Hedgehog Pathway Inhibitors and Advanced Basal Cell...
Transcript of Hedgehog Pathway Inhibitors and Advanced Basal Cell...
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