3/26/2012
MET Inhibitors in Non-Small-Cell Lung Cancer
David R. Spigel, MD Director, Lung Cancer Research Sarah Cannon Research Institute Nashville, TN
MET Signaling •
c-MET (MET) is the receptor for hepatocyte growth factor (HGF)
•
MET activation → cell-cell d detachment, h proliferation, lif i invasion, i i angiogenesis, and survival – assoc w/ poor prognosis in NSCLC
•
MET activation associated with EGFR TKI resistance
•
MET activation results from: •
Receptor overexpression (frequent in NSCLC)
•
Activating mutations (rare in NSCLC)
•
Gene amplification
•
Autocrine / paracrine (stromal) secretion of HGF
Cappuzzo, JCO 2009 Ding, Nature 2008
Peruzzi, Clin Cancer Res 2006 2
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Inhibiting MET Signaling
Experimental Drug (Drug Maker) Monoclonal Anti-HGF Antibodies Rilotumumab (AMG102) (Amgen) Monoclonal Anti-Met Antibodies Onartuzumab (MetMAb) (Genentech)
Spectrum of Targets * (Clinical Application) IgG2 monoclonal Ab against HGF that prevents receptor binding (Malignant glioma, RCC, GEJ cancers) Monovalent HGF antagonist Ab against MET (Advanced solid tumors)
Adapted from Sattler and Salgia, Update Cancer Ther 3 2009
Inhibiting MET Signaling Experimental Drug (Drug Maker) Small Molecule MET Inhibitors
Spectrum of Targets * (Clinical Application)
JNJ38877605 (Johnson & Johnson)
Selective MET TKI (Pancreatic neoplasms, microphthalmia transcription factor associated tumors alveolar soft part sarcoma, tumors, sarcoma clear cell sarcoma, RCC, other solid tumors) Broad spectrum TKI (MET, VEGFR2, PDGFRß, KIT, FLT3, TIE2, RON) (SCC, gastric cancer, papillary RCC, other solid tumors) A selective MET TKI (Solid tumors)
MK2461 (Merck)
A small molecule inhibitor of MET (Solid tumors)
MP470 (SuperGen)
Broad spectrum TKI (MET, RET, KIT, AXL, PDGFRα and FLT3) - Also suppresses the DNA repair protein Rad51 (Solid tumors, tumors HL/NHL) MET and ALK kinase inhibitor (Systemic Anaplastic LCL, NSCLC, other tumors) A MET kinase inhibitor (Solid tumors)
Tivantinib (ARQ197) (ArQule/Daichi) GSK1363089 (XL880) (GlaxoSmithKline)
Crizotinib (Pfizer) PF-04217903 (Pfizer) Cabozantinib (XL184) (Exelixis)
MET, VEGFR2, and RET small molecule inhibitor (Medullary thyroid cancer, NSCLC, lymphoma, thyroid cancer, GBM, other solid tumors)
4 Adapted from Sattler and Salgia, Update Cancer Ther 2009
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Tivantinib: a Selective c-MET TKI • Non-ATP competitive oral inhibitor of c-MET
• Stabilizes inactive conformation of c-MET
• Broad-spectrum anti-tumor activity in xenografts (including NSCLC) • In vivo anti-tumor activity of ARQ 197 + EGFR inhibitor greater than either drug alone • Safety and linear PK in phase I combination with erlotinib Munshi , Mol Cancer Ther 2010;Epub ahead of print Unpublished; courtesy of ArQule, Inc. and Kyowa Hakko Kirin Co., Ltd Laux , ASCO 2009 Goldman, IASLC 2009
Tivantinib: Study Design
Randomized placebo-controlled double-blind phase II trial
NSCLC • Inoperable locally adv/metastatic dz. • ≥1 prior chemo
(no prior EGFR TKI))
p Endpoints • 1° PFS • 2° ORR, OS • Subset analyses • Crossover: ORR
R A N D O M I Z E
Erlotinib 150 mg PO QD + ARQ 197 360 mg PO BID 28-day cycle PD
Erlotinib 150 mg PO QD + Placebo 28-day cycle
• 33 sites in 6 countries • Study accrual over 11 months (10/08-9/09) • Randomization stratified by prognostic factors: gender, age, smoking, histology, PS, prior therapy, best response, and geography (U.S. vs. ex-U.S.)
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Tivantinib: Progression-Free Survival (ITT)
Prroportion of patients progressio on-free
1.0
• HR=0.81 (95% CI: 0.57, 1.15); p=0.24 • Adjusted HR=0.68 (95% CI: 0.47, 0.98); p 4
19/18
3.6 (1.9 - 5.7)
3.6 (1.7 - 3.8)
c-MET FISH > 5
8/11
5.6 (3.8 - NE)
3.6 (1.8 - 7.3)
EGFR mutant
6/11
5.6 (1.9 - 7.5)
4.9 (1.9 - 8.4)
EGFR wt
51/48
3.2 (1.9 - 4.2)
1.9 (1.8 - 2.3)
KRAS mutant
10/5
2.3 (1.8 - NE)
1.0 (0.3 - 1.9)
KRAS wt
49/45
3.6 (1.9 - 4.2)
2.3 (1.9 - 3.7)
•
Unadjusted HR
Tivantinib/Erlotinib Placebo/Erlotinib
A PFS benefit associated with tivantinib plus erlotinib was observed in patients with tumors harboring amplified c-MET, wild-type EGFR, or mutant KRAS
1.05 0 71 0.71 0.71 0.45 1.23 0.70 0.18 1 01 1.01
0
0.5
1.0
1.5
2.0
5.0
Favors tivantinib/erlot. Favors placebo/erlotinib
Cox proportional hazard ratio analysis of median progression-free survival by patient subgroup. Abbreviations: CI, confidence interval; FISH, fluorescence in situ hybridization; HR, hazard ratio; PFS, progression-free survival; wt, wild type
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MARQUEE Phase III study design A multicenter, phase 3, randomized, double-blind, placebo-controlled clinical trial Phase III in NSCLC Inoperable, locally advanced t t ti disease di or metastatic Non-squamous histology 1 - 2 regimens of prior chemo (no prior EGFR TKI) Prior platinum-based doublet therapy required Endpoints 1°: OS (ITT population) 2°/Exploratory: population) p ) PFS ((ITT p PK and PD analysis OS and PFS in EGFR wt patients Safety and toxicity QOL/FACT-L Biologic subgroup analysis
R A N D O M I Z E
Arm A: Tivantinib +
Erlotinib
360 mg PO BID 150 mg PO QD
Arm B: Placebo PO BID
+
Erlotinib 150 mg PO QD
Stratification by EGFR and KRAS mutational status
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MetMAb is an Anti-Met Monovalent Antibody that Inhibits HGF-Mediated Activation HGF
HGF
One-armed format designed to prevent HGF-mediated p stimulation of pathway
MetMAb
Preclinical activity across multiple tumor models
Met
Met
Growth, Migration, Survival
No Activity
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Patient Diagnosis, Treatment Cohort, and Administered Cycles
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Moss, AACR 2011
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Phase II: Erlotinib +/- Onartuzumab in 2nd/3rd-line NSCLC (N=137)
Onartuzumab (15 mg/kg IV Q3W) +
Study Population
Erlotinib
Key eligibility: • Stage IIIB/IV NSCLC • 2nd/3rd-line NSCLC • Tissue required • PS 0–2
(150 mg daily) R 1:1
Placebo
Option to Crossover ((N=27)
+
Erlotinib (150 mg daily) Stratification factors: • Tobacco history • Performance status • Histology
Co-primary objectives: • PFS in ‘Met Diagnostic Positive’ patients (est. 50%) • PFS in overall ITT population
*128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010 Data presented includes >5 additional months of follow-up
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MetMAb plus Erlotinib in Met Dx+ Patients PFS: HR=0.53
OS: HR=0.37
Placebo + MetMAb + erlotinib erlotinib
Probability of progression free
0.8
15 1.5
29 2.9 0.53 (0.28–0.99) 0.04 27 20
Median (mo) 3.8 3 8 12 6 12.6 0.37 HR (0.19–0.72) (95% CI) 0.002 Log-rank p-value No. of events 26 16
10 1.0
Prob bability of survival
Median (mo) HR (95% CI) Log-rank p-value No. of events
10 1.0
Placebo + MetMAb + erlotinib erlotinib
0.6
0.4
0.2
0.0
0.8
0.6
0.4
0.2
0.0 0
3
6
9
12
15
Time to progression (months)
18
0
3
6
9
12
15
18
21
Overall survival (months) 9
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MetMAb plus Erlotinib in Met Dx- Patients PFS: HR=1.82
OS: HR=1.78
Placebo + MetMAb + erlotinib erlotinib
Probability of progression free
0.8
27 2.7
14 1.4 1.82 (0.99–3.32) 0.05 24 26
Median (mo) 15.3 15 3 81 8.1 1.78 HR (0.79–3.99) (95% CI) 0.16 Log-rank p-value 13 17 No. of events
10 1.0
Prob bability of survival
Median (mo) HR (95% CI) Log-rank p-value No. of events
10 1.0
Placebo + MetMAb + erlotinib erlotinib
0.6
0.4
0.2
0.0
0.8
0.6
0.4
0.2
0.0 0
3
6
9
12
15
18
0
Time to progression (months)
3
6
9
12
15
18
21
Overall survival (months) 10
Phase III: Erlotinib +/- Onartuzumab in 2nd/3rd-line NSCLC (N=480)
Onartuzumab (15 mg/kg IV Q3W) +
Study Population Key eligibility: • Stage IIIB/IV NSCLC • MET Dx Positive* • 2nd/3rd-line NSCLC • Tissue required • PS 0–1 • No prior EGFR inhib.
Erlotinib (150 mg daily) R 1:1
Placebo +
Erlotinib (150 mg daily)
Stratification factors: • EGFR Mut Status • MET IHC 2+ v. 3+ • No. of prior therapies • Histology
*Central Testing for MET and EGFR
Primary objective: • OS Secondary Objectives: PFS QoL ORR Safety 16
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Rilotumumab (AMG 102) is an Investigational Fully Human Monoclonal Antibody Rilotumumab selectively targets HGF, the only ligand of the MET receptor
Rilotumumab HGF/SF
In preclinical models, antiHGF/SF antibody:
blocked downstream signaling pathways led to the inhibition of HGF/SFdependent tumor growth in vivo
MET Receptor
Burgess T, et al. Cancer Res. 2006;66:1721-1729.
Study Schema ClinicalTrials.gov identifier NCT00719550
Phase 2 R A N D O M I Z E Stratification factors: ECOG PS 0 vs 1 LA vs Metastatic
ARM A Rilotumumab (15 mg/kg) + ECX Q3W (n = 40)
ARM B Rilotumumab (7.5 mg/kg) + ECX Q3W (n = 40)
ARM C Placebo + ECX Q3W (n = 40) E: Epirubicin: 50 mg/m2 IV, Day 1 C: Cisplatin: 60 mg/m2 IV, Day 1 X: Capecitabine: 625 mg/m2 BID orally, Days 1-21
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PFS and OS in c-MetHigh Patients Patients with P pro ogression-free survival (%) s
100
Progression-Free Survival
Median Months HR (80% CI) (80% CI) -------------------------------------------------Arms A+B (c-Met High, n = 27) 6.9 (5.1, 7.5) 0.53 (0.25, 1.13) Arm C (c-Met High, n = 11) 4.6 (3.7, 5.2)
80 60 40 20 0 0
1
2
3
4
5
6
Patients at risk: Arms A+B (c-Met High): 27 Arm C (c-MetHigh): 11
7 8 9 10 11 12 13 14 15 16 Months
27 10
23 10
20 8
18 7
15 4
12 1
10 1
5 1
4 0
4 0
8 0
2 0
1 0
1 0
0 0
Overall Survival
Median Months HR (80% CI) (80% CI) -------------------------------------------------Arms A+B (c-Met High, n = 27) 11.1 (9.2, 13.3) 0.29 (0.11, 0.76) Arm C (c-Met (c Met High, n = 11) 5.7 (4.5, 10.4)
100 Patients with progressio on-free survival (%)
7 1
80 60 40 20 0
Patients at risk:
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Months
Arms A+B (c-Met High): 27 27 26 25 25 24 23 20 19 17 13 12 Arm C (c-MetHigh): 11 10 10 10 9 7 4 4 4 3 3 1
8 0
5 0
2 0
2 0
1 0
0 0
Ongoing Clinical Trials in Thoracic Malignancies
Phase
Population
Regimen
NCT
Ib/II
ES-SCLC
AMG 102 or 479 in combination with platinum-based chemo
00791154
II
Mesothelioma
AMG 102 + Cisplatin/Pemetrexed
01105390
I/II
2nd/3rd line NSCLC
AMG 102 + erlotinib
01233687
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Cabozantinib (XL184) • Oral inhibitor MET, VEGFR2, and RET pathways • Phase I – 85 pts (37 medullary thyroid CA- MTC) • •
MTD 175 mg po daily DLTs •
•
HFS, mucositis, AST/ALT, lipase elevations
Responses seen in MTC •
10/35 (29%) PR, PR+SD in 68% of MTC
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Kurzrock JCO 2011
Cabozantinib + Erlotinib: NSCLC
• 8 of 53 evaluable patients had a best time point response of > 30% tumor shrinkage
• 4 of 53 evaluable patients (8%) had a confirmed partial response (PR)
• 19 patients had stable disease (SD)/PR ≥ 4 months (range 3.5-15 months)
Wakelee PASCO 2010 #3017
• Two patients had confirmed MET gene copy number gain – both experienced tumor shrinkage • Of the 20 patients with an activating EGFR mutation, 9 also had a T790M mutation; 7 of these patients had SD as their best 22 response
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MET in NSCLC Summary • MET is an important receptor tyrosine kinase involved in cell proliferation, motility, and metastasis
• MET can be overexpressed, p , mutated,, amplified, p , and activated by y paracrine/autocrine ligand production
• MET activation is a negative prognostic factor in NSCLC • Several MET inhibitors are in development, including Tivantinib and MetMAb which are entering phase III trials
• Work to identify predictive markers for treatment is in progress
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