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Targeting MET in NSCLC

John Heymach, MD, PhDAssociate Professor

Thoracic/Head and Neck Medical Oncology and Cancer Biology

9th Annual Winter Lung Cancer Conference

Hollywood, FLFeb. 11, 2012

The hepatocyte growth factor/c-Met signaling pathway in cancer

Adapted from Liu, Trends Mol Med, 2010; Mayor, Lancet Oncology, 2011

• Met Small Molecule Inhibitors

– XL184

– ARQ197

– PF-02341066/Crizotinib

– BMS-777607

• Met/HGF Antibodies

– MetMAb

– AMG102

Therapeutic antibodies(e.g., AMG102, MetMAb, TAK-701 and SCH900105)

C-MET kinase inhibitors(e.g., ARQ197, PF2341066. PF4217903, JNJ38877606, INCB028060, XL880, XL184, MP470, MK2461, MGCD265, BMS777607, and AMG208)

Interacting proteins(e.g., RON, EGFRs, 6ß4 integrin, plexin B1, CD44, and FAS)

TRENDS in Molecular Medicine

c-MET as a Therapeutic Target in NSCLC

• HGF/MET axis is associated with invasiveness and is regulated in part by the HIF and EGFR pathways

• MET amplifications are associated with EGFR inhibitor resistance

• HGF/MET may promote resistance to VEGF inhibitors

Xu L, et al. Oncogene. 2010;29:2616-2627. Engelman JA, et al. Science. 2007;316:1039-1043. Cascone, et al. ASCO 2010.

c-Met receptor tyrosine kinase inhibitors – promising therapeutic target in NSCLC

Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

• ARQ-197, a novel and selective non-ATP competitive inhibitor of c-MET

• ARQ 209 enrolled 167 advanced NSCLC patients

Endpoints

•Primary: PFS

•Secondary: ORR, OS

•Subset analyses

•Crossover: ORR

RANDOMIZE

Erlotinib 150 mg PO QD + ARQ 197 360 mg PO BID

28-day cycle

Erlotinib 150 mg PO QD + Placebo

28-day cycle

PD

• 33 sites in 6 countries

• Study accrual over 11 months (10/08–9/09)

• Randomization stratified by prognostic factors including sex, age, smoking, histology, performance status, prior therapy, best response, and geography (US vs ex-US)

Randomized, placebo-controlled, double-blind clinical trial

NSCLC

•Inoperable locally adv/metastatic dz.1 prior chemo (no prior EGFR TKI)

ARQ-197 plus erlotinib was associated with improvements in PFS and OS

compared with erlotinib alone

*Cox regression model. Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

E + A (n = 84)

E + placebo (n = 83)

Hazard ratio p-value

PFS 16.1 weeks 9.7 weeks 0.68 <0.05

OS 36.6 weeks 29.4 weeks 0.68 0.52*

PFS and OS benefits most pronounced in patients with non-squamous cell carcinoma

*Cox regression model. Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

E + A (n = 84)

E + placebo (n = 59)

Hazard ratio p-value

PFS 18.9 weeks 9.7 weeks 0.61 <0.05*

OS 43.1 weeks 29.4 weeks 0.58 <0.05*

PFS in histologic and molecular subgroups

Schiller JH, et al. J Clin Oncol 2010;28:18s (abstr LBA7502 and oral presentation)

c-MET FISH >5, HR = 0.45

KRAS mutant, HR = 0.18

Arm A (n = 64)Erlotinib (150 qd-oral) + MetMAb (15 mg/kg IV q3w)

Addition of MetMAb*

Stratification factors:

Tobacco history

Performance status

Histology

PD

* If eligible

Co-primary objectives: PFS in “Met High” patients PFS in overall ITT population Other key objectives: OS in “Met High” patients OS in overall ITT patients Overall response rate Safety/tolerability

OAM4558g study design: randomized Phase II study of erlotinib +/- MetMAb

Arm B (n = 64)

Erlotinib (150 qd-oral) +placebo (IV q3w)

Key eligibility:

• Stage IIIB/IV NSCLC

• 2nd/3rd-line NSCLC

• Tissue required

• PS 0–2

RANDOMIZATION

1:1n = 128

n = 23-Enrollment from 3/2009 to 3/2010-Data cut-off: 8 June 2010

Spigel et al, J Clin Oncol 29: 2011 (suppl; abstr 7505)

PFS and OS: ITT population

– Objective response rates: Erlotinib + Placebo n = 3 (4.7%), Erlotinib + MetMAb n = 4 (6.3%)

– 23 patients from the Erlotinib + Placebo arm crossed over to MetMAb

mPFS and mOS are consistent with previously reported findings in a similar disease setting

Spigel et al, J Clin Oncol 29: 2011 (suppl; abstr 7505)

Erlotinib + placebo (n = 64)

Erlotinib + MetMAb(n = 64)

HR (95% CI)

Log-rank p-value

Median PFS (wk)

11.1 9.6 1.09 (0.71-1.67) 0.6988

Median OS (mo)

8.2 7.1 1.09 (0.62-1.91) 0.7642

PFS and OS: Met high population

MetMAb + Erlotinib improves both PFS and OS in Met high NSCLC patients

Spigel et al, J Clin Oncol 29: 2011 (suppl; abstr 7505)

Erlotinib + placebo (n = 30)

Erlotinib + MetMAb(n = 35)

HR (95% CI)

Log-rank p-value

Median PFS (wk)

6.4 12.4 0.56 (0.31-1.02) 0.0547

Median OS (mo)

7.4 7.7 0.55 (0.26-1.16) 0.1113

PFS and OS: Met low population

Met low NSCLC patients do worse with MetMAb + Erlotinib

Spigel et al, J Clin Oncol 29: 2011 (suppl; abstr 7505)

Erlotinib + placebo (n = 29)

Erlotinib + MetMAb(n = 27)

HR (95% CI)

Log-rank p-value

Median PFS (wk)

11.4 6.0 2.01 (1.04-3.91) 0.0354

Median OS (mo)

9.2 5.5 3.02 (1.13-8.11) 0.0212

HGF/MET axis and resistance to VEGF inhibitors

Cascone, Proc AACR 2011

Stromal and tumor MET expression is increased in VEGFR TKI resistant

H1975 xenografts

Ectopic HGF overexpression induces relative resistance to VEGF/R inhibition

in NSCLC xenografts

Dual MET/VEGFR targeting is more effective than VEGFR

or MET targeting alone

Patterns of tumor revascularization associated with VEGF inhibitor resistance: Normalized vs sprouting revascularization

Adapted from Cascone T et al. 2010

Acquired Resistance: Normalized Revascularization

Long-termAnti-VEGF

Short-term Anti-VEGF

Sensitive phaseReduced MVD

Primary Resistance:Sprouting Vascularization

Baseline

Tumor endothelium Tumor cells

Pericytes

HGF

Elevations in bFGF and HGF Develop Prior to Progression on Bevacizumab and Chemotherapy

Kopetz et al, JCO 2010

"Several proangiogenic cytokines were elevated before progression, notably basic fibroblast growth factor (bFGF),

PlGF, and HGF."

Summary

• MET and its ligand HGF are overexpressed in cancers and are associated with metastatic spread

• MET may contribute to resistance to EGFR, VEGF inhibitors– Amplification of MET gene seen in some cases of acquired

resistance to EGFR TKIs in NSCLC

• MET inhibition shows promise in MET+ tumors in combination with erlotinib

• Phase III trials in progress in NSCLC– Erlotinib +/- MetMAb

– Erlotinib +/- ARQ197

Saturday, February 11, 2012Hollywood, Florida

Faculty

Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD

Co-Chair and ModeratorNeil Love, MD

Chandra P Belani, MDJohn Heymach, MD, PhDPasi A Jänne, MD, PhD

Thomas J Lynch Jr, MDHeather Wakelee, MD