Update on Non-Melanoma Skin Cancer

William Sharfman, MD, FACP Associate Professor of Oncology and Dermatology

Johns Hopkins University School of Medicine July 5, 2013

Non-Melanoma Skin Cancer

• Basal Cell Carcinoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma

Incidence of Skin Cancer in the United States

• Skin cancer is the most commonly diagnosed cancer in the United States

– BCC - > 1 million cases per year1

– Squamous cell carcinoma - 250,000 – Melanoma – 70,000

3

1. Rogers HW et al. Arch Dermatol. 2010;146:283-287. 2. Siegel R et al. CA Cancer J Clin. 2012;62:10-29.

Basal Cell Carcinoma (cont)

4 Photo courtesy of Dr. Sharfman.

Genetic Conditions Associated With Basal Cell Carcinoma

• Gorlin syndrome (NBCCS) • Bazex syndrome • Rombo syndrome • Xeroderma pigmentosum • Unilateral basal cell nevus syndrome

5

NBCCS = nevoid basal cell carcinoma syndrome. Castori M et al. Eur J Dermatol. 2012;22:299-309.

Gorlin Syndrome (NBCCS)

• Multiple BCCs (few to 1000s) • Patients are exceedingly sensitive to ionizing radiation • Bone cysts–odontogenic keratocysts of the jaw • Multiple skeletal abnormalities • Calcification of the falx cerebri • Dysmorphic features–broad nasal root • Plantar and palmar pits • Medulloblastoma • Meningioma • Borderline intelligence • Defects in PTCH1 gene on chromosome 9

6 Lo Muzio L. Orphanet J Rare Dis. 2008;3:32.

The Hedgehog (Hh) Signaling Pathway as a Therapeutic Target for Advanced or Metastatic Basal Cell

Carcinoma

7

Hh Signaling Pathway

• Hh ligands (sonic, indian, desert) bind the transmembrane receptor PTCH1

• In the absence of ligand, PTCH1 represses activity of the transmembrane receptor SMO

• Binding of ligand to PTCH1 releases its inhibition of SMO and activates downstream Hh signaling through the activity of GLI proteins

8

SMO = Smoothened; GLI = glioma-associated oncogene homolog. Reprinted from McMillan R et al. Clin Cancer Res. 2012;18:4883-4888 with permission from AACR © 2012.

The Hh Signaling Pathway and Basal Cell Carcinoma

• Hh signaling regulates events during early embryogenesis, as well as the morphogenesis of specific organs and tissues, but is subsequently silenced in adult tissue

• Cancer cells can reactivate Hh signaling, resulting in tumorigenesis

• There is evidence for aberrant activation of Hh signaling in BCC – Gorlin syndrome is caused by germline mutations in PTCH11

– PTCH1 (loss-of-function) or SMO (gain-of-function) mutations are present in 90% of spontaneously arising BCCs2

9

1. Hahn H et al. Cell. 1996;85:841-851. 2. Epstein EH. Nat Rev Cancer. 2008;8:743-754.

Inhibition of the Hh Pathway in Advanced Basal Cell Carcinoma

• A Phase 1 trial of the oral agent vismodegib • 33 patients with metastatic (n = 18) or locally advanced

(n = 15) BCC • 18 patients had objective response: 2 CR, 16 PR, 11 SD, 4 PD • Median duration of response was 8.8 months • Response rate in patients with locally advanced tumors was 60% • Recommended Phase 2 dose was 150 mg daily • Common side effects: fatigue, muscle spasm, hyponatremia and

dysgeusia

CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease. Von Hoff DD et al. N Engl J Med. 2009;361:1164-1172.

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EVIRANCE BCC/SHH4476g Trial: Vismodegib for Treatment of Advanced or Metastatic Basal Cell

Carcinoma • A Phase 2 multicenter, international,

nonrandomized trial of vismodegib • 104 patients with metastatic (n = 33) or locally

advanced (n = 63) BCC • No control group: patients were given 150 mg

vismodegib once daily until disease progression, unacceptable toxic effects, or discontinuation of the study

• Primary endpoint: independently assessed objective response rate

11 Sekulic A et al. N Engl J Med. 2012;366:2171-2179.

Inclusion Criteria

• Tumor size ≥10mm in diameter • Locally invasive BC extending into underlying tissue, cartilage,

bone, or nerve • Tumor is in a location where surgery or radiation would result

in significant disfigurement or loss of function • Expected morbidity or deformity if surgery or radiation were

to be performed • Curative resection unlikely or contraindicated • Recurrence in the same location after ≥2 surgical procedures • Metastasis to the regional lymph nodes, lung, liver, bone

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Sekulic A et al. N Engl J Med. 2012;366:2171-2179.

Primary and Secondary Efficacy Endpoints Following Treatment

With Vismodegib Outcome

Metastatic BCC (N = 33)

Locally Advanced BCC (N = 63)

Independent review

Site investigators

Independent review

Site investigators

Objective response — no. (%) 10 (30) 15 (45) 27 (43) 38 (60)

95% CI 16-48 28-62 30-56 47-72

P value 0.001 <0.001

Stable disease — no. (%) 21 (64) 15 (45) 24 (38) 15 (24)

Progressive disease — no. (%) 1 (3) 2 (6) 8 (13) 6 (10)

Data missing or could not be evaluated — no. (%) 1 (3) 1 (3) 4 (6) 4 (6)

Median duration of response — months 7.6 12.9 7.6 7.6

Median progression-free survival, based on independent review — months 9.5 9.5

Duration of treatment — months

Median 10.0 9.7

Range 0.7-16.4 1.1-18.7

Patients still receiving treatment — no./total no. (%) 19/33 (58) 32/71

(45)

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Sekulic A et al. N Engl J Med. 2012;366:2171-2179. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Maximum Tumor Shrinkage Following Treatment With Vismodegib

100

50

0

-50

-100 Chan

ge in

Les

ion

Dia

met

er (%

)

Metastatic BCC Locally Advanced BCC

Progressive disease

Stable disease Partial response

Chan

ge In

Les

ion

Dia

met

er (%

)

100

50

0

-50

-100

*

Progressive disease

Stable disease Partial response

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Sekulic A et al. N Engl J Med. 2012;366:2171-2179. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Commonly Reported Adverse Events

*These adverse events occurred in at least 20% of all patients and were coded with the use of the Medical Dictionary for Regulatory Activities (MedDRA), version 13.1. The highest grade of event is reported for each patient.

Percentage of Patients

Event* Any Grade Grade 1 Grade 2 Grade 3 or 4

Muscle spasms 68 48 16 4

Alopecia 63 49 14 0

Dysgeusia 51 28 23 0

Decrease in weight 46 27 14 5

Fatigue 36 27 5 4

Nausea 29 21 7 1

Decrease in appetite 23 14 6 3

Diarrhea 22 16 5 1

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Sekulic A et al. N Engl J Med. 2012;366:2171-2179. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Vismodegib in Patients With Gorlin Syndrome

• Phase 2 trial investigating the use of vismodegib in patients with Gorlin syndrome

• Patients with Gorlin syndrome randomized to receive either placebo (n = 15) or 150 mg vismodegib (n = 26) for 18 months

• Primary endpoint: reduction in the incidence of new BCCs that were eligible for surgical resection

16 Tang JY et al. N Engl J Med. 2012;366:2180-2188.

Reduced Number of New Basal Cell Carcinomas Following Treatment With

Vismodegib vs Placebo • Common adverse events associated with vismodegib include grade 1/2

dysgeusia, muscle cramps, hair loss, and weight loss

40

30

20

10

0 0 5 10 15

Months

Vismodegib (n = 26)

No.

of N

ew S

EBs

40

30

20

10

0 12 15 9 6 3 0

Months

Placebo (n = 11)

No.

of N

ew S

EBs

17

SEB = surgically-eligible BCCs. Tang JY et al. N Engl J Med. 2012;366:2180-2188. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Future Directions in the Treatment of Basal Cell Carcinoma

• Targeting GLI1 – GANT61

• Vitamin D3 • Arsenic Trioxide • Itroconazole

• Other Hh pathway inhibitors: clozapine,

chlorpromazine, haloperidol

18 Weiss G. Cancer. 2012 Apr 17 [Epub ahead of print].

Skin Squamous Cell Carcinoma

Phase II Study of Cetuximab as First-Line Single-Drug Therapy in Patients with Unresectable Squamous Cell Caricinoma of the Skin. Maubec et al. JCO Sept 2011

• N=36 • Weekly Cetuximab at Standard Dosing • DCR = 69% • OR in 10 patients

Representative examples of patients showing response to cetuximab.

Maubec E et al. JCO 2011;29:3419-3426

©2011 by American Society of Clinical Oncology

Kaplan-Meier plot of (A) overall survival and (B) progression-free survival in the intention-to-treat population and per-protocol population.

Maubec E et al. JCO 2011;29:3419-3426

©2011 by American Society of Clinical Oncology

Merkel Cell Carcinoma

Fig. 2. (A) Schematic of MCV genome.

H Feng et al. Science 2008;319:1096-1100

Published by AAAS

Survivin is a Therapeutic Target Merkel Cell Carcinoma. Reety Arora et al. Sci Transl Med 4, 133ra56(2012)

PD-L1 Expression in the Merkel Cell Carcinoma Microenvironment: Association of Inflammation, Merkel Cell Polyomavirus, and Overall Survival. Lipson et al. Cancer Immunology Research. May 21, 2013.