Developing Personalized Strategies for Managing Acquired...

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3/29/2011 1 Developing Personalized Strategies for Managing Acquired EGFR TKI Resistance Lecia V. Sequist, MD, MPH MGH Cancer Center Assistant Professor of Medicine Harvard Medical School Moderator: Dr H. Jack West President & CEO Global Resource for Advancing Cancer Education (GRACE) in partnership with

Transcript of Developing Personalized Strategies for Managing Acquired...

3/29/2011

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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

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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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The promise of genotype-directed therapy

Treatment B

Treatment CTreatment D

Treatment A

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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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Mok, NEJM 2009

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Mok, NEJM 2009

Mok, NEJM 2009

Med PFS G 9.6 mo

C/P 6.3 moMed PFS G 1.6 mo

C/P 5.5 mo

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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