This slidedeck presents an up-to-date disease overview of BCC, reviews current treatment options in BCC, explains the hedgehog signaling pathway and its role in BCC, review recent data of the first-in-class hedgehog inhibitor, vismodegib, and other novel agents in clinical trials. Faculty will also review recently approved novel agents in melanoma, to include treatment planning and managing adverse events. Case studies will demonstrate the practical application of current and emerging clinical evidence for the treatment of BCC and melanoma. During the panel discussion, faculty will discuss the importance of cross-communication in the treatment planning process and strategies to optimize the continuum of care for patients with BCC.

2. DISCLAIMER
Participants have an implied responsibility to use the newly acquired information
to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis
or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients’ conditions and possible
contraindications on dangers in use, review of any applicable manufacturer’s
product information, and comparison with recommendations of other authorities.
DISCLOSURE OF UNLABELED USE
This activity may contain discussion of published and/or investigational uses of
agents that are not indicated by the FDA. PIM and IMER do not recommend the
use of any agent outside of the labeled indications.
The opinions expressed in the activity are those of the faculty and do not
necessarily represent the views of PIM and IMER. Please refer to the official
prescribing information for each product for discussion of approved indications,
contraindications, and warnings.

3. Disclosure of Conflicts of Interest
 Jean Y. Tang, MD, PhD, reported a financial
interest/relationship or affiliation in the form of:
Consultant, Genentech, Inc.
 Keith T. Flaherty, MD, reported a financial
interest/relationship or affiliation in the form of:
Consultant, Genentech, Inc.
 Vernon K. Sondak, MD, reported a financial
interest/relationship or affiliation in the form of:
Consultant, Merck & Co., Inc., Navieda
Biopharmaceuticals; Speakers' Bureau, Merck & Co.,
Inc.

4. Learning Objectives
Upon completion of this activity, participants
should be better able to:
 Identify the patient symptoms and disease characteristics that
influence the diagnosis and treatment strategy of BCC
 Describe the mechanism of action and emerging evidence
supporting the clinical utility of hedgehog inhibitors in treating BCC
 Demonstrate the management of treatment-related side effects in
patients with BCC taking hedgehog inhibitors
 Evaluate novel agents in ongoing clinical trials for the treatment of
BCC and melanoma
 Describe molecular tests and patient characteristics that facilitate
individual treatment planning for melanoma
 Evaluate newly approved treatment options for advanced/metastatic
melanoma

5. Introduction to Faculty Panel
 Jean Y. Tang, MD, PhD (Chairperson)
– Stanford School of Medicine
 Keith T. Flaherty, MD
– Harvard Medical School
– Massachusetts General Hospital Cancer Center
 Vernon K. Sondak, MD
– H. Lee Moffitt Cancer Center & Research Institute

6. Activity Agenda
 Introduction (5 mins) – Jean Y. Tang, MD, PhD
 Overview of Basal Cell Carcinoma (5 mins) – Jean Y. Tang, MD, PhD
 Current Treatment Approaches in Basal Cell Carcinoma (15 mins) –
Jean Y. Tang, MD, PhD
 Basal Cell Carcinoma Clinical Advances With Novel Targeted Agents
(40 mins) – Keith T. Flaherty, MD
 Beyond Basal Cell Carcinoma: Novel Approaches to Treating
Melanoma (40 mins) – Vernon K. Sondak, MD and Keith T. Flaherty,
MD
 Panel Discussion: Multi-Disciplinary Perspectives in Basal Cell
Carcinoma (10 mins) – All Faculty
 Activity Conclusion/Q&A (5 mins)

7. Overview of Basal Cell
Carcinoma
Jean Y. Tang, MD, PhD
Stanford School of Medicine

8. Types of Skin Cancer
Approximately 3.6 Million Americans Will Be
Diagnosed With Skin Cancer This Year
BCC SCC Melanoma
BCC = basal cell carcinoma; SCC = squamous cell carcinoma.
Images courtesy of Jean Y. Tang, MD, PhD.
Rogers et al, 2010; ACS, 2012.

9. Basal Cell Carcinoma: Clinical Need
 1 in 5 Caucasians
 Treatment: Mainly surgery
 Prevention: None
 Cost: $5 billion per year
Images courtesy of Jean Y. Tang, MD, PhD.
Goppner et al, 2011.

10. Epidemiology of BCC
 Estimated 1 million BCC cases per year in US
– According to the ACS, 75% of all skin cancers are BCC
 Rare risk of metastasis: 0.003%–0.5%
 5th most costly cancer for Medicare
 The age-adjusted incidence per 100,000 Caucasians
– 475 cases in men
– 250 cases in women
 The estimated lifetime risk of BCC in Caucasian
population is 33%–39% in men and 23%–28% in women
 Risk of second BCC: 44% in 3 years
ACS = American Cancer Society.
Ridky, 2007; ACS, 2012; Rubin et al, 2005; Housman et al, 2003; Christenson et al, 2005; Marcil et al, 2000.

11. BCC Risk Factors
*This syndrome is an autosomal dominant disorder, characterized by BCC, atrophoderma vermiculata, milia, hypotrichosis,
trichoepithelioma, and peripheral vasodilatation.
† This syndrome is an X-linked dominant disorder, characterized by BCC, follicular atrophoderma, hypotrichosis, and localized anhidrosis.
‡ This syndrome is an autosomal dominant disorder, characterized by BCC, palmoplantar pits, odontogenic keratocysts, bifid ribs, frontal
bossing, and central nervous system defects.
Rubin et al, 2005.

12. Subtypes of BCC
Images courtesy of Jean Y. Tang, MD, PhD.

13. High Risk for Recurrence
(NCCN Guidelines)
 Diameter
– ≥ 20 mm on trunk/extremities
– ≥ 10 mm on cheeks/forehead/neck
– ≥ 6 mm anywhere else on face
 Poor tumor borders
 Immunosuppressed patient
 Prior radiation
 Subtype: Morphea, infiltrative, mixed
 Perineural
NCCN = National Comprehensive Cancer Network.
NCCN, 2012a.

14. Key Takeaways
 BCC is the most common cancer in the US
 BCC incidence is increasing

15. Current Treatment Approaches
in Basal Cell Carcinoma
Jean Y. Tang, MD, PhD
Stanford School of Medicine

16. Common Treatment Options for BCC
(NCCN Guidelines)
 Curettage and electrodesiccation
 Surgical excision
 Mohs micrographic surgery
 Cryosurgery
 Creams
– Imiquimod
– 5-FU
 Radiation therapy
 PDT
5-FU = 5-fluoruracil; PDT = photodynamic therapy.
NCCN, 2012a.

17. Rationale for Treatment Selection
 Location
– Face (near critical structures) and scarring
– Trunk
 Size
 Subtype
 Patient age, comorbidities, and compliance
NCCN, 2012a.

18. Locally Advanced or Metastatic BCC
Image courtesy of Jean Y. Tang, MD, PhD.

19. Advanced BCC
 Radiation therapy
 Cisplatin and doxorubicin
 EGFR inhibitors
 Targeted therapies with Hedgehog pathway
antagonists
EGFR = epidermal growth factor receptor.
Ganti et al, 2011.

20. BCC Have Mutations in Genes Involved
in the Hedgehog Signaling Pathway
ON
Images courtesy of Jean Y. Tang, MD, PhD.
Von Hoff et al, 2009.

21. Vismodegib Is a Small Molecule Inhibitor
of the Hedgehog Signaling Pathway
Vismodegib
OFF
Images courtesy of Jean Y. Tang, MD, PhD.
Von Hoff et al, 2009.

22. Basal Cell Nevus Syndrome (BCNS)
Patients Have Mutations in PTCH1 Gene
Image courtesy of Jean Y. Tang, MD, PhD.

23. No Effective Chemopreventive
Agents for BCC
 Oral retinoids in immunocompetent patients
fail to prevent BCC
 Selenium does not prevent
 Field treatment with 5-FU, Imiquimod, PDT
De Graaf et al, 2004; Duffield-Lillico et al, 2003.

24. Investigator-Initiated, Randomized,
Double-Blinded Trial for 18 Months
 Vismodegib at 150 mg pill vs. placebo (2:1)
 41 patients with BCNS
3 clinical centers: September 2009 to
December 2010
 Primary end point: Prevention of new BCC
 Secondary end point
– Reduction in size of existing BCC
– Safety/tolerability
Tang, 2011.

25. Two Groups Are Similar at
Baseline
Vismodegib Placebo
(N = 26) (N = 15)
Age (years) 54 53
% female 30 40
Weight (lbs) 222 222
No. BCC at baseline 29 27
(median)
Average follow-up (months) 9 7
2,000 existing BCCs
694 new BCCs
Tang, 2011.

26. Baseline Month 9
Images courtesy of Jean Y. Tang, MD, PhD.

27. Baseline Baseline
Month 5
Month 5 Month 5
Images courtesy of Jean Y. Tang, MD, PhD.

28. Vismodegib Prevents New BCCs
Vismodegib Placebo
Tang, 2011.

29. Key Takeaways
 Curerate is excellent for most BCC with
current surgical or topical therapies
 Limited
therapeutic options for locally
advanced or metastatic BCC
 Vismodegib
works for BCC prevention in
BCNS patients

30. Basal Cell Carcinoma Clinical
Advances With Novel Targeted Agents
Keith T. Flaherty, MD
Harvard Medical School
Massachusetts General Hospital Cancer Center

31. Systemic Chemotherapy for BCC
 Cisplatin-based therapy was “standard-of
care” based on case reports
 Single-agent cisplatin
– 1 complete and 1 partial response noted in a
phase I trial of cisplatin (1978)
– 1 complete response (1983)
 Cisplatin and doxorubicin
– 5 complete and 2 partial responses in 8 patients
– 4 complete, 5 partial in 12 patients
Salem et al, 1978; Wieman et al, 1983; Guthrie et al, 1985, 1990.

32. Targeted Therapy for BCC
 EGFR highly expressed in 38% of BCC
– Expression not a good marker of sensitivity to
EGFR targeted therapy in lung or colon cancer
– Case report: “Dramatic response” with cetuximab
(EGFR antibody)
– Case report: 2 cisplatin-refractory patients with
stable disease with cetuximab
Krahn et al, 2001; Muller et al, 2008; Caron et al, 2009.

33. Hedgehog/Smoothened Signaling
in BCC
 Mutations in patched gene identified in
Gorlin’s syndrome/BCNS (1996)
 90% of sporadic BCC have patched
mutations
 10% of sporadic BCC have smoothened
mutations (binding partners of patched)
Johnson et al, 1996; Gailani et al, 1996; Caro et al, 2010.

34. Patched/Smoothened Function
vismodegib
 Gli first identified as an amplified oncogene in glioblastoma
Image adapted from Metcalfe et al, 2011; Kinzler et al, 1987.

35. Small Molecule Smoothened
Inhibitors in Clinical Development
 GDC-0449 (vismodegib)
 IPI-926
 BMS-833923
 LDE225
 PF-04449913
 LEQ506
 TAK-441
Metcalfe et al, 2011.

36. Vismodegib Phase I Trial
 33 BCC patients received
– 150 mg QD (n = 17)
– 270 mg QD (n = 15)
– 540 mg QD (n = 1)
QD = per day; CR = complete response;
PR = partial response; SD = stable disease;
PD = progressive disease.
Von Hoff et al, 2009.

37. ERIVANCE BCC:
Pivotal Phase 2 Study in Advanced BCC
Metastatic BCC
RECIST
(RECIST-measurable)
REGISTRATION
• Progression
Vismodegib • Intolerable toxicity
 laBCC • Withdrawal from
• Inoperable Composite
study
• Surgery inappropriate end point
Primary end point: Secondary end points:
ORR per IRF ORR per investigator
– Metastatic BCC: RECIST DOR
– laBCC: Novel composite end PFS
point
Absence of residual BCC on
Dose 150 mg QD biopsy (laBCC only)
RECIST = Response Evaluation Criteria In Solid Tumors; laBCC = locally advanced basal cell carcinoma; ORR = objective
response rate; IRF = independent review facility; DOR = duration of response; PFS = progression-free survival.
Sekulic et al, 2011.

38. ERIVANCE BCC: Demographics
Efficacy Evaluable Patients
Metastatic BCC laBCC
(n = 33) (n = 63)
Age Mean (SD) 61.6 (11.4) 61.4 (16.9)
Median 62.0 62.0
(range) (38–92) (21–101)
Sex Male, n (%) 24 (72.7) 35 (55.6)
Female, n (%) 9 (27.3) 28 (44.4)
Race White, n (%) 33 (100) 63 (100)
IaBCC Inoperable, n (%) 24 (38.1)
Surgery inappropriate, n (%) 39 (61.9)
Multiple recurrence, n (%) 16 (25.4)
Significant morbidity/deformity, n (%) 32 (50.8)
Sekulic et al, 2011.

39. Tumor Response Criteria
 Tumor response
– Metastatic BCC: ≥ 30% size reduction by CT (RECIST)
– laBCC: Novel composite end point
∀ ≥ 30% size reduction (physical exam and/or CT)
and/or
• Complete resolution of ulceration
 Progression
≥ 20% size increase
– New lesions or new ulcerations
 SD: Does not meet criteria for response or progression
CT = computed tomography.
Sekulic et al, 2011.

40. Maximum Decrease in Tumor Size by IRF
Locally Advanced Cohort
100
Response
Stable disease
Progressive disease
50
Change in lesion diameter (%)
0
-50
-100
Sekulic et al, 2011.

41. Vismodegib Demonstrates a Significant
ORR in Locally Advanced BCC
laBCC
(n = 63)
Independent Investigator
review assessment
Responders, n (%) 27 (42.9) 38 (60.3)
SD, n (%) 24 (38.1) 15 (23.8)
PD, n (%) 8 (12.7) 6 (9.5)
Unevaluable/missing, n (%) 4 (6.3) 4 (6.3)
95% CI for objective response (30.5–56.0) (47.2–71.7)
p value (RR > 20%) < .0001
Median DOR (months) 7.6 7.6
CI = confidence interval.
Sekulic et al, 2011.

42. Vismodegib Demonstrates a Significant
ORR in Metastatic BCC
Metastatic BCC
(n = 33)
Independent Investigator
review assessment
Responders, n (%) 10 (30.3) 15 (45.5)
SD, n (%) 21 (63.6) 15 (45.5)
PD, n (%) 1 (3.0) 2 (6.1)
Unevaluable/missing, n (%) 1 (3.0) 1 (3.0)
95% CI for objective response (15.6–48.2) (28.1–62.2)
p value (RR > 10%) .0011
Median DOR (months) 7.6 12.9
Sekulic et al, 2011.

43. Vismodegib in laBCC
Baseline Week 12
Sekulic et al, 2011.

44. Vismodegib in laBCC (cont.)
Baseline Week 8 Week 48
Week 24: 4 out of 5 target lesion biopsies no BCC
Sekulic et al, 2011.

45. Most Common Adverse Events
All Treated Patients (n = 104)
All adverse Grade 1 Grade 2 Grade 3–4
Toxicity events mild moderate severe
(%) (%) (%) (%)
Muscle spasms 68 48 16 4
Alopecia 64 49 14 0
Dysgeusia 51 28 23 0
Weight
46 27 14 5
decreased
Fatigue 36 27 5 4
Nausea 29 21 7 1
Decreased
23 14 6 3
appetite
Diarrhea 22 16 5 1
Sekulic et al, 2011.

46. Vismodegib Toxicity Management
 Starting dose is 150 mg orally daily
– Supplied as 150 mg capsules
 In phase I trials, discontinuation due to
toxicity was uncommon
 Intolerable toxicities managed with temporary
dose interruption
Von Hoff et al, 2009; Erivedge® prescribing information, 2012.

47. Case Study 1:
Advanced BCC

48. Case Study
 68-year-oldwidower presents with enlarging,
bleeding mass on right ear, and post-
auricular scalp
 Extensive sun exposure history secondary to
lifelong outdoor construction work
 Hasn’t seen a doctor in 25 years
 Biopsy reveals BCC

49. ARS Question:
Next Steps
What would be your next step?
1) CT of the head and neck
2) Referral to plastic surgeon
3) Referral to radiation oncologist
4) Initiate cisplatin-based chemotherapy

50. Further Evaluation
 After further consultation with a surgeon and
radiation oncologist:
– The patient is deemed unresectable
– Radiation oncologist feels that radiation is likely to
help reduce bleeding, but unlikely to provide
significant regression or make him resectable

51. ARS Question:
Choosing Therapy
What systemic therapies would you
recommend?
1) Cisplatin-based chemotherapy
2) Oral inhibitor of Hedgehog/Smoothened
3) EGFR inhibitor
4) No systemic therapy, supportive measures
only

52. Key Takeaways
 Chemotherapy has some activity in advanced/metastatic BCC
 Discovery of mutations in patched/smoothened created opportunity
to target smoothened
 ~ 80% of patients with advanced BCC have regression of disease
(30%–60% have objective responses)
 Possibility of using smoothened inhibitors as neoadjuvant therapy
for locally advanced patients needs to be studied
 On January 30, 2012, the FDA approved vismodegib for the
treatment of adults with metastatic BCC, or with laBCC that has
recurred following surgery or who are not candidates for surgery,
and who are not candidates for radiation
– Recommended dose is 150 mg taken orally once daily
Erivedge® prescribing information, 2012.

53. Beyond Basal Cell Carcinoma:
Novel Approaches to Treating
Melanoma
Vernon K. Sondak, MD
H. Lee Moffitt Cancer Center & Research Institute
Keith T. Flaherty, MD
Harvard Medical School
Massachusetts General Hospital Cancer Center

54. Ten Leading Cancer Types for the
Estimated New Cancer Cases by Sex, 2012
Estimated New Cases
Prostate 241,740 29%
Male Female Breast 226,870 29%
Lung & bronchus 116,470 14% Lung & bronchus 109,690 14%
Colon & rectum 73,420 9% Colon & rectum 70,040 9%
Urinary bladder 55,600 7% Uterine corpus 47,130 6%
#5 Melanoma of the skin 44,250 5% Thyroid 43,210 5%
Kidney & renal pelvis 40,250 5% Melanoma of the skin #6 32,000 4%
Non-Hodgkin lymphoma 38,160 4% Non-Hodgkin lymphoma 31,970 4%
Oral cavity & pharynx 28,540 3% Kidney & renal pelvis 24,520 3%
Leukemia 26,830 3% Ovary 22,280 3%
Pancreas 22,090 3% Pancreas 21,830 3%
All Sites 848,170 100% All Sites 790,740 100%
Siegel et al, 2012.

55. Annual Age-Adjusted Cancer Incidence Rates
for Selected Cancers by Sex, 1975–2008
Siegel et al, 2012.

56. Ten Leading Cancer Types for the
Estimated New Cancer Deaths by Sex, 2012
Estimated Deaths
Lung & bronchus 87,750 29% Males Females Lung & bronchus 72,590 26%
Prostate 28,170 9% Breast 39,510 14%
Colon & rectum 26,470 9% Colon & rectum 25,220 9%
Pancreas 18,850 6% Pancreas 18,540 7%
Ovary 15,500 6%
Liver & intrahepatic bile duct 13,980 5%
Leukemia 10,040 4%
Leukemia 13,500 4%
Non-Hodgkin lymphoma 8,620 3%
Esophagus 12,040 4%
Uterine corpus 8,010 3%
Urinary bladder 10,510 3%
Liver & intrahepatic bile duct 6,570 2%
Non-Hodgkin lymphoma 10,320 3%
Brain & other nervous system 5,980 2%
Kidney & renal pelvis 8,650 3%
All Sites 275,370 100%
All Sites 301,820 100%
Siegel et al, 2012.

57. Death Rate (per 100,000) Change
Male 1990* 2007 Absolute % %Contribution†
All malignant cancers 279.82 217.79 -62.03 -22.17
Decreasing
Contribution of Lung & bronchus 90.56 65.23 -25.33 -27.97 38.5
Individual Cancer Prostate
Colorectum
38.56
30.77
23.50
20.05
-15.06
-10.72
-39.06
-34.84
22.9
16.3
Sites to Change Stomach 8.86 5.01 -3.85 -43.45 5.9
Oral cavity & pharynx 5.61 3.85 -1.76 -31.37 2.7
in Male Cancer Non-Hodgkin lymphoma 9.97 8.29 -1.68 -16.85 2.6
Death Rates, Leukemia
Larynx
10.71
2.97
9.44
2.05
-1.27
-0.92
-11.86
-30.98
1.9
1.4
1990–2007 Brain & other nervous system 5.97 5.10 -0.87 -14.57 1.3
Myeloma 4.83 4.39 -0.44 -9.11 0.7
Urinary bladder 7..97 7.56 -0.41 -5.14 0.6
Kidney & renal pelvis 6.16 5.79 -0.37 -6.01 0.6
Hodgkin lymphoma 0.85 0.50 -0.35 -41.18 0.5
Other decreasing 38.66 35.89 -2.77 -7.17 4.2
Total 262.45 196.65 -65.80 100.0
Increasing
Liver & intrahepatic bile duct 5.27 7.92 2.65 50.28
Esophagus 7.16 7.67 0.51 7.12
Melanoma of the skin 3.80 3.98 0.18 4.74
Other increasing 0.84 1.29 0.45 53.57
Total 17.07 20.86 3.79
No change
Bones & joints 0.55 0.55 0.00 0.00
Siegel et al, 2011.

58. Melanoma
2012 ACS Incidence Predictions
 131,810 new cases of melanoma in the US
predicted for 2012
– 55,560 noninvasive cases
(melanoma in situ)
– 76,250 invasive cases
– 9,250 cases predicted for California
– 5,450 cases predicted for Florida
 9,180 deaths predicted for 2012
Image courtesy of Vernon K. Sondak, MD.
Siegel et al, 2012.

59. Cutaneous Malignant Melanoma
AJCC Staging System
TUMOR NODES
 T1 ≤ 1.00 mm*  N0 all nodes -ve
 T2 1.01–2.00 mm  N1 1 +ve node
 T3 2.01–4.00 mm  N2 2–3 +ve nodes
 T4 > 4.00 mm  N3 ≥ 4 +ve nodes
a) non-ulcerated a) microscopic
b) ulcerated (*or mitoses b) macroscopic
≥ 1/mm2)
AJCC, 2009.

60. Cutaneous Malignant Melanoma
2012 Surgical Guidelines
TUMOR SURGERY
 < 1 mm  1 cm excision
 1–2 mm  1–2 cm excision
 > 2 mm  2 cm excision
 Any positive nodes  Complete LN dissection
LN = lymph node.
Bichakjian et al, 2011.

61. Cutaneous Malignant Melanoma
2012 Surgical Guidelines (cont.)
TUMOR SURGERY
 < 1 mm  1 cm excision, no SLN Bx*
 1–2 mm  1–2 cm excision, SLN Bx
 > 2 mm  2 cm excision, SLN Bx
 Any positive nodes  Complete LN dissection
*Selected patients < 1 mm (young age or “high-risk
histology”) should be considered for SLN Bx.
Bx = biopsy; SLN = sentinel lymph node.
Bichakjian et al, 2011.

62. Sentinel Node Biopsy Update
 Sentinel node status remains the most important
predictor of melanoma-specific survival for thinner,
intermediate, and thick melanomas
 Sentinel node biopsy reliably detects nodal metastases
which, if left in place, would result in clinical recurrence
– 4%–5% of patients with negative sentinel nodes fail in the
regional nodes (~ 15% of positive nodes are missed)
 The evidence continues to indicate that patients with a
positive node benefit from earlier lymphadenectomy both
in terms of melanoma-specific survival (intermediate
thickness subset) and with less lymphedema from node
dissection
Bichakjian et al, 2011.

63. FDA Approved Drugs in Use for
Melanoma (as of February 2011)
 Dacarbazine, 1970s
– RR: < 10% in unselected stage IV melanoma patients
– No proven impact on survival
– Temozolomide, carbo-taxol frequently used instead
 High-dose IFN, 1995
– The only approved adjuvant therapy
– Consistent benefit on relapse-free survival, controversial survival benefit
 High-dose IL-2, 1998
– RR: 16% in highly selected stage IV melanoma patients
– Durable responses: ~ 5%
– Rarely used outside of a high-volume centers
IFN = interferon; IL-2 = interleukin-2.
Intron®A prescribing information, 2012; Proleukin® prescribing information, 2012; DTIC-Dome® prescribing information, 2012;
Middleton et al, 2000; Mansfield et al, 2009; Fyfe et al, 1995; Kammula et al, 1998; Atkins et al, 2000.

64. Drugs Approved for Melanoma
by the FDA in 2011
 Pegylated IFN-2b
– Improved relapse-free survival in adjuvant therapy of stage III melanoma
– No proven impact on survival
– 5-year treatment regimen
 Ipilimumab (anti-CTLA4 monoclonal antibody)
– Immunotherapy for stage IV melanoma
– Improved OS in 2 phase III trials
 Vemurafenib (V600 mutant BRAF inhibitor)
– For patients with BRAF V600 mutant melanoma
– Rapid responses, rarely durable
– Improved OS in a phase III trial compared to DTIC
CTLA4 = cytotoxic T-lymphocyte antigen 4; OS = overall survival.
Zelboraf® prescribing information, 2012; Yervoy® prescribing information, 2012; Sylatron® prescribing information, 2012.

65. Anti-CTLA4 Antibodies
Vernon K. Sondak, MD
H. Lee Moffitt Cancer Center & Research Institute

66. Targeted Immunotherapy CTLA4 Blockade
Taking the Brakes Off T-Cell Activation
T-cell T-cell T-cell
activation inactivation activation
CTLA-4
CTLA-4
T cell T cell
T cell
TCR CD28
HLA B7 Ipilimumab
APC APC APC
TCR = T-cell receptor; APC = antigen presenting cell.
Image adapted from Weber et al, 2008b.

67. Targeting T Cells With Ipilimumab (anti-CTLA4
antibody) Leads to Durable Response
Treatment SD
= Ipilimumab Treatment, 10 mg/kg
100
PR
80
Tumor Size (%)
60
40 Response
CR ongoing years
20 later with no
new lesions
0
0 10 20 30 40 50 60
Post-Treatment Initiation (weeks)
Weber, 2008a.

68. Progression Followed by Response in
Melanoma Patient Treated With Ipilimumab
Screening Week 8: “Progression” Week 12: Improved
Week 16: Continued Week 72: Complete Week 108: Still in
Improvement Remission Complete Remission
Images courtesy of Jedd Wolchok, MD.
Hoos et al, 2010; Maggon, 2011.

69. Ipilimumab (3 mg/kg x 4) Improves OS in
Previously Treated Stage IV Melanoma
Ipilimumab + gp100
Ipilimumab alone
gp100 alone
1 2 Years 3 4
Ipi + gp100 Ipi + pbo gp100 + pbo
Survival Rate
(N = 403) (N = 137) (N = 136)
1 year 44% 46% 25%
2 years 22% 24% 14%
Hodi et al, 2010.

70. Ipilimumab (10 mg/kg) + DTIC Improves OS in
Previously Untreated Stage IV Melanoma
No. of deaths: 196 vs. 218, HR 0.72 (0.59–0.87) p < .001
1-year survival 47.3% vs. 36.3%
2-year survival 28.5% vs. 17.9%
3-year survival 20.8% vs. 12.2%
HR = hazard ratio.
Robert et al, 2011.

71. Randomized Phase 2 Trial of 3 Doses of Ipilimumab
(0.3 mg/kg, 3.0 mg/kg, 10 mg/kg) in Stage IV Melanoma
Dose 0.3 mg/kg 3 mg/kg 10 mg/kg
RR (%) 0 4.2 11.1
Wolchok et al, 2010.

72. When Going Downhill With No Brakes,
A Steering Wheel Is A Great Idea!
Images courtesy of Vernon K. Sondak, MD.

73. Ipilimumab Treatment and irAEs
 Blockade of CTLA-4 frequently leads to the development
of irAEs, due to T cells losing tolerance to self-antigens
 Common autoimmune adverse events
– Dermatitis
– Hepatitis
– Endocrinopathies/pituitary dysfunction
– Enterocolitis
 Diarrhea is often the first manifestation of autoimmune
toxicity, and requires prompt and aggressive treatment
– Antidiarrheal agents (loperamide or diphenoxylate/atropine)
– Intravenous and/or oral corticosteroids
– Oral budesonide
– Infliximab (anti-TNFα antibody)
– Surgery in extreme cases (< 1%)
 Toxicity does not equal response, but there appears to be
an association
irAEs = immune-related adverse events.
Images courtesy of Vernon K. Sondak, MD.
Yervoy® prescribing information, 2011; Thumar & Kluger, 2011; Hodi et al, 2010; Ledezma, 2009.

74. The Future of Melanoma Immunotherapy
PD1 Blockade Reviving Exhausted T Cells
T-cell T-cell
exhaustion reactivation
T cell
T cell
TCR PD1
HLA PDL1 Anti-PD1
Tumor Tumor
Image adapted from Topalian et al, 2012.

75. BRAF Inhibitors
Keith T. Flaherty, MD
Harvard Medical School
Massachusetts General Hospital Cancer Center

76. Oncogenes in Melanoma
Year Target Prevalence (%) Drug
1984 NRAS 20 –
2002 BRAF 50 Sorafenib, PD0325901,
AZD6244, RAF-265, XL281,
Vemurafenib, GSK2118436
2005 c-Kit 1 Imatinib, Dasatinib, Nilotinib
2008 GNAQ/GNA11 1a –
80%–90% of uveal.
a
Padua et al, 1984; Davies et al, 2002; Willmore-Payne et al, 2005; Van Raamsdonk et al, 2009.

77. Distribution of Commonly Mutated Oncogenes
by Body Site of Primary Melanoma
GNAQ 45%
GNA11 32 % uveal
BRAF 28%
scalp/face NRAS 18%
BRAF 57%
NRAS 10% trunk/legs
NRAS 18%
BRAF 20%
c-Kit 36% acral
mu
c os
a l c-Kit 39%
ac NRAS 10%
ra
l BRAF 5%

78. Signaling Pathways Downstream
of Melanoma Oncogenes
c-kit
BRAF CRAF NRAS
GNA11
GNAQ PI3K
MEK
AKT
PKC
ERK
mTOR
Van Raamsdonk et al, 2010; Curtin et al, 2006; Lee et al, 2011; Perez-Lorenzo et al, 2012.

79. BRAF Mutation Testing Guidelines
 As vemurafenib is FDA approved for the
treatment of metastatic disease, testing for a
BRAF mutation for metastatic patients is
considered standard of care
 For patients with high risk, resected
melanoma physicians may consider ordering
BRAF mutation testing based on the
assumption that systemic therapy may be
needed quickly upon recurrence
Zelboraf® prescribing information, 2012.

80. BRAF Mutation Testing
 Visceral metastatic tissue or lymph node
metastases are typically used as source
serial for mutation testing
 Testing can be performed either on formalin
fixed, paraffin embedded tumors, or fresh
tumor biopsies placed in formalin
 The FDA has approved 1 BRAF mutation
test: Cobas® 4800 BRAF V600 Mutation Test
Zelboraf® prescribing information, 2012.

81. Phase 2 Study of Vemurafenib in
Previously Treated Patients With Metastatic
Melanoma
Previously treated End Points
V600 mutant Vemurafenib Primary: RR
metastatic melanoma (960 mg PO bid) Secondary: DOR,
(N = 132) PFS, OS, Safety
Eligibility Criteria
• PD after prior IL-2 or standard chemotherapy
• ECOG PS 0 or 1
• Brain metastases allowed if treatment with stereotactic RT or surgery,
and stable for > 3 mos
Statistical Considerations
• Target ORR 30%
• Assume 10% ineligibility
• Total of 90 patients needed to demonstrate the lower boundary of
the exact 95% CI is ≥ 20%
ECOG PS = Eastern Cooperative Oncology Group performance status; RT = radiotherapy.
Sosman et al, 2010; Ribas et al, 2011.

82. Patient Demographics
N = 132
Patient/Disease Characteristics (%) %/%
Sex, Female/Male 39 / 61
Race, Caucasian/Hispanic 98 / 2
Median age (years) 51.5
Age < 65/≥ 65 81 / 19
ECOG PS, 0/1 46 / 54
Stage at Diagnosis, M1a/M1b/M1c 25 / 14 / 61
Serum LDH, Normal/Elevated 51 / 49
Number Prior Therapies, 1/2/≥ 3 51 / 27 / 22
Previous IL-2, No/Yes 61 / 39
Previous Ipilimumab or Tremelimumab (No/Yes) 95 / 5
LDH = lactate dehydrogenase.
Sosman et al, 2010; Ribas et al, 2011.

83. Tumor Regression in
Approximately 90% of Patients
7 confirmed CRs
CR = confirmed response.
Ribas et al, 2011.

84. PFS
100 Median PFS 6.7 months (95% CI: 5.5, 7.8 months)
90 PFS at 6 months 54% (95% CI: 45, 63%)
Probability of PFS (%)
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
No. At Risk Time (months)
132 129 115 93 85 73 62 45 41 33 25 18 11 6 1
Ribas et al, 2011.

85. OS
100
90
Probability of OS (%)
80
70
60
50
Median OS Not Reached
40
OS at 6 months 77% (95% CI: 70, 85)
12 months 58% (95% CI: 49, 67)
30
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
No. At Risk Time (months)
132 131 128 122 118 109 97 90 83 78 71 55 34 19 7 0
Ribas et al, 2011.

86. Most Commonly Reported Drug-Related AEs
Includes AEs Reported in ≥ 20 Patients
All grades Grade 3 Grade 4
n (%) n (%) n (%)
Arthralgia 78 (59) 8 (6) –
Rash 69 (52) 9 (7) –
Photosensitivity
69 (52) 4 (3) –
Reaction
Fatigue 56 (42) 2 (2) –
Alopecia 48 (36) – –
Pruritus 38 (29) 3 (2) –
Skin Papilloma 38 (29) – –
cuSCC (KA)* 34 (26) 34 (26) –
Nausea 30 (23) 2 (2) –
Elevated Liver Enzymes 23 (17) 8 (6) 4 (3)
*Cases of cuSCC/KA were managed with simple excision and did not require dose modification.
AE = adverse event; cuSCC/KA = cutaneous squamous cell carcinoma/keratoacanthomas.
Ribas et al, 2011.

87. AEs Leading to Drug Modifications,
Interruptions, and Discontinuations
n (%)
Total dose modifications 59 (45)
Dose reductions
Reduction to 720 mg bid 37
Reduction to 480 mg bid 21
Reduction to < 480 mg bid 1
Dose interruptions 85 (64)
Discontinuations 4 (3)
Common AEs leading to dose modifications/interruptions were rash, arthralgia, LFT
abnormalities, and photosensitivity
LFT = live function test.
Ribas et al, 2011.

88. Phase 2 Trial of GSK2118436 in Patients
With BRAF Mutation-Positive (V600E/K)
Metastatic Melanoma
• Single arm, phase II, open label
• Green-Dahlberg 2-Stage: Ho: ORR ≤ 25% vs. Ha: ORR ≥ 40%
Patients
Screened
Metastatic melanoma n = 211
Confirmed V600E
n = 76
BRAFV600E/K GSK2118436
mutation 150 mg bid
Enrolled until PD, death,
Absence of brain n = 92 or unacceptable
metastases AE
V600K
n = 16
No prior treatment
with MEK or BRAF
inhibitors
Primary objective: RR in V600E mutated
Trefzer et al, 2011.

89. Study Population
Population Description N
All Treated Subjects All subjects that received at least 1 92
dose of GSK2118436
V600E Subjects with a V600E mutation 76
V600K Subjects with a V600K mutation 16
M-status, n (%)
M1 1 (1%)
M1a 16 (17%)
M1b 14 (14%)
M1c 58 (63%)
Missing 3 (3%)
Trefzer et al, 2011.

90. Most Common AEs
AE N = 92
n (%)
Arthralgia 30 (33%)
Hyperkeratosis 25 (27%)
Pyrexia 22 (24%)
Fatigue 20 (22%)
Headache 19 (21%)
Nausea 18 (20%)
SCC 8 (9%)
Trefzer et al, 2011.

91. Best Tumor Response:
V600E Population
M-Stage at screening M1 M1a M1b M1c Missing
Trefzer et al, 2011.

92. Best Tumor Response:
V600K Population
M-Stage at screening M1 M1a M1b M1c Missing
Scans unavailable for 1 patient
Trefzer et al, 2011.

93. PFS
V600E Median PFS (weeks): 27.4, Progressed: 40 (53%)
V600K Median PFS (weeks): 19.7, Progressed: 13 (81%)
1.0
Estimated PFS Function (%)
0.8
0.6
0.4
0.2
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Time Since First Dose (Weeks)
Trefzer et al, 2011.

94. Phase 3 Trial Comparing Vemurafenib to
DTIC in Patients With V600 Mutated
BRAF Melanoma
BRAFV600 mutation
Vemurafenib
by Cobas® 4800 test
960 mg PO bid
(n = 337)
Randomization
N = 675
Stratification
DTIC
• Stage
1,000 mg/m2 IV q3wks
• ECOG PS (0 vs. 1)
(n = 338)
• LDH elevated vs.
normal
• Geographic region
DTIC = dacarbazine; IV = intravenous.
Chapman et al, 2011.

95. Patient Demographics
Dacarbazine (n = 338) Vemurafenib (n = 337)
Median age (years)
52.5 56.0
Male, no. (%) 181 (54) 200 (59)
ECOG PS, no. (%)
0 108 (32) 108 (32)
1 230 (68) 229 (68)
Stage, no. (%)
Unresectable IIIc 13 (4) 20 (6)
M1a 40 (12) 34 (10)
M1b 65 (19) 62 (18)
M1c 220 (65) 221 (66)
LDH > ULN 142 (42) 142 (42)
ULN = upper limit of normal.
Chapman et al, 2011.

96. OS
100
84% of patients alive at 6 months
90
Vemurafenib (n = 336)
80
70
64% of patients alive at 6 months
OS (%)
60
50
Dacarbazine (n = 336)
40
30
HR 0.37
20 (95% CI: 0.26–0.55)
10
Log-rank p < .0001
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (months)
No. Patients in Follow-Up
Dacarbazine 336 283 192 137 98 64 39 20 9 1 1
Vemurafenib 336 320 266 210 162 111 80 35 14 6 1
Chapman et al, 2011.

97. Efficacy Data From Vemurafenib
Phase 3, Phase 2, and Phase 1:
Cross Trial Comparison
Study Phase 3 Phase 2 Phase 1
6-month OS (%) 84 77 87
1-year OS (%) Not yet reached 58 > 50
2-year OS (%) Not yet reached Not yet reached 37.5
Median OS (months) Not yet reached Not yet reached 14.9
Median PFS (months) 5.3 6.7 7.8
Confirmed
48 53 56
Response (%)
Chapman et al, 2011; Ribas et al, 2011; Flaherty et al, 2010; Kim et al, 2011; McArthur et al, 2011.

98. A Phase II Study of the MEK1/MEK2 Inhibitor GSK1120212 in
Metastatic BRAF-V600E or K Mutant Cutaneous Melanoma
Patients Previously Treated With or Without a BRAF Inhibitor
< 3 CR/PR
 Green-Dahlberg 2-Stage Stop due to
futility
Prior
Patients BRAFi
(Cohort A)
Metastatic n = 30 n = 25
Cutaneous
Melanoma
Enroll, then GSK1120212 dosed at 2 mg qd
BRAFV600E/K/D
Stable Brain
n = 30 n = 25
Metastases Prior
Therapy,
no BRAFi
(Cohort B)
Kim et al, 2011.

99. Patient Characteristics
Cohort A Cohort B Cohort A Cohort B
Characteristic N = 40 N = 57 Characteristic N = 40 N = 57
(%) (%) (%) (%)
Mean age, years 55.6 54.0 LDH > ULN 55 42
Gender, Male 63 75 Stage
IIIc 0 2
ECOG 0 48 74
M1a 13 12
Prior brain
13 21 M1b 15 11
metastases
M1c 73 75
BRAF mutation
83 81 Prior therapies
V600E 10 14 1–2 50 87
V600K 3 2 ≥3 50 13
K601E 0 2 Chemotherapy 62 86
V600K/R1 3 2 Immunotherapy3 42 54
V600K/E1 3 0
Both chemo/immuno 33 40
Unknown2
1
Same tissue with different results in different assays.
2
BRAF mutation positive; details unknown.
3
3 patients in each cohort received prior ipilimumab; all 6 also received prior chemotherapy.
Kim et al, 2011.

100. Most Common Treatment-Related
AEs ≥ 20%
Events n = 97 (%)  Only one Grade 4
G1–2 G3 Total treatment-related event
Skin-related toxicity1 76 10 87
– Pulmonary embolism
Rash 45 6 52
Dermatitis acneiform 25 4 30
 Dose reductions due to
AEs in 15% of patients
Diarrhea 47 4 52
– Most frequently for rash
Peripheral edema 26 3 29
and dermatitis acneiform
Fatigue 23 2 26
 3% of patients
Pruritis 26 1 27
permanently withdrew
Nausea 30 0 30
GSK1120212 due to
Dry skin 22 0 22 toxicity
1
Skin-related toxicity includes multiple terms.
Kim et al, 2011.

101. Cohort A Tumor Response (n = 40)
266% 155%
Unconfirmed Response Rate (RR): 5% (95% CI, 0.6, 16.9)
1 CR, 1 PR, 10 SD
*
Change at Maximum Reduction From
Baseline Measurement (%)
K
K
K
K
*
K V600K
* Discontinued prior BRAFi due to toxicity *
M-Stage at screening M1a M1b M1c
Scans unavailable for 5 patients: 2 died and 1 withdrew before first scan,
2 had incomplete scan
Kim et al, 2011.

102. Cohort A PFS (n = 40)
Median PFS 1.8 months (95% CI, 1.8, 2.0)
1.0
0.8
PFS (%)
0.6
0.4
0.2
0.0
0 1 2 3 4 5 6 7 8 9
Time (months)
Kim et al, 2011.

103. Cohort B Tumor Response (n = 57)
Confirmed Response Rate (RR): 25% (95% CI, 14.1, 37.8)
256% 1 CR, 13 PR, 29 SD
Unconfirmed RR: 35% (95% CI, 22.9, 48.9)
Change at Maximum Reduction From
2 CR, 18 PR, 23 SD
Baseline Measurement (%)
Median DOR: 5.7 months
* (95% CI 3.7, 9.2)
*
K
* K
*
* *
K
*
K
K
*
*
K
*
* *
K
K
K V600K
* Prior history of brain metastases
M-Stage at screening M0 M1a M1b M1c
Scans unavailable for 2 patients: 1 progressed before scan, 1 had incomplete scan
Kim et al, 2011.

104. Cohort B PFS (n = 57)
Median PFS 4.0 months (95% CI, 3.6, 5.6)
1.0
0.8
0.6
PFS (%)
0.4
0.2
0.0
0 50 100 150 200 250 300 350 400
Time (Days)
Kim et al, 2011.

105. Ongoing Targeted Therapy Trials
 BRAF mutated
– Dabrafenib (GSK2118436) vs. DTIC (first-line)
– Trametinib (GSK1120212) vs. DTIC or paclitaxel (first or second-
line)
 CKIT mutated
– Nilotinib phase II (first-line)
– Imatinib phase II (first-line)
– Dasatinib phase II (first-line)
– Sunitinib phase II (second-line)
 GNAQ/GNA11
– AZD6244 vs. temozolomide randomized phase II

106. Phase II Trial of imatinib in Patients With c-kit
Genetic Aberrations: Patient Characteristics
Patients (N = 35)
Median age 56 (27–76)
Gender (M/F) 17/18
Primary site
16:10:4:2:3
(Acral: Mucosal: CSD: NSD: MM)
Previous regimen (0: 1: 2: 3) 4:17:13:1
Stage (M1a: M1b: M1c) 7:2:26
KIT status (Exon 9:11:13:17:18: amplif) 2:14:8:3:5:3
CSD: Melanoma on skin with chronic sun-induced damage; Non-CSD: Melanoma on skin without chronic sun-induced damage;
MM: Metastatic melanoma with unknown primary.
Guo et al, 2010.

107. Change in Tumor Size Compared
to Baseline
M1a M1b M1c
Guo et al, 2010.

108. Correlations of Response and KIT
Aberrations
KIT Status PR SD PR + SD
KIT Amp 1/3 0/3 1/3
Exon11 2/12 8/12 10/12
70%
Exon13 3/8 1/8 4/8
Exon17 0/3 1/3 1/3
Exon18 0/4 2/4 2/4
Multiple gene aberrations* 3/4 1/4 4/4
*4 patients respectively harbored multiple KIT aberrations as following: (13)K642E+Amplification; (13) I817T(T2450C);
(18)F848L(T2542C); (11)L576P+Amplification.
Guo et al, 2010.

109. Systemic Therapies for Advanced or
Metastatic Melanoma: NCCN Guidelines
 Clinical trial
 Ipilimumab
– Approved on 3/25/11 for unresectable or metastatic melanoma
 Vemurafenib (BRAFV600E)
– Approved on 8/17/11 for BRAFV600E mutation-positive
metastatic melanoma
 HD-IL2
 Paclitaxel/carboplatin/cisplatin
 Dacarbazine, temozolomide
NCCN, 2012b; Zelboraf® prescribing information, 2012; Yervoy® prescribing information, 2012.

110. Currently Accruing Clinical Trials
in Melanoma
Agent Trial Name Phase
Nilotinib vs. DTIC NCT01028222 2
TIL + IL-2 vs. observation NCT00200577 3
AZD6244 NCT00866177 2
DTIC vs. paclitaxel + cisplatin vs. treosulfan + cytarabine ChemoSensMM 3
Ipilimumab vs. HD IFN-2b NCT01274338 3
Masitinib vs. DTIC NCT01280565 3
RO5185426 NCT01307397 3
Ipilimumab 3 mg/kg vs. 10 mg/kg NCT01515189 3

111. Case Study 2:
First-Line Treatment Options for
Stage IV Metastatic Melanoma

112. Case Study
 A 28-year-old woman is diagnosed with
metastatic melanoma in the lungs, liver, and
bone 3 years after undergoing wide excision of
an ulcerated 1.2 mm melanoma of the left upper
arm
 Serum LDH is 3x the upper limit of normal and a
brain MRI is negative
 The patient is severely symptomatic due to bone
pain, although imaging studies have not shown
any evidence of a pathologic fracture

113. ARS Question:
Testing
What testing would be appropriate at this point?
1) None required
2) BRAF V600E
3) Fluorescence In Situ Hybridization
(FISH)
4) ImmunoHistoChemisty (IHC)
5) KRAS

114. Biopsy Results
 Mutation
analysis performed on a core biopsy
specimen from a lung nodule
– Positive for BRAF V600E mutation

115. ARS Question:
Treatment Options
At this point, the treatment option associated with the best
chance of symptomatic relief and achieving objective
response is:
1) Stereotactic radiosurgery to any
symptomatic bone lesions without
systemic therapy
2) Single-agent dacarbazine or
temozolomide
3) HD IL-2
4) Ipilimumab
5) Vemurafenib

116. Key Takeaways on the Management
of Stage IV Melanoma
 If possible, resect all disease and consider an adjuvant therapy
clinical trial
 For unresectable disease, consider high dose IL-2 first for patients
with excellent performance status, few/no comorbidities and limited
tumor burden
 For IL-2 failures or patients who are not candidates, ipilimumab if
BRAF negative or BRAF V600 mutant with limited disease burden
 Vemurafenib has a high response rate, improved progression-free
and overall survival compared to chemotherapy
– Represents a new treatment option for patients with V600 mutations
 GSK2118436 (BRAF) and GSK1120212 (MEK) are emerging as
promising agents as well for V600 mutation positive melanoma
 Always consider clinical trials

117. Panel Discussion:
Multi-Disciplinary
Perspectives in Basal Cell
Carcinoma
Jean Y. Tang, MD, PhD – Dermatologist
Keith T. Flaherty, MD – Medical Oncologist
Vernon K. Sondak, MD – Surgical Oncologist

118. Topics for Discussion
 When are surgical options no longer
appropriate?
 WhichBCC patients are best candidates for
systemic therapy?
 When should dermatologists refer a patient to
an oncologist?
 How to best manage patients in an era of
targeted therapy?