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3/29/2011
1
Developing Personalized Strategies for Managing
Acquired EGFR TKI Resistance
Lecia V. Sequist, MD, MPH
MGH Cancer CenterAssistant Professor of Medicine
Harvard Medical School
Moderator: Dr H. Jack WestPresident & CEO
Global Resource for AdvancingCancer Education (GRACE)
in partnership with
3/29/2011
2
Disclosures
Compensated consulting: GSK
Uncompensated consulting: Boehringer-Ingelheim, Merrimack Pharamaceuticals, Daiichi-Sankyo
Overview
Quick review of EGFR mutation-positive NSCLC
Mechanisms of resistance to EGFR TKIs
Possible avenues for treatment of EGFR TKI resistance
Repeat biopsies
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Advanced NSCLC Therapy
Targeted therapyBest supportive care Single-agent platinum Doublets
~2-4 months~6 months
~8-10 months
12+ months
Median O
SFirst-line Second-line Third-line Not approved
1970 1980 1990 2000 2010
Molecular targeting of cancer
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Before…. …and After
Oncogene Addiction: EGFR in lung cancer
EGFR
PI3K P42/44 MAPK
Jak/Stat
gefitinib
Apoptosis
Gefitinib-Sensitive
PTEN
IGFR
K-Ras (G12V)
PI3K MAPK Jak/Stat
EGFR
De novo resistant
• Unlike EGFR mutant cancers, most cancers probably don’t have “addiction” to a single RTK
• No single therapy may “gefitinib” effect.
• May require a combination of therapies
• EGFR mutant cancers are “simple”-one RTK controls all downstream signaling.
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TKI resistance mechanisms
Clinical Information
Biopsy
Routine and Molecular Pathology
Targeted Therapy
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T790M Most common mechanism of resistance
to EGFR TKIs (50-68%)
May have a better prognosis than non-T790M mechanisms (Oxnard, CCR 2010)
0
20
40
60
80
100
120
gefitinib
HKI-272
EKB-569
Drug concentration (M)
0 .02 .2 2 20
Rel
ativ
e ce
ll vi
abili
ty (%
)
P-AKT
P-MAPK
Total EGFR
P-EGFR
Total AKTTotal MAPK
untre
ated
0.00
1
0.01
0.1
1 10
gefitinib (M)
untre
ated
0.00
1
0.01
0.1
1 10
HKI-272 (M)
NCI-H1975 (L858R and T790M)
Overcoming T790M: Irreversible TKIs
Kwak, PNAS 102:7665, 2005
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Irreversible TKIs in Clinical Trials
HKI-272 (EGFR + Her2) RR 2% in TKI-resistant patients Intriguing responses in G719X patients (Sequist, JCO 2010)
XL-647 (EGFR, Her2, VEGF) RR 2% in TKI-resistant patients (Pennell, Chicago Lung ’08)
BIBW-2992 (EGFR + Her2) RR 7% in TKI-resistant patients, 2mo PFS advantage (Miller, ESMO’10) Interesting ongoing study combining afatinib and cetuximab based on a
mouse model that was successfully treated w/ this combo
PF-299804 (EGFR + Her2) RR 7% in TKI-resistant patients (Janne, ASCO ’09)
EGFR
HGF
MET
TKI Resistance via MET Amplification
Engelman et al., Science 2007: 316; 1040.
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1/30/08 3/31/08
Pre-Rx ‘08 Resistant ‘09
Proof of principle: 63 year old man with an EGFR mutant lung cancer
erlotinibDeveloped Resistance
Rx on clinical trial
2/25/09
Met Inhibitors in Clinical Trials
ARQ-197, specific MET inhibitor Randomized phase II of erlotinib +/- ARQ-197 in TKI-naïve patients
showed some benefit of combo but wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Schiller, ASCO 2010)
Met-mab Randomized phase II of erlotinib +/- MET-Mab in TKI-naïve paitents
showed some benefit of combo but again wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Spigel , ESMO 2010)
XL-184, MET + RET + VEGF Randomized phase II of erlotinib +/- XL-184 in TKI-resistant
patients, completed but not reported yet
PF-02341066: Still in phase I
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On the bright side….
There are many ongoing trials looking at novel ways to attack resistance MM121 (her3 Mab) + erlotinib
Afatinib + cetuximab
PF0299804 + crizotinib
Hsp90 inhibitors
HDAC inhibitors
PI3K inhibitors
MTOR inhibitors
Repeat Biopsies?
Pros
Discover more about resistance
Point patients toward appropriate clinical trials
Cons
Cost
Safety – pretty good so far
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Acquired Resistance to EGFR inhibitors
How can we improve outcomes?• Could these combinations produce greater TTP if they were used as initial therapy (similar to strategies for lymphoma, HIV, and TB)?
• Can we identify how cancers will become resistant prior to initial therapy?
• Are there other therapeutic strategies that would overcome multiple resistance mechanisms???
Is there a way to identify the eventual mechanism of resistance from the pre-treatment specimen?
• In CML, data suggests that resistance mutations exist prior to treatment
Can we detect other types of resistance mechanisms in the pre-Rx specimen?
Maheswaran and Sequist et al, NEJM, 2008
• Similarly, highly sensitive methods can detect EGFR T790M in some samples prior to treatment
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Cell Line No of Cells Analyzed No of Positive Cells HCC827 4237 6 (0.14%) HCC827 N1 4812 4 (0.08%) HCC827 C1 5057 7 (0.14%) HCC827 C2 6670 2 (0.06%) H3255 1164 0 (0%) PC-9 5630 0 (0%)
MET amplified cancer cells pre-exist (0.01%) in untreated HCC827 cells
Subclones derived from single HCC827 cells
Turke, Zejnullah et al, Cancer Cell, 2010
Summary: Research Focuses
Genotype-directed therapy paradigm is a good start but has room for improvement
Treatment of resistance has proven to be complicated, but many trials are ongoing
Prevention may be a potent strategy, especially since pre-disposition toward certain mechanisms may be identifiable
Need less invasive alternatives to biopsies
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Thank you!MGH Thoracic Research GroupJeff EngelmanBelinda WaltmanAlice ShawPanos FidiasMike LanutiHenning WillersNoah ChoiRay MakSubba DigumarthyPat McCarthyLisa FreehaferDiane DaviesBeth Kennedy
Translational Research LabJohn IafrateDora Dias-SantagataMari Mino-KenudsonDarrell BorgerLeif Ellisen
Haber LabDaniel HaberShyamala MaheswaranMike Rothenberg
Toner LabMehmet TonerSunitha NagrathShannon Stott
Other CollaboratorsScott GettingerTom LynchJoel NealPasi JanneJonathan GoldbergJoan SchillerWilliam PaoGreg Reily