Transcript Research To Practice

Please note, these are the actual video-recorded
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New Targets
Mark A. Socinski, MD
Professor of Medicine and Thoracic Surgery
Director, Lung Cancer Section, Division of
Hematology/Oncology
Co-Director, UPMC Lung Cancer Center of Excellence and
Lung and Thoracic Malignancies Program
University of Pittsburgh
c-met
hsp90
PARP inhibitors
custirsen
c-met
Hepatocyte growth factor (HGF)/MET signaling pathway
transduces invasive growth signals from mesenchymal
to epithelial cells.
Adapted from Appleman L J JCO 2011;29:4837-4838
Randomized Phase II Trials with Met inhibitors in
Advanced NSCLC
• Tivantinib
Design – Erlotinib +/- tivantinib (placebo-controlled); 10 Endpt - PFS
Population - > 1 prior regimen (n=167)
PFS – erlotinib 9.7 wks, erlotinb/tivantinib 16.1 wks
(HR 0.81, p=0.24, adjusted HR 0.68, p < 0.05)
No toxicity concerns
Signal greatest in non-squamous and in KRAS mutants
• MetMAb
Design – Erlotinib +/- MetMAb (placebo-controlled); 10 Endpt – PFS
Population – 2nd/3rd line NSCLC (n=137)
Trial was negative in all-comers but co-10 Endpt analyzed by IHC
Met + PFS HR 0.54, p=0.04, Met – PFS HR 1.82, p=0.05
Toxicity – peripheral edema
ARQ 197 KRAS MUTATION CLINICAL TRIAL
NSCLC
• 98 patients
• Inoperable locally
adv/metastatic dz.
• Documented
KRAS mutation +
• ≥ 1 prior chemo
R
A
N
D
O
M
I
Z
E
• No prior MET or
EGFR TKI
Erlotinib 150 mg PO QD
+ARQ 197 360 mg PO BID
Dealer’s Choice of:
1. Gemcitabine
2. Docetaxel
3. Pemetrexed
• 1° Endpoint PFS (ITT population)
•21 day cycles
• 2°/Exploratory Endpoints incl:
•Every 6 week CT-based tumor
- OS (ITT population)
assessment
- ORR
•Crossover allowed
- ORR in crossover population
•Assumptions: 10 vs. 5 week
doubling in median PFS (9.7 v. 4.3)
- Safety and toxicity
Phase III Met Trials
• Two phase III trials ongoing
• Both randomize 2nd line + NSCLC pts to erlotinib +/c-met inhibitor (placebo-controlled)
• Patient selection/eligibility differ
- Tivantinib – histology (non-squamous)
- MetMAb – met IHC diagnostic high (+)
hsp90
Inhibiting the Chaperone Degrades
Client Proteins
Inactive client
protein
Hsp90 binds to client
Activated client; cell
survival, proliferation
(AKT, BCR-ABL, BRAF,
EGFR, FLT3, HER2,
HIF1A, KIT, MET,
VEGFR, ALK, ER, …)
Inactive client, degraded
through proteasome
Inhibitor prevents
Hsp90 binding to client
HSP 90 Inhibitors in Clinical Development
Agent
Sponsor
Administration
NCI/Kosan
iv
KOS-953 (tanespimycin)
Kosan
iv
17DMAG
Kosan
Iv & oral
IPI-504 (Retaspimycin)
Infinity
iv
STA-9090 (Ganetespib)
Synta
iv
AUY-922
Novartis
iv
DS-2248
Daiichi
Oral
XL-888
Exelexis
Oral
IPI-493
Infinity
Oral
MPC-3100
Myrexis
Oral
SNX-5422
Serenex
Oral
CNF-2024
Biogen Idec
Oral
17AAG
Source: Clinicaltrials.gov, accessed 3/29/2011.
Study Design
Ganetespib 200 mg/m2 once weekly for 3 weeks of 4 week cycle
•
•
ECOG - PS 0, 1
•
Documented
disease
progression at
study entry
•
Stratification
Previously treated
stage IIIB/IV
NSCLC
A: mEGFR (n=16)
B: mK-Ras (n=17)
C: wild-type EGFR/wild-type K-Ras (n=25)
D: Adenocarcinoma only (n=37)
Stage 1 n = 14;
Genotyping*
CT scans
n=96*
ITT population
Stage 2
(if n ≥ 2 progression-free
at wk 16)
Primary endpoint: PFS at 16 weeks
*1 patient with unknown genotype
Secondary endpoints: ORR,
First Patient First Visit, Dec, 2009;
DCR at 8, 16 wks; PFS, OS,
Last Patient first visit, May, 2011
Wong,….,Shapiro,Socinski
ASCO 2011
F/U
Until
PD
Time to treatment failure,
Safety and Tolerability
CT scans
every 8 wks
Evaluable
population
n = 76
Research To Practice could not obtain permission
to reproduce this slide at the time of publication.
For further information, please see the following:
Shapiro G et al. An open-label phase II study
of the Hsp90 inhibitor ganetespib (STA-9090)
as monotherapy in patients with advanced
non-small cell lung cancer (NSCLC).
Presentation. ASCO 2011. No abstract available
Research To Practice could not obtain permission
to reproduce this slide at the time of publication.
For further information, please see the following:
Shapiro G et al. An open-label phase II study
of the Hsp90 inhibitor ganetespib (STA-9090)
as monotherapy in patients with advanced
non-small cell lung cancer (NSCLC).
Presentation. ASCO 2011. No abstract available
Ganetespib in ALK+ NSCLC - PFS
Hazard Ratio (95% CI): 0.204 (0.071,
0.589) (ALK + vs -)
© 2011 Synta Pharmaceuticals Corp.
IPI-504 Inhibits ALK Signaling
The Hsp90 inibitor IPI-504 rapidly
lowers EML4-ALK levels and induces
tumor regression in ALK-driven
NSCLC models
Normant et al, Oncogene 30:2581-86, 2011.
Ganetespib activity in crizotinib refractory
ALK positive NSCLC
• 24 y. old male with NSCLC, diagnosed Jan 2009
• pem/cis w pem maintenance until Feb 2010
• EML4-ALK positive
• crizotinib for ~ 1 year; re-biopsy shows resistance
mutation
• Start Ganetespib May 9, 2011
• Evidence of response relatively early
Preclinical data support
complementary activity
G shows superior potency to criz in
criz-sensitive ALK+ NSCLC cells;
retains activity in criz-resistant lines
(H2228 ALK+ NSCLC cells)
Synergy with taxanes: cell cycle effects
Induction of G0/G1 & G2/M arrest enhances taxane M-phase cell-killing
Ganetespib
Ganetespib
Cell-cycle genes
inhibited by ganetespib
Gene
Fold
Change
CDC2
-21.0
E2F-7
-15.2
Cyclin E2
-12.0
Cyclin F
-10.2
CDC25A
-6.1
CDC25C
-5.3
Cyclin E1
-5.1
DHFR
-4.6
E2F-1
-3.7
Cyclin A2
-3.6
Ganetespib
HEL92.1.7 cells treated for 24 hrs
Adapted from W. Ying et al. Molec Canc Therap Dec 2011; D. Proia et al PLoS One 2011;6:e18552
GALAXY Trial: Phase 2b/3 NSCLC
GALAXY Trial Protocol – Stage IIIB/IV NSCLC, 2nd-line
Stage 1 (Ph 2b)
(A) Docetaxel
N=240
Docetaxel +
(B)
Ganetespib
Stage 2 (Ph 3)
Biomarker data
Enrich population
Regulatory input
PFS endpoint
Co-primary: ITT, KRAS
Power ~90% ITT: 3mo (A)  5mo (B),
KRAS: 5 wk (A)  10 wk (B)
(A) Docetaxel
N~500
(B)
PFS or OS endpoint TBD
Docetaxel 75mg/m2 q3w , ganetespib 150 mg/m2 (d1,15)
Stage 1
Interim data: Q2 2012
Final PFS data: Q3 2012
OS data: Q4 2012
Docetaxel +
Ganetespib
Stage 2
Initiation: 2H 2012
60 top-tier centers US, Canada, Europe
PARP inhibitors
Iniparib in Untreated Stage IV
Squamous NSCLC
DNA replication
DNA DSB
DNA SSB
Chemo
PARP
Base excision repair
Iniparib
ATM/ATR
wt p53/
mt p53
γ-H2AX
BRCA1
Rad50
MRE11
NBS1
RAD51
BRCA2
Rad52/4
RPA
ERCC1
Adapted from N.J. Curtin, 2006
Homologous Recombination Repair (HR)
Target Cancers = defective in HR
BRCA1/2 mutant (breast, ovarian),
ERCC1 abnormalities (colon, NSCLC),
p53 mutant tumors.
ECLIPSE Study Overview
N= 825
International, Open-label
Gemcitabine + Carboplatin
Patient Population:
• Advanced squamous cell
carcinoma
R
Endpoints:
Primary: OS
Secondary: PFS, TTP, ORR,
safety/tolerability, QoL
Doses:
Gemcitabine 1000 mg/m2 D 1 & 8 q3wk
Carboplatin AUC 5 D1 q3wk;
Iniparib 5.6 mg/kg IV D 1, 4, 8 & 11 q3wk
1:1
• Patients restaged by CT scans (per RECIST 1.1
version) q 2 cycles (6 wks)
• Patients may remain on study regimen after 6 cycles
if there is no evidence of PD or the presence of DLTs
Gemcitabine + Carboplatin
+ Iniparib
First Patient Enrolled: March 5, 2010
Clin Cancer Res 2007;13:3033-3042
Phase I/II* Study of Veliparib (ABT-888)
Added to Chemotherapy for Stage III NSCLC
Eligibility (N = 122)
Stage IIIA or IIIB NSCLC (no small cell
carcinoma component)
Unresectable
R
One lesion measurable in at least one
dimension as >20 mm with conventional
techniques or as >10 mm with spiral CT
No prior therapy for NSCLC
*Dose escalation followed by randomized Phase II study
Primary endpoint: DLT and MTD of ABT-888 concurrent
with carboplatin/paclitaxel and XRT (Phase I); PFS with
Chemoradiotherapy plus ABT-888 (Phase II)
ClinicalTrials.gov, Accessed 2/9/12
XRT
ABT-888 PO days 1-50
Carboplatin
Paclitaxel
XRT
Placebo PO days 1-50
Carboplatin
Paclitaxel
custirsen
Custirsen — 2nd-Generation Antisense
Oligonucleotide Targeting Clusterin
Clusterin inhibits apoptosis and is associated with
treatment resistance
Ribosome
Transcription
Normal
Clusterin
mRNA
DNA
Custirsen
-sense
oligo
Translation
into protein
Breakdown
of mRNA
Antisense
treatment
Custirsen
-sense
binds to
clusterin
mRNA
No translation
of clusterin
protein
By  clusterin protein levels, custirsen promotes tumor cell
death and sensitizes cells to anticancer agents.
Laskin JJ et al. J Thoracic Oncol 2011 [epub ahead of print].
Phase I/II Trial Schema
Eligibility (N = 81)
Stage IIIB (N3 and/or pleural or
pericardial effusion) or Stage IV
NSCLC
Phase I Safety Lead-In (n=10)
480 mg or 640 mg custirsen +
gem/cis OR gem/carbo
NSCLC unresectable or amenable to
RT
One lesion at least 10mm by CT
scan or at least 20 mm by standard
techniques
No prior chemotherapy or biological
therapy
Phase II (n=71)
640 mg custirsen + gem/cis
OR gem/carbo
Laskin JJ et al. J Thoracic Oncol 2011 [epub ahead of print].
Efficacy Summary
Custirsen + gem/cis OR
gem/carbo
Clinical Parameter
ORR
(n=81)
31%
Median PFS
4.3 mos
Median OS
14.1 mos
1-Yr OS rate
54%
2-Yr OS rate
30%
•
Median OS was increased for patients who achieved a median clusterin serum level of ≤38 g/ml
versus those who did not (27.1 mos vs 16.1 mos, p = 0.02).
•
Based on study results, Phase III study in NSCLC of custirsen in the first line is planned for 2012.
Laskin JJ et al. J Thoracic Oncol 2011 [epub ahead of print].
Thank you
Sunday, February 12, 2012
Hollywood, Florida
Co-Chairs
Rogerio C Lilenbaum, MD
Mark A Socinski, MD
Co-Chair and Moderator
Neil Love, MD
Faculty
Walter J Curran Jr, MD
David Jablons, MD
Mark G Kris, MD
Suresh Ramalingam, MD
Alan B Sandler, MD