Hedgehog Pathway Inhibitors and Advanced Basal Cell Carcinoma

Ted Rosen, MD Baylor College of Medicine

Houston, Texas

Conflict of Interest Disclosure

• Consultant and Speaker, Genentech

Basal cell carcinoma, nodular

BCC most common human neoplasm, 2.5-5 million/year USA

Generally slow growing with good prognosis (near 100% survival)

Low recurrence rate if adequately treated (<5% in 5 years)

Multiple surgical options: ED&C, Excision, Moh’s surgery

Others: Imiquimod, Radiotherapy, Cryotherapy, Photodynamic RxJ Dermatol Surg Oncol. 1992; 18:471-47

Br J Plast Surg. 2005;58:795-805

Facial Plast Surg Clin N Am. 2012;20:445-54.

J Cutan Aesthet Surg. 2012;5:3-10

J Invest Dermatol. 2013;133:1188-1196

Basal Cell Carcinoma, nodular

Why Do We Need New Therapies for BCC?

Basal Cell Carcinoma, Locally Aggressive

• Poorly defined

• May relate to: size, location, extent

• May be called: disfiguring or debilitating

• May relate to projected difficulty to clear

• May relate to history: recurrence or lack of response to prior interventions (surgical, radiotherapy)

• YOU KNOW IT WHEN YOU SEE IT

Cancer Metastasis Rev. 2004;23:389-402

Locally aggressive BCC?

Gorlin’s Syndrome and BCC

Locally aggressive BCC!

Basal Cell Carcinoma, Metastatic

• Rare; Less than 1% BCC

• TO: nodes, lungs, liver, bone

• Overall survival quite variable, from months to >7 years

• Conventional chemotherapy and radiotherapy not very satisfactory

Cancer. 1980;46:748-757

J Am Acad Dermatol. 1984;10:1043-1060

JAMA Dermatol. 2013;14:615-616

Br J Dermatol 2013; 169:673-76 Figure courtesy of Dr. Omid Hamid

Hedgehog Pathway

• Hedgehog pathway important in

embryogenesis, silenced in most

adult tissues

• SMO causes cellular proliferation

• PTCH suppresses SMO

• Sporadic BCC (80%+) and

Gorlin’s Syn BCC (100%) have

inactivating PTCH mutations

• NO SMO suppression leads to

constant cellular proliferationClin Cancer Res. 2012;18:4883-4888

N Engl J Med. 2005;353:2262-2269

Hedgehog Pathway inhibitors: Active

AGENT / COMPANY STATUS

GDC-0449, Vismodegdib (Genentech/Curia) Approved: Locally aggressive and metastatic BCC

LDE225, Sonidegib (Novartis) Multiple Phase II studies for laBCC and mBCC

BMS-833923 (Bristol-Myers Squibb) Phase I studies in BCC, other sold tumors

LY2940680, Taladegib (Eli-Lily) Phase I study in BCC, June 2014 complete

LEQ-506 (Novartis) Phase I, dose-escalation study in BCC

TAK-41 (Millenium) Phase I, dose-escalation study in BCC

Br J Dermatol. 2005;152:43-51

Clin Cancer Res. 2012;18:4883-4888

N Engl J Med. 2012;366:2171-2179.

Semin Cutan Med Surg. 2012;31:140-149

Clin Cancer Res. 2014 Feb 12 (e-pub)

Vismodegib: Clinical Results

• ERIVANCE, STEVIE, BCNS Study published results

• ERIVANCE (Phase II): mBCC (n=33) ans laBCC (n=63)

- Inoperable, recurrence after multiple surgeries

- Unsuccessful or recurrent after radiation therapy

- Vismodegib at standard dose (150mg/day)

- Initial evaluation (~one year) and then repeated assessments

- Objective Response Rate:

** 30% decrease visible (radiographic) dimensions

** Complete response was verified by biopsy

** Determined by panel independent reviewers

N Engl J Med. 2012;366:2171-9

Vismodegib: Clinical results (laBCC) ERIVANCE

ParameterInitial Evaluation

(12 months)Followup (+18months) Followup (+24 months)

Objective Response Rate 43% 60.3% 60.3%

Complete response 21% 31.7% 31.7%

Partial response 22% 28.6% 28.6%

Median response duration 7.6 months 20.3 months 26.2 months

Median PFS 9.5 months 12.9 months 12.9 months

Adverse events:

Discontinuation12%

ASCO and EADV 2013, Posters

J Clin Oncol 2013;31 (Suppl):abstract 9037

Vismodegib: Clinical results (mBCC)

ParameterInitial Evaluation

(12 months)Followup (+18months) Followup (+24 months)

Objective Response Rate 30% 48.5% 48.5%

Complete response 0% 0% 0%

Partial response 30% 48.5% 48.5%

Median response duration 7.6 months 14.7 months 12.9 months

Median PFS 9.5 months 9.3 months 9.3 months

Adverse events:

Discontinuation12%

Clinical Benefit= CR+PR+SD = 94%

Other Data

• STEVIE (interim analysis, n=300 of 800 target subjects)

• laBCC = 278 and mBCC = 22

• Pooled data

• Median duration of treatment = 176.5 days

• CR = 17.5% PR = 39.8% Stable disease = 39%

• Clinical benefit (CR + PR + SD) = 96.5%

• Discontinuation due to AEs = 12%

J Clin Oncol 2013;31 (Suppl): Abstract 9036

Other Data

• BCNS study (n=41)

• At least 10 surgically removable BCC at entry (or last 2 years)

• Randomized 2 : 1 as follows: Vismodegib : Placebo

• Placebo arm discontinued (mean duration Rx 8 months)

• Rate of NEW BCC occurrence lower in Vismodegib arm v. placebo arm (2 versus 29)

• Size of existing BCC at enrollment reduced by 65% Vismodegib arm v. 11% placebo arm

• Visomdegib subjects had fewer surgical removals compared to placebo subjects (mean .31 vrs 4.4)

• Near complete remissions noted in some patients

• 54% discontinued vismodegib due to AEs

N Engl J Med. 2012;366:2180-2188

Vismodegib: Adverse events

Adverse Event Study Percent experienced

Muscle spasms ERIVANCE-STEVIE-BCNS 68%-59.3%-81%

Alopecia 63%-49.3%-62%

Dysgeusia 51%-41.9%-85%

Weight loss 46%-40%-42%

Fatigue Erivance 36%

Nausea Erivance 29%

Anorexia Erivance 23%

Dirrhea Erivance 22%

Vast Majority of AEs were Grade 1 or 2, with less than 5% of any AE being Grade 3/4

Boxed Warning

EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS

• Vismodegib can result in embryo-fetal death or severe birth defects

• Verify pregnancy status prior to initiation of treatment

• Advise male and female patients of these risks

• Advise females of need for contraception and advise males of potential risk of vismodegib exposure through semen

• See full prescribing information for complete boxed warning

ERIVEDGE (vismodegib) capsule for oral use [prescribing information]. South San Francisco, CA: Genentech USA, Inc; 2012.

Vismodegib in Patients With Operable Nodular BCC *

• Single-arm study of ability of vismodegib to produce complete

histological clearance in 24 pts with operable nodular BCC• 12 wks oral vismodegib 150 mg qd

• Mohs micrographic surgery assessment following Tx

• Clinical responses in 96% of pts

• 42% Actually had complete histological clearance by pathologic

assessment, but this diverged from the clinical assessment!• Clinical assessment: 21% CR; 17% PR; 4% SD

• Similar AEs as described previously; mostly grade 1 or 2

*Off-label useJ Invest Dermatol. 2012;132(suppl 1s):S92. Abstract 543.

Vismodegib: Acquired resistance

• All inhibitors developed to date have identical binding sites on extracellular portion of smoothened

• Acquired resistance has been identified• SMO variants with reduced HH inhibitor binding

• Gli over-amplification as compensation for SMO inhibition

• Activation of other cell replicative pathways

• Potential to add agents which prevent mutant neoplastic cells from escaping negative effects of HH inhibitors?

Cancer Cell 2013;23:23-34

Vismodegib: Future?

• Use of HH inhibitor PRIOR to surgical excision?

• Use of HH inhibitor PRIOR to Mohs surgery?

• Use of HH inhibitor AFTER either excision or Mohs surgery?

• Use of HH inhibitor concurrent, before or after radiotherapy, PDT, IRM?

• Use of HH inhibitor in aggressive subtypes of BCC?

• Use of HH inhibitor in combination protocols?

• How to prevent acquired resistance to HH inhibitors?

• Methods to reduce occurrence/severity of AEs?

• Stay tuned!JAMA Dermatol 2013;149:639-41

JAMA Ophthalmol 2013;131:1364-1366

Hedgehog Pathway

• Blocked by Smoothened inhibition

• Blocked by other mechanisms• Itraconazole

• Cancer cell 2010;17:388-99

• Cancer res 2012;72(8Suppl1): abstract LB-223

• J Clin Oncol 2014;Feb 3 e-pub

• Vitamin D3• PLoS Biol 2006; 4:e232

• Mol Cancer Ther. 2011;10:2179-88

• Bioorg Med Chem Lett 2012; 22:4859–4863

Hedgehog Pathway and BCC: Itraconazole

• 29 patients, 19 received itra and 10 placebo

• At least one BCC > 4mm

• Itra dose either 200mg BID or 100mg BID (1-2 mo)

• Two AEs in itra group, one of which was congestive heart failure

• Itra: reduced cell proliferation (measured by Ki67) by 45%

• Itra: reduced HH activity (measured by GLI1 mRNA) by 65%

• Itra: reduced tumor area by 24%

• Multiple tumors….partial response seen in some

J Clin Oncol 2014;Feb 3 e-pub

Discontinued HH Pathway Inhibitors (BCC)

AGENT STATUS

IPI-926, Saridegib Disappointing clinical data, D/C June, 2012

PF-04449913 Good response to max dose; Ongoing only for AML

SEN-794 Preclinical work positive; Strategically D/C

MK-5710 Preclinical work positive; No further work

Curr Opin Oncol. 2014;26:184-95

Hedgehog Pathway inhibitors

•OFFER HOPE….. for advanced BCC and metastatic BCC