence rates

8792

8 8

181524

18

2820

29

0

10

20

30

40

50

60

70

80

90

100

%

3mCRR

12mRR

24mRR

36mRR

48mRR

60mRR

Europe

Australia

Horn et al; Br J Dermatol 2003; 149(6):1242–1249; Vincuillo et al; Poster, World Congress of Cancers of the Skin, 2003

Page 19: Gorlin Group Talk Nov 2012

Geisse et al. 2004

Imiquimod - Phase III Studies

• 724 patients enrolled

• Imiquimod 5% cream administered either 5x/week or 7x/week for 6 weeks vs vehicle

• Biopsy confirmed sBCC meeting study size requirements (between 0.5 and 2.0 cm²)

• Tumour site clinically evaluated 12 weeks’ post-treatment, excised and evaluated histologically

Page 20: Gorlin Group Talk Nov 2012

Geisse et al. 2004

Comparison of Clin / Histo, and Histological Clearance

0

10

20

30

40

50

60

70

80

90

100 Clinical& histologicalclearance (ITT)

Histologicalclearance (ITT)

IMIQ 5x/week

Res

pons

e ra

te (

%)

Veh 5x/week IMIQ 7x/week Veh 7x/week

Treatment group

p<0.001 vs vehicle groups

75

82

2 3

7379

2 3

Page 21: Gorlin Group Talk Nov 2012

Geisse et al. 2004

Correlation between Histological Clearance and LSR

Imiquimod 5x/week

0

10

20

30

40

50

60

70

80

90

100

Erythema

% C

ompl

ete

re

spon

ders

Erosion Scabbing/crustingTest for trend: p<0.001 p=0.026 p<0.001

Severe

Moderate

MildNone

Page 22: Gorlin Group Talk Nov 2012

Imiquimod 5x/week in the Treatment of sBCC:Location: Upper mid back

Screening visit Treatment initiation Treatment week 3

Treatment week 6 Week 4 post-treatment Week 12 post-treatment

Page 23: Gorlin Group Talk Nov 2012

Gollnick et al. Poster presented at AAD 62nd Annual Meeting, Washington DC, 7-9 Feb 2004

Evaluation of Long-term Efficacy• Multicentre, phase III, open label, long-term

follow-up study

• Imiquimod 5x per week for 6 weeks• 182 patients (120m, 62f)• Mean age 65 yrs• Fitzpatrick skin phototypes II and III (90%)• Majority of target tumours (62%) located on

trunk• Target tumours ranged in size from 0.5 cm² to

2.0 (maximum diameter)

Page 24: Gorlin Group Talk Nov 2012

Gollnick, presented at AAD 2004 & data on file

Long-term sBCC Study: Results to 2-yearEstimate of sustained clearance of BCC during long-term follow-up (ITT) with 5x week dosing

for 6 weeks

Month 3

Cle

ara

nce

rate

(%

)

97.5%

Month 6 Month 12

94.9% 93.7%

0

10

20

30

40

50

60

70

80

90

10088.7%

Month 24

Page 25: Gorlin Group Talk Nov 2012

ConclusionsImiquimod 5% cream:

• High clearance rates, comparable to conventional treatment, with a sustained effect up to one year

• Non-invasive, non-scarring treatment option

– Excellent cosmetic results

Page 26: Gorlin Group Talk Nov 2012

Cryotherapy• 395 patients• Overall cure rate of 97%. • Recurrences were seen in 6 out of 225 (2.7%), at median 18

months. • The patients were treated as out-patients using local anaesthesia

and all tolerated the treatment well. 2 x 30 seconds

• Cryosurgery safe, low cost and effective method of treating selected non-melanoma skin cancer

• Follow up carefully for 2 years post-operatively.

• Br J Dermatol. 1988 Aug;119(2):231-40. Holt P

Page 27: Gorlin Group Talk Nov 2012

5 Flourouracil

• Fluorouracil clearance rates: • 90% for superficial BCC and • 27% to 85% for SCC in situ. • Up to 100% applying fluorouracil, experienced at

least 1 adverse event. Adverse event intensity ranged from mild to severe; erythema, pruritus, and pain were common.

• Love WE. Arch Dermatol. 2009 Dec;145(12):1431-8.

Page 28: Gorlin Group Talk Nov 2012

Oral Agents

• See next presentation/Slides 47 to 58

Page 29: Gorlin Group Talk Nov 2012

29

Advanced Basal Cell Carcinoma (aBCC)

• BCC is the most commonly diagnosed human cancer worldwide1

• Most BCCs are curable by surgery; however, some can progress to locally advanced (la) or metastatic (m) disease2,3

• For patients with advanced forms of BCC, no standard therapies exist2-4

Page 30: Gorlin Group Talk Nov 2012

30

Oral Agents

• LDE in development• 33 patients with metastatic or locally advanced BCC• Median treatment 9.8 months.• NEJM 2009 Sep 17;361(12):1164-72. Von Hoff DD et al.

Page 31: Gorlin Group Talk Nov 2012

31

STEVIE: a Single-Arm Open-Label Study to Assess the Safety of the Hedgehog Pathway

Inhibitor, Vismodegib, in Patients with Advanced Basal Cell Carcinoma: Second

Interim Analysis

Page 32: Gorlin Group Talk Nov 2012

32

Hedgehog signalling is critical for embryonic development1

Activation of SMO or functional loss of PTCH in >90 % of BCC2-5

1. Scales SJ, de Sauvage FJ. Trends Pharmacol Sci 2009;30:303–12. 2. Teh MT, et al. Cancer Res 2005;65:8597–603. 3. Kallassy M, et al. Cancer Res 1997;57:4731–5. 4. Unden AB, et al. Cancer Res 1997;57:2336–40. 5. Reifenberger J, et al. Cancer Res 1998;58:1798–803.

Page 33: Gorlin Group Talk Nov 2012

33

Vismodegib is a first-in-class, oral, selective Hedgehog pathway inhibitor (HPI)

1. Dirix L, Rutten A. Future Oncol 2012;8:915–28

• Vismodegib is a small-molecule, Hedgehog pathway inhibitor, that binds to SMO1

• Molecular weight 421.3 g/mol• Vismodegib is a highly potent,

selective inhibitor of SMO

Page 34: Gorlin Group Talk Nov 2012

34

ERIVANCE BCC, the pivotal study for vismodegib• ERIVANCE BCC led to approval of vismodegib by the FDA in

January 2012 For the treatment of adults with metastatic BCC, or with locally

advanced BCC that has recurred following surgery or who are not candidates for surgery and who are not candidates for radiation therapy

Sekulic A et al. New Engl J Med 2012;366:2171–9

Page 35: Gorlin Group Talk Nov 2012

35

STEVIE: study design and objectives

Vismodegib(150 mg orally once daily)

Treatment until progressive disease, unexpected toxicity

or patient request to discontinue

Other anti-BCC therapy(to be decided by treating physician)

Progressive disease

Patients with locally advanced, inoperable

or metastatic BCC(n = up to 800)

• STEVIE is a single-arm open-label study to assess the safety of vismodegib in patients with advanced BCC

Primary objective:• SafetySecondary objectives:• Overall response (based on Response Evaluation Criteria in Solid Tumors

[RECIST]); objective response rate, duration of response, progression-free survival (PFS) and overall survival

• Quality of Life http://clinicaltrials.gov/ct2/show/NCT01367665 Accessed September 2012

Page 36: Gorlin Group Talk Nov 2012

36

Conclusions

• Each topical therapy has positives / negatives, great to have a choice, but non-specific action

• Topical therapy increasingly important• Specific pathway inhibition, promise orally, side

effect profile limits use