DISCLAIMERDISCLAIMERParticipants 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 USEDISCLOSURE OF UNLABELED USEThis 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.

Disclosure of Conflicts of InterestDisclosure 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.

Learning ObjectivesLearning ObjectivesUpon completion of this activity, participants Upon completion of this activity, participants

should be better able to: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

Introduction to Faculty PanelIntroduction 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

Activity AgendaActivity 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)

Overview of Basal Cell Overview of Basal Cell CarcinomaCarcinoma

Jean Y. Tang, MD, PhDStanford School of Medicine

Types of Skin CancerTypes of Skin CancerApproximately 3.6 Million Americans Will Be Approximately 3.6 Million Americans Will Be

Diagnosed With Skin Cancer This YearDiagnosed With Skin Cancer This Year

BCC = basal cell carcinoma; SCC = squamous cell carcinoma.Images courtesy of Jean Y. Tang, MD, PhD.Rogers et al, 2010; ACS, 2012.

BCC SCC Melanoma

Basal Cell Carcinoma: Clinical NeedBasal 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.

Epidemiology of BCCEpidemiology 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.

*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.

BCC Risk FactorsBCC Risk Factors

Subtypes of BCCSubtypes of BCC

Images courtesy of Jean Y. Tang, MD, PhD.

High Risk for Recurrence High Risk for Recurrence (NCCN Guidelines)(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.

Key TakeawaysKey Takeaways

BCC is the most common cancer in the US

BCC incidence is increasing

Current Treatment Approaches Current Treatment Approaches in Basal Cell Carcinomain Basal Cell Carcinoma

Jean Y. Tang, MD, PhDStanford School of Medicine

Common Treatment Options for BCCCommon Treatment Options for BCC(NCCN Guidelines)(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.

Rationale for Treatment SelectionRationale for Treatment Selection

Location

– Face (near critical structures) and scarring

– Trunk

Size

Subtype

Patient age, comorbidities, and compliance

NCCN, 2012a.

Locally Advanced or Metastatic BCCLocally Advanced or Metastatic BCC

Image courtesy of Jean Y. Tang, MD, PhD.

Advanced BCCAdvanced BCC

Radiation therapy

Cisplatin and doxorubicin

EGFR inhibitors

Targeted therapies with Hedgehog pathway antagonists

EGFR = epidermal growth factor receptor.Ganti et al, 2011.

BCC Have Mutations in Genes Involved BCC Have Mutations in Genes Involved in the Hedgehog Signaling Pathwayin the Hedgehog Signaling Pathway

ON

Images courtesy of Jean Y. Tang, MD, PhD. Von Hoff et al, 2009.

Vismodegib Is a Small Molecule Inhibitor Vismodegib Is a Small Molecule Inhibitor of the Hedgehog Signaling Pathway of the Hedgehog Signaling Pathway

Vismodegib

OFFImages courtesy of Jean Y. Tang, MD, PhD. Von Hoff et al, 2009.

Basal Cell Nevus Syndrome (BCNS) Basal Cell Nevus Syndrome (BCNS) Patients Have Mutations in Patients Have Mutations in PTCH1PTCH1 Gene Gene

Image courtesy of Jean Y. Tang, MD, PhD.

No Effective Chemopreventive No Effective Chemopreventive Agents for BCCAgents 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.

Investigator-Initiated, Randomized, Investigator-Initiated, Randomized, Double-Blinded Trial for 18 MonthsDouble-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.

Two Groups Are Similar at Two Groups Are Similar at Baseline Baseline

Vismodegib(N = 26)

Placebo (N = 15)

Age (years) 54 53

% female 30 40

Weight (lbs) 222 222

No. BCC at baseline (median)

29 27

Average follow-up (months) 9 7

2,000 existing BCCs 694 new BCCs

Tang, 2011.

Images courtesy of Jean Y. Tang, MD, PhD.

Baseline Baseline Month 9Month 9

BaselineBaseline

Month 5

BaselineBaseline

Month 5Month 5

Images courtesy of Jean Y. Tang, MD, PhD.

Vismodegib Prevents New BCCsVismodegib Prevents New BCCs

Vismodegib Placebo

Tang, 2011.

Key TakeawaysKey Takeaways

Cure rate 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

Basal Cell Carcinoma Clinical Basal Cell Carcinoma Clinical Advances With Novel Targeted AgentsAdvances With Novel Targeted Agents

Keith T. Flaherty, MDHarvard Medical School

Massachusetts General Hospital Cancer Center

Systemic Chemotherapy for BCCSystemic 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.

Targeted Therapy for BCCTargeted 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.

Hedgehog/Smoothened Signaling Hedgehog/Smoothened Signaling in BCCin 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.

Patched/Smoothened FunctionPatched/Smoothened Function

Image adapted from Metcalfe et al, 2011; Kinzler et al, 1987.

Gli first identified as an amplified oncogene in glioblastoma

vismodegibvismodegib

Small Molecule Smoothened Small Molecule Smoothened Inhibitors in Clinical DevelopmentInhibitors in Clinical Development

GDC-0449 (vismodegib)

IPI-926

BMS-833923

LDE225

PF-04449913

LEQ506

TAK-441

Metcalfe et al, 2011.

Vismodegib Phase I TrialVismodegib 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.

ERIVANCE BCC:ERIVANCE BCC:Pivotal Phase 2 Study in Advanced BCCPivotal Phase 2 Study in Advanced BCC

RE

GIS

TR

AT

ION

• Progression• Intolerable toxicity• Withdrawal from

study

RECIST

Compositeend point

Vismodegib

Metastatic BCC (RECIST-measurable)

laBCC• Inoperable• Surgery inappropriate

Primary end point:

ORR per IRF

– Metastatic BCC: RECIST

– laBCC: Novel composite end point

Dose 150 mg QD

Secondary end points:

ORR per investigator

DOR

PFS

Absence of residual BCC on 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.

ERIVANCE BCC: Demographics ERIVANCE BCC: Demographics Efficacy Evaluable PatientsEfficacy Evaluable Patients

Metastatic BCC(n = 33)

laBCC(n = 63)

Age Mean (SD)

Median

(range)

61.6 (11.4)

62.0

(38–92)

61.4 (16.9)

62.0

(21–101)

Sex Male, n (%)

Female, n (%)

24 (72.7)

9 (27.3)

35 (55.6)

28 (44.4)

Race White, n (%) 33 (100) 63 (100)

IaBCC Inoperable, n (%)

Surgery inappropriate, n (%)

Multiple recurrence, n (%)

Significant morbidity/deformity, n (%)

24 (38.1)

39 (61.9)

16 (25.4)

32 (50.8)

Sekulic et al, 2011.

Tumor Response CriteriaTumor 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.

Maximum Decrease in Tumor Size by IRFMaximum Decrease in Tumor Size by IRFLocally Advanced CohortLocally Advanced Cohort

Response

Stable disease

Progressive disease

-100

-50

0

50

100

Chan

ge in

lesi

on d

iam

eter

(%)

Sekulic et al, 2011.

Vismodegib Demonstrates a Significant Vismodegib Demonstrates a Significant ORR in Locally Advanced BCCORR in Locally Advanced BCC

laBCC(n = 63)

Independent review

Investigator assessment

Responders, n (%)

SD, n (%)

PD, n (%)

Unevaluable/missing, n (%)

27 (42.9)

24 (38.1)

8 (12.7)

4 (6.3)

38 (60.3)

15 (23.8)

6 (9.5)

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.

Vismodegib Demonstrates a Significant Vismodegib Demonstrates a Significant ORR in Metastatic BCCORR in Metastatic BCC

Metastatic BCC(n = 33)

Independent review

Investigator assessment

Responders, n (%)

SD, n (%)

PD, n (%)

Unevaluable/missing, n (%)

10 (30.3)

21 (63.6)

1 (3.0)

1 (3.0)

15 (45.5)

15 (45.5)

2 (6.1)

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.

Vismodegib in laBCCVismodegib in laBCC

Baseline Week 12

Sekulic et al, 2011.

Vismodegib in laBCC (cont.)Vismodegib in laBCC (cont.)

Week 48

Week 24: 4 out of 5 target lesion biopsies no BCC

Baseline Week 8

Sekulic et al, 2011.

Most Common Adverse EventsMost Common Adverse EventsAll Treated Patients (n = 104)All Treated Patients (n = 104)

ToxicityAll adverse

events(%)

Grade 1 mild (%)

Grade 2 moderate

(%)

Grade 3–4 severe

(%)

Muscle spasms 68 48 16 4

Alopecia 64 49 14 0

Dysgeusia 51 28 23 0

Weight decreased

46 27 14 5

Fatigue 36 27 5 4

Nausea 29 21 7 1

Decreased appetite

23 14 6 3

Diarrhea 22 16 5 1

Sekulic et al, 2011.

Vismodegib Toxicity ManagementVismodegib 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.

Case Study 1:Case Study 1:Advanced BCCAdvanced BCC

Case StudyCase Study

68-year-old widower 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

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

ARS Question:Next Steps

Further EvaluationFurther 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

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

ARS Question:Choosing Therapy

Key TakeawaysKey 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.

Beyond Basal Cell Carcinoma: Beyond Basal Cell Carcinoma: Novel Approaches to Treating Novel Approaches to Treating

MelanomaMelanoma

Vernon K. Sondak, MDH. Lee Moffitt Cancer Center & Research Institute

Keith T. Flaherty, MDHarvard Medical School

Massachusetts General Hospital Cancer Center

Prostate 241,740 29%

Lung & bronchus 116,470 14%

Colon & rectum 73,420 9%

Urinary bladder 55,600 7%

Melanoma of the skin 44,250 5%

Kidney & renal pelvis 40,250 5%

Non-Hodgkin lymphoma 38,160 4%

Oral cavity & pharynx 28,540 3%

Leukemia 26,830 3%

Pancreas 22,090 3%

All Sites 848,170 100%

Breast 226,870 29%

Lung & bronchus 109,690 14%

Colon & rectum 70,040 9%

Uterine corpus 47,130 6%

Thyroid 43,210 5%

Melanoma of the skin 32,000 4%

Non-Hodgkin lymphoma 31,970 4%

Kidney & renal pelvis 24,520 3%

Ovary 22,280 3%

Pancreas 21,830 3%

All Sites 790,740 100%

Siegel et al, 2012.

#5

#6

Ten Leading Cancer Types for the Ten Leading Cancer Types for the Estimated New Cancer Cases by Sex, 2012Estimated New Cancer Cases by Sex, 2012

Estimated New Cases

Male Female

Annual Age-Adjusted Cancer Incidence Rates Annual Age-Adjusted Cancer Incidence Rates for Selected Cancers by Sex, 1975–2008for Selected Cancers by Sex, 1975–2008

Siegel et al, 2012.

Ten Leading Cancer Types for the Ten Leading Cancer Types for the Estimated New Cancer Deaths by Sex, 2012 Estimated New Cancer Deaths by Sex, 2012

Siegel et al, 2012.

Lung & bronchus 87,750 29%

Prostate 28,170 9%

Colon & rectum 26,470 9%

Pancreas 18,850 6%

Liver & intrahepatic bile duct 13,980 5%

Leukemia 13,500 4%

Esophagus 12,040 4%

Urinary bladder 10,510 3%

Non-Hodgkin lymphoma 10,320 3%

Kidney & renal pelvis 8,650 3%

All Sites 301,820 100%

Lung & bronchus 72,590 26%

Breast 39,510 14%

Colon & rectum 25,220 9%

Pancreas 18,540 7%

Ovary 15,500 6%

Leukemia 10,040 4%

Non-Hodgkin lymphoma 8,620 3%

Uterine corpus 8,010 3%

Liver & intrahepatic bile duct 6,570 2%

Brain & other nervous system 5,980 2%

All Sites 275,370 100%

Estimated Deaths

Males Females

Contribution of Contribution of Individual Cancer Individual Cancer Sites to Change Sites to Change in Male Cancer in Male Cancer Death Rates, Death Rates, 1990–2007 1990–2007

Siegel et al, 2011.

Death Rate (per 100,000) Change

Male 1990* 2007 Absolute % %Contribution†

All malignant cancers 279.82 217.79 -62.03 -22.17

Decreasing

Lung & bronchus 90.56 65.23 -25.33 -27.97 38.5

Prostate 38.56 23.50 -15.06 -39.06 22.9

Colorectum 30.77 20.05 -10.72 -34.84 16.3

Stomach 8.86 5.01 -3.85 -43.45 5.9

Oral cavity & pharynx 5.61 3.85 -1.76 -31.37 2.7

Non-Hodgkin lymphoma 9.97 8.29 -1.68 -16.85 2.6

Leukemia 10.71 9.44 -1.27 -11.86 1.9

Larynx 2.97 2.05 -0.92 -30.98 1.4

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

Melanoma Melanoma 2012 ACS Incidence Predictions 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.

Cutaneous Malignant Melanoma Cutaneous Malignant Melanoma AJCC Staging SystemAJCC Staging System

TUMOR T1 ≤ 1.00 mm*

T2 1.01–2.00 mm

T3 2.01–4.00 mm

T4 > 4.00 mm

a) non-ulcerated

b) ulcerated (*or mitoses ≥ 1/mm2)

NODES N0 all nodes -ve

N1 1 +ve node

N2 2–3 +ve nodes

N3 ≥ 4 +ve nodes

a) microscopic

b) macroscopic

AJCC, 2009.

Cutaneous Malignant MelanomaCutaneous Malignant Melanoma2012 Surgical Guidelines2012 Surgical Guidelines

TUMOR < 1 mm

1–2 mm

> 2 mm

Any positive nodes

SURGERY 1 cm excision

1–2 cm excision

2 cm excision

Complete LN dissection

LN = lymph node.

Bichakjian et al, 2011.

Cutaneous Malignant MelanomaCutaneous Malignant Melanoma2012 Surgical Guidelines (cont.)2012 Surgical Guidelines (cont.)

TUMOR < 1 mm

1–2 mm

> 2 mm

Any positive nodes

SURGERY 1 cm excision, no SLN Bx*

1–2 cm excision, SLN Bx

2 cm excision, SLN Bx

Complete LN dissection

Bx = biopsy; SLN = sentinel lymph node.

Bichakjian et al, 2011.

*Selected patients < 1 mm (young age or “high-risk histology”) should be considered for SLN Bx.

Sentinel Node Biopsy UpdateSentinel 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.

FDA Approved Drugs in Use for FDA Approved Drugs in Use for Melanoma (as of February 2011)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.

Drugs Approved for Melanoma Drugs Approved for Melanoma by the FDA in 2011by 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.

Anti-CTLA4 Antibodies Anti-CTLA4 Antibodies

Vernon K. Sondak, MDH. Lee Moffitt Cancer Center & Research Institute

Targeted Immunotherapy CTLA4 Blockade Targeted Immunotherapy CTLA4 Blockade Taking the Brakes Off T-Cell ActivationTaking the Brakes Off T-Cell Activation

T-cell inactivation

APC

CTLA-4T cell

Ipilimumab

APC

T-cell T-cell activationactivation

T cell

T-cell T-cell activationactivation

T cell

APC

CD28CD28

B7B7

TCRTCR

HLAHLA

CTLA-4

TCR = T-cell receptor; APC = antigen presenting cell. Image adapted from Weber et al, 2008b.

Targeting T Cells With Ipilimumab (anti-CTLA4 Targeting T Cells With Ipilimumab (anti-CTLA4 antibody) Leads to Durable Response antibody) Leads to Durable Response

Tu

mo

r S

ize

(%)

Post-Treatment Initiation (weeks)

Response Response ongoing ongoing

years later years later with nowith no

new lesionsnew lesions0

20

40

60

80

100

0 10 20 30 40 50 60

PR

CR

= Ipilimumab Treatment, 10 = Ipilimumab Treatment, 10 mg/kgmg/kg

SDTreatment

Weber, 2008a.

Progression Followed by Response in Progression Followed by Response in Melanoma Patient Treated With IpilimumabMelanoma Patient Treated With Ipilimumab

Screening Week 8: “Progression” Week 12: Improved

Week 16: Continued Improvement

Week 72: Complete Remission

Week 108: Still in Complete Remission

Images courtesy of Jedd Wolchok, MD.Hoos et al, 2010; Maggon, 2011.

Survival RateIpi + gp100

(N = 403)

Ipi + pbo

(N = 137)

gp100 + pbo

(N = 136)

1 year 44% 46% 25%

2 years 22% 24% 14%

11 22 33 44YearsYears

Ipilimumab (3 mg/kg x 4) Improves OS in Ipilimumab (3 mg/kg x 4) Improves OS in Previously Treated Stage IV MelanomaPreviously Treated Stage IV Melanoma

Hodi et al, 2010.

Ipilimumab + gp100Ipilimumab alonegp100 alone

HR = hazard ratio.Robert et al, 2011.

No. of deaths: 196 vs. 218, HR 0.72 (0.59–0.87) p < .0011-year survival 47.3% vs. 36.3%2-year survival 28.5% vs. 17.9%3-year survival 20.8% vs. 12.2%

Ipilimumab (10 mg/kg) + DTIC Improves OS in Ipilimumab (10 mg/kg) + DTIC Improves OS in Previously Untreated Stage IV MelanomaPreviously Untreated Stage IV Melanoma

Wolchok et al, 2010.

Dose 0.3 mg/kg 3 mg/kg 10 mg/kg

RR (%) 0 4.2 11.1

Randomized Phase 2 Trial of 3 Doses of Ipilimumab Randomized Phase 2 Trial of 3 Doses of Ipilimumab (0.3 mg/kg, 3.0 mg/kg, 10 mg/kg) in Stage IV Melanoma(0.3 mg/kg, 3.0 mg/kg, 10 mg/kg) in Stage IV Melanoma

When Going Downhill With No Brakes, When Going Downhill With No Brakes, A Steering Wheel Is A Great Idea!A Steering Wheel Is A Great Idea!

Images courtesy of Vernon K. Sondak, MD.

Ipilimumab Treatment and irAEsIpilimumab 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.

Tumor

The Future of Melanoma ImmunotherapyThe Future of Melanoma ImmunotherapyPD1 Blockade Reviving Exhausted T CellsPD1 Blockade Reviving Exhausted T Cells

Anti-PD1

T-cell T-cell reactivationreactivation

T cell

T-cell T-cell exhaustionexhaustion

T cell

Tumor

PD1PD1

PDL1PDL1

TCRTCR

HLAHLA

Image adapted from Topalian et al, 2012.

BRAF InhibitorsBRAF Inhibitors

Keith T. Flaherty, MDHarvard Medical School

Massachusetts General Hospital Cancer Center

Oncogenes in MelanomaOncogenes 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 –

a80%–90% of uveal.Padua et al, 1984; Davies et al, 2002; Willmore-Payne et al, 2005; Van Raamsdonk et al, 2009.

Distribution of Commonly Mutated Oncogenes Distribution of Commonly Mutated Oncogenes by Body Site of Primary Melanomaby Body Site of Primary Melanoma

GNAQ 45%GNA11 32 %

BRAF 57%NRAS 18%

BRAF 28%NRAS 18%

c-Kit 39%NRAS 10%BRAF 5%

NRAS 10%BRAF 20%c-Kit 36%

mucosal

mucosal

acralacral

scalp/facescalp/face

trunk/legstrunk/legs

uvealuveal

acral

acral

NRASCRAFBRAF

PI3K

MEK

ERK

AKT

mTOR

c-kit

Signaling Pathways Downstream Signaling Pathways Downstream of Melanoma Oncogenesof Melanoma Oncogenes

GNAQ

GNA11

PKC

Van Raamsdonk et al, 2010; Curtin et al, 2006; Lee et al, 2011; Perez-Lorenzo et al, 2012.

BRAF Mutation Testing GuidelinesBRAF 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.

BRAF Mutation TestingBRAF 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.

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%

End Points

Primary: RRSecondary: DOR, PFS, OS, Safety

Previously treated V600 mutant

metastatic melanoma (N = 132)

Vemurafenib(960 mg PO bid)

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

Phase 2 Study of Vemurafenib in Previously Phase 2 Study of Vemurafenib in Previously Treated Patients With Metastatic MelanomaTreated Patients With Metastatic Melanoma

ECOG PS = Eastern Cooperative Oncology Group performance status; RT = radiotherapy.Sosman et al, 2010; Ribas et al, 2011.

Patient DemographicsPatient DemographicsN = 132N = 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.

Tumor Regression in Tumor Regression in Approximately 90% of PatientsApproximately 90% of Patients

7 confirmed CRs7 confirmed CRs

CR = confirmed response.Ribas et al, 2011.

PFSPFS100

90

80

70

60

50

40

30

0

Pro

babi

lity

of P

FS

(%

)

20

10

Time (months)

0 1 4 6 8 10 12 142 3 5 7 9 11 13

132 129 85 62 41 25 11 1115 93 73 45 33 18 6

No. At Risk

Median PFS 6.7 months (95% CI: 5.5, 7.8 months) PFS at 6 months 54% (95% CI: 45, 63%) Median PFS 6.7 months (95% CI: 5.5, 7.8 months) PFS at 6 months 54% (95% CI: 45, 63%)

Ribas et al, 2011.

OSOS100

90

80

70

60

50

40

30

0

Pro

babi

lity

of O

S (

%)

20

10

Time (months)

0 1 4 6 8 10 12 152 3 5 7 9 11 13

132 131 118 97 83 71 34128 122 109 90 78 55 19

No. At Risk14

7 0

Median OS Not Reached

OS at 6 months 77% (95% CI: 70, 85) 12 months 58% (95% CI: 49, 67)

Median OS Not Reached

OS at 6 months 77% (95% CI: 70, 85) 12 months 58% (95% CI: 49, 67)

Ribas et al, 2011.

Most Commonly Reported Drug-Related AEsMost Commonly Reported Drug-Related AEs

All grades n (%)

Grade 3n (%)

Grade 4n (%)

Arthralgia 78 (59) 8 (6) –

Rash 69 (52) 9 (7) –

Photosensitivity Reaction

69 (52) 4 (3) –

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)

Includes AEs Reported in ≥ 20 Patients

*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.

AEs Leading to Drug Modifications, AEs Leading to Drug Modifications, Interruptions, and DiscontinuationsInterruptions, 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.

Phase 2 Trial of GSK2118436 in Patients Phase 2 Trial of GSK2118436 in Patients With BRAF Mutation-Positive (V600E/K) With BRAF Mutation-Positive (V600E/K)

Metastatic MelanomaMetastatic Melanoma• Single arm, phase II, open label• Green-Dahlberg 2-Stage: Ho: ORR ≤ 25% vs. Ha: ORR ≥ 40%

Patients

Metastatic melanoma

Confirmed BRAFV600E/K mutation

Absence of brain metastases

No prior treatment with MEK or BRAF inhibitors

Screenedn = 211

V600En = 76

V600Kn = 16

GSK2118436 150 mg bid

until PD, death, or unacceptable

AE

Enrolledn = 92

Primary objective: RR in V600E mutated

Trefzer et al, 2011.

Study PopulationStudy Population

Population Description N

All Treated Subjects All subjects that received at least 1 dose of GSK2118436

92

V600E Subjects with a V600E mutation 76

V600K Subjects with a V600K mutation 16

M-status, n (%) M1 M1a M1b M1c Missing

1 (1%)16 (17%)14 (14%)58 (63%)

3 (3%)

Trefzer et al, 2011.

Most Common AEsMost Common AEs

AE N = 92n (%)

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.

Best Tumor Response:Best Tumor Response:V600E PopulationV600E Population

M1cM1aM1 M1bM-Stage at screening Missing

Trefzer et al, 2011.

Best Tumor Response:Best Tumor Response:V600K PopulationV600K Population

M1cM1aM1 M1b

Scans unavailable for 1 patient

M-Stage at screening Missing

Trefzer et al, 2011.

PFSPFS

V600E Median PFS (weeks): 27.4, Progressed: 40 (53%)

V600K Median PFS (weeks): 19.7, Progressed: 13 (81%)

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)

0.2

0.0

0.4

0.6

0.8

1.0

Est

ima

ted

PF

S F

un

ctio

n (

%)

Trefzer et al, 2011.

Phase 3 Trial Comparing Vemurafenib to Phase 3 Trial Comparing Vemurafenib to DTIC in Patients With V600 Mutated DTIC in Patients With V600 Mutated

BRAF MelanomaBRAF Melanoma

RandomizationN = 675

BRAFV600 mutation by Cobas®

4800 test

Stratification• Stage• ECOG PS (0 vs. 1)• LDH elevated vs. normal• Geographic region

Vemurafenib960 mg PO bid

(n = 337)

DTIC1,000 mg/m2 IV q3wks

(n = 338)

DTIC = dacarbazine; IV = intravenous.Chapman et al, 2011.

Patient DemographicsPatient DemographicsDacarbazine (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.

100

90

80

70

60

50

40

30

20

10

0

OS

(%

)

No. Patients in Follow-Up

Dacarbazine

Vemurafenib

0 1 2 3 4 5 6 7 8 9 10 11 12

84% of patients alive at 6 months

Vemurafenib (n = 336)

Time (months)

336

336

283

320

192

266

137

210

98

162

64

111

39

80

20

35

1

6

1

1

64% of patients alive at 6 months

Dacarbazine (n = 336)

9

14

HR 0.37 (95% CI: 0.26–0.55) Log-rank p < .0001

OS OS

Chapman et al, 2011.

Efficacy Data From Vemurafenib Efficacy Data From Vemurafenib Phase 3, Phase 2, and Phase 1:Phase 3, Phase 2, and Phase 1:

Cross Trial ComparisonCross 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

Response (%)48 53 56

Chapman et al, 2011; Ribas et al, 2011; Flaherty et al, 2010; Kim et al, 2011; McArthur et al, 2011.

n = 30 n = 25

n = 30 n = 25

A Phase II Study of the MEK1/MEK2 Inhibitor GSK1120212 in A Phase II Study of the MEK1/MEK2 Inhibitor GSK1120212 in Metastatic BRAF-V600E or K Mutant Cutaneous Melanoma Metastatic BRAF-V600E or K Mutant Cutaneous Melanoma

Patients Previously Treated With or Without a BRAF InhibitorPatients Previously Treated With or Without a BRAF Inhibitor

Green-Dahlberg 2-Stage

Patients

Metastatic Cutaneous Melanoma

BRAFV600E/K/D

Stable Brain Metastases

Enroll, then GSK1120212 dosed at 2 mg qd

< 3 CR/PR Stop due to

futility

PriorPriorTherapy,Therapy,no BRAFino BRAFi

(Cohort B) (Cohort B)

PriorPriorBRAFiBRAFi

(Cohort A)(Cohort A)

Kim et al, 2011.

Patient CharacteristicsPatient Characteristics

CharacteristicCohort A

N = 40(%)

Cohort BN = 57

(%)

Mean age, years 55.6 54.0

Gender, Male 63 75

ECOG 0 48 74

Prior brain metastases

13 21

BRAF mutation V600E

V600K

K601E

V600K/R1

V600K/E1

Unknown2

83

10

3

0

3

3

81

14

2

2

2

0

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.

CharacteristicCohort A

N = 40(%)

Cohort BN = 57

(%)

LDH > ULN 55 42

StageIIIcM1aM1bM1c

0131573

2121175

Prior therapies1–2

≥ 3ChemotherapyImmunotherapy3

Both chemo/immuno

5050624233

8713865440

Kim et al, 2011.

Most Common Treatment-RelatedMost Common Treatment-RelatedAEs ≥ 20%AEs ≥ 20%

Only one Grade 4 treatment-related event

– Pulmonary embolism

Dose reductions due to AEs in 15% of patients

– Most frequently for rash and dermatitis acneiform

3% of patients permanently withdrew GSK1120212 due to toxicity

Events n = 97 (%)

G1–2 G3 Total

Skin-related toxicity1

Rash

Dermatitis acneiform

76

45

25

10

6

4

87

52

30

Diarrhea 47 4 52

Peripheral edema 26 3 29

Fatigue 23 2 26

Pruritis 26 1 27

Nausea 30 0 30

Dry skin 22 0 22

1Skin-related toxicity includes multiple terms.

Kim et al, 2011.

Cohort A Tumor Response (n = 40)Cohort A Tumor Response (n = 40)Unconfirmed Response Rate (RR): 5% (95% CI, 0.6, 16.9)

1 CR, 1 PR, 10 SD

* Discontinued prior BRAFi due to toxicityK V600K

Scans unavailable for 5 patients: 2 died and 1 withdrew before first scan,2 had incomplete scan

M1cM1a M1bM-Stage at screening

266% 155%

K

K

K

K

*

Ch

ang

e a

t M

axim

um

Re

du

ctio

n F

rom

Bas

elin

e M

easu

rem

ent

(%)

*

*

Kim et al, 2011.

Cohort A PFS (n = 40)Cohort A PFS (n = 40)

Median PFS 1.8 months (95% CI, 1.8, 2.0)

PF

S (

%)

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 2 43 51 6 7 8 9

Kim et al, 2011.

Cohort B Tumor Response (n = 57)Cohort B Tumor Response (n = 57)Confirmed Response Rate (RR): 25% (95% CI, 14.1, 37.8)

1 CR, 13 PR, 29 SD

Unconfirmed RR: 35% (95% CI, 22.9, 48.9) 2 CR, 18 PR, 23 SD

Median DOR: 5.7 months(95% CI 3.7, 9.2)

* Prior history of brain metastases K V600K

Scans unavailable for 2 patients: 1 progressed before scan, 1 had incomplete scanM1cM1aM0 M1bM-Stage at screening

256%

K

*

*

*

** *

*

**

*

* *

K

K

KK

K

K

KCh

ang

e a

t M

axim

um

Re

du

ctio

n F

rom

Bas

elin

e M

easu

rem

ent

(%)

Kim et al, 2011.

Cohort B PFS (n = 57) Cohort B PFS (n = 57)

Median PFS 4.0 months (95% CI, 3.6, 5.6)

0 50 100 150 200 250 300 350 400

1.0

0.8

0.6

0.4

0.2

0.0

PF

S (

%)

Time (Days)

Kim et al, 2011.

Ongoing Targeted Therapy TrialsOngoing 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

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.

Patients (N = 35)

Median age 56 (27–76)

Gender (M/F) 17/18

Primary site

(Acral: Mucosal: CSD: NSD: MM) 16:10:4:2:3

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

Phase II Trial of imatinib in Patients With c-kit Phase II Trial of imatinib in Patients With c-kit Genetic Aberrations: Genetic Aberrations: Patient CharacteristicsPatient Characteristics

Change in Tumor Size Compared Change in Tumor Size Compared to Baselineto Baseline

Guo et al, 2010.

M1b M1cM1a

KIT Status PR SD PR + SD

KIT Amp 1/3 0/3 1/3

Exon11 2/12 8/12 10/12

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.

70%

Correlations of Response and KIT Correlations of Response and KIT AberrationsAberrations

Guo et al, 2010.

Systemic Therapies for Advanced or Systemic Therapies for Advanced or Metastatic Melanoma: NCCN GuidelinesMetastatic 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.

Currently Accruing Clinical Trials Currently Accruing Clinical Trials in Melanomain 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

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

Case StudyCase 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

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

ARS Question:Testing

Biopsy ResultsBiopsy Results

Mutation analysis performed on a core biopsy specimen from a lung nodule

– Positive for BRAF V600E mutation

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

ARS Question:Treatment Options

Key Takeaways on the Management Key Takeaways on the Management of Stage IV Melanomaof 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

Panel Discussion:Panel Discussion:Multi-Disciplinary Multi-Disciplinary

Perspectives in Basal Cell Perspectives in Basal Cell CarcinomaCarcinoma

Jean Y. Tang, MD, PhD – Dermatologist

Keith T. Flaherty, MD – Medical Oncologist

Vernon K. Sondak, MD – Surgical Oncologist

Topics for DiscussionTopics for Discussion

When are surgical options no longer appropriate?

Which BCC 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?