Karl D. Lewis, MDAssociate Professor of MedicineUniversity of Colorado DenverCutaneous Oncology Program

Locally Advanced and Metastatic Basal Cell Carcinoma: Medical Oncology Perspective

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Basal Cell Carcinoma

• Arise from the keratinocytes of the basal layer of the epidermis

• Generally have a low metastatic potential

• However, can be locally aggressive with destruction of skin and surrounding structures

• Most common skin cancer in US– Imprecise because no cancer

registry– ACS in 2000: ~975,000 cases

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BCC - risk factors

• UV light exposure–Sun exposure (habits) is

most important environmental factor (along with individuals phenotype)

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BCC - risk factors

• Basal Cell Nevus Syndrome–Robert Gorlin (dentist) identified a syndrome in which multiple

abnormalities occur1.

–Autosomal dominant

–Prevalence varies from 1/57,000 to 1/256,000

–Patients can develop hundreds of BCCs - usually starting by age 35

–Histologic appearance does not differ from sporadic BCCs 1. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine 1987;66:98-113.

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Basal cell nevus syndrome

• Major Criteria–Multiple BCCs or one under 20

yrs–Odontogenic keratocysts–Palmar/plantar pits–Bilamellar calcification of the flax

cerebri–Bifid, fused or splayed ribs–Affected 1st degree relatives

• Minor Criteria–Macrocephaly–Congenital malformations (eg,

cleft lip)–Ovarian fibroma–Skeletal abnormalities–Medulloblastoma

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palmer/plantar pitting

Bone cysts (mandible)

Bifid ribs

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Basal Cell Nevus Syndrome (BCNS)

• Positional cloning and subsequent screening identified a spectrum of PTCH mutations in BCNS patients

• BCCs develop secondary to activation of target genes of Hh pathway in cells that have lost both normal copies of PTCH

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Hedgehog Signaling Pathway

Basal cell nevus syndrome:Germline mutation in PTCHgene

The hedgehog pathway is active during embryonic development but dormant after birth

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Sporadic BCCs

• Majority show allelic loss for chromosome 9q22 and inactivating mutations of PTCH

• Activating mutations of SMO in 10-20% sporadic BCCs

• Suggests abnormal Hh signaling involved in most (all?) BCCs - high levels of Hh target genes such as GLI1

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Basal Cell CarcinomaTreatment

• Low risk lesions:–Cryosurgery–Electrodessication–Topical therapy: 5-FU or imiquimod

• High risk lesions:–Surgical excision–Mohs micrographic surgery–Radiation therapy (cure rates 85-95%)

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Basal Cell CarcinomaTreatment

• Low risk lesions:–Cryosurgery–Electrodessication–Topical therapy: 5-FU or

imiquimod

• High risk lesions:–Surgical excision–Mohs micrographic

surgery–Radiation therapy (cure

rates 85-95%)

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Medical Oncologist Role in Treatment of BCC

• Historically: little to none

• No clinical trials demonstrating chemotherapy benefit

• Chemotherapy responses on case-report basis only

• NCCN Guidelines: recommend clinical trials (Hhi) for metastatic BCC

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Medical Oncologist Role in Treatment of BCC

• Metastatic BCC–First case of metastatic BCC reported in 18941

–Since then have been >300 cases reported

–Accurate incidence difficult to obtain: no good registry

–Estimated rates reported to be: 0.0028% to 0.55%2,3

• However, these data are old and based on single institutions or small subsets

• The lower incidence would translate to 1 in 35,000 patients (seems too high considering total number of patients reported in the literature)4,51. Beadles DF. Trans Pathol Soc 1894.

2. Paver K et al Australas J Dermatol 19733. Cade S et al 19404. Wadhera A et al Dermatol Online J 20065. Ganti AK et al Cancer Treat Rev 2011

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Chemotherapy for BCC• Metastatic

–Numerous agents on case-report basis:• Cyclophosphamide, etoposide, 5-FU, MTX, bleomycin,

doxorubicin, cisplatin, carboplatin, paclitaxel–Cisplatin (alone or combination) likely most effective:

• 12 patients treated with platinum containing regimen1:– 5 CR (3 to 18 months)– 4 PR– 3 SD

1. Carneiro BA et al Cancer Invest, 2006

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Chemotherapy for BCC

• Problems with case-reports:–No consistent treatment regimen

• Dose• Schedule• Timing of response

–Selection bias of patients• What prompted treatment vs no treatment• Much more likely to report responders than non-responders

–No standardization of response evaluation!!!!• Even though chemo responses seem encouraging it is not

known what the true response rate is.

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BCC

• Since the HH pathway seems to be ubiquitously expressed in BCC, there may be a potential for targeted therapy.

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Cyclopamine

Anomalous development due to disruption of Hedgehog signaling

Veratrum Californicum Cyclopic lamb

Enabled by the ingenuity of Lynn James, from the US Department of Agriculture, in investigating the curious case of an epidemic of cyclopic

lambs in Idaho, 1957

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• Genentech: GDC-0449 (Vismodegib) Approved • Infinity: IPI-926 (Saridegib) Ph1• Novartis: LDE225 (Erismodegib) Ph2• AstraZeneca: AZD8542 Ph1• BMS: BMS-833923 (XL139) Ph1• Millennium: TAK-441 Ph1• Novartis: LEQ506 Ph1

Hedgehog inhibitors in the clinic

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ERIVANCE BCC: Pivotal Phase 2 study in advanced BCC

• Locally advanced BCC:– Inoperable–Surgery inappropriate

• 1 cm • 2 recurrences after surgery and curative resection unlikely and/or

anticipated substantial morbidity and/or deformity from surgery

Metastatic BCC (RECIST-measurable)

Locally advanced BCC

REG

ISTR

ATIO

N

•Progression• Intolerable

toxicity•Withdrawal from

study

RECIST

Compositeendpoint

Vismodegib

19RECIST, Response Evaluation Criteria In Solid Tumors

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ERIVANCE BCC: Study Objectives

• Primary endpoint: Objective response rate by independent review–Hypotheses tested:

• Overall response rate is significantly greater than 10% in patients with mBCC or 20% in patients with laBCC

• Secondary endpoints included:–Objective response rate by investigator–Progression-free survival–Duration of response–Absence of residual BCC in patients with laBCC

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Vismodegib demonstrates a significant objective response rate in mBCC

mBCC(n = 33)

IRF (1°) INV (2°)

Responders, n (%)Stable disease, n (%)Progressive disease, 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 0.0011

Median duration of response, months 7.6 12.9

21CI, confidence interval; IRF, independent review; INV, investigator reviewSekulic A et al. N Engl J Med. 2012;366:2171-2179.

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Maximum decrease in tumor size by IRFMetastatic cohort

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Cha

nge

in le

sion

dia

met

er (%

) Partial responseStable diseaseProgressive disease

-100

-50

0

50

100

Maximum decrease in size prior to IRF-determined disease progressionSekulic A et al. N Engl J Med. 2012;366:2171-2179.

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Vismodegib demonstrates a significant objective response rate in laBCC

laBCC(n = 63)

IRF (1°) INV (2°)

Responders, n (%) Stable disease, n (%)Progressive disease, 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 <0.0001

Median duration of response, months 7.6 7.6

23Sekulic A et al. N Engl J Med. 2012;366:2171-2179.

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Maximum decrease in tumor size by IRFLocally advanced cohort

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ResponseStable diseaseProgressive disease

-100

-50

0

50

100

Cha

nge

in le

sion

dia

met

er (%

)

Maximum decrease in size prior to IRF-determined disease progressionSekulic A et al. N Engl J Med. 2012;366:2171-2179.

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Vismodegib in locally advanced BCC

Week 20

Week 16: no BCC on biopsy

Baseline Week 8

25Sekulic A et al. N Engl J Med. 2012;366:2171-2179.

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Vismodegib in locally advanced BCCWeek 24

Week 24: residualBCC on biopsy

Baseline

26Sekulic A et al. N Engl J Med. 2012;366:2171-2179.

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Week 32 Baseline

Week 24: no residual BCC on biopsy

Sekulic A, et al. Presented at EADO. 2011 (abstr CO14).

ERIVANCE* (SHH4476g) Phase II Vismodegib in Advanced BCC: Vismodegib in Locally Advanced BCC

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Week 24

Week 24: no residual BCC on biopsy

Baseline Week 8

Sekulic A, et al. Presented at EADO. 2011 (abstr CO14).

ERIVANCE* (SHH4476g) Phase II Vismodegib in Advanced BCC: Vismodegib in Locally Advanced BCC

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Most common adverse eventsAll treated patients (n=104)

MedDRA preferred term

All 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

29MedDRA, Medical Dictionary for Regulatory Activities

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

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ERIVANCE: 12 Month Update Efficacy Conclusions

• At the 12-month update both INV- and IRF-assessed ORRs remained similar to those reported at the primary analysis Four additional patients became responders

• Median DOR remained similar to the primary analysis

• For both the mBCC and laBCC cohorts, the median PFS per IRF assessment at the 12-month update was similar to that at the primary analysisAmong patients with laBCC the median PFS by INV was 1.6 months longer than the

median PFS at the primary analysis

• As of 28 November 2011, median OS was 24.1 months in the mBCC cohort and was not estimable in the laBCC cohort

• One-year survival rates at this 12-month update were similar to those at the primary analysis

Sekulic A, et al. Ann Oncol. 2012;23(Suppl 9):abstr 1112PD.

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LDE225 800 mg PO daily

LDE225 200 mg PO daily

Treatment continues until:• Disease progression• Intolerable toxicity• Death• Study termination• Withdrawal of consent

Primary endpoint: ORRSecondary endpoint: TTR, DoR, PFS, OS, safety, PK profile, CRchEstimated completion: September 2014ORR = overall response rate; TTR = time to tumor response; DoR = duration of response; PFS = progression-free survival; OS = overall survival; PK= pharmacokinetic; CRch = complete histological clearance.

Available at: http://clinicaltrials.gov/ct2/show/NCT01327053. Accessed October 11, 2012.

RANDOMIZE

2:1

BCC patients (N=156)• Locally advanced or metastatic disease• Not amendable to radiation therapy, surgery, or other local therapies

Stratification• Stage of disease• Histological subtype (for locally advanced disease)

Phase 2 BOLT Trial: Investigating Basal Cell Carcinoma Outcomes in

LDE225 (Erismodegib) Trial

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Conclusions

• BCC is very common cancer that rarely becomes locally advanced or metastatic (but when it does it is a major problem!).

• Cisplatin containing chemotherapy regimens likely has activity: but no clinical trials to guide clinicians.

• HHi showing very encouraging activity in clinical trials.

• Further supports the concept of molecularly targeted therapies.