Repeat Biopsies and the Potential Value of Biologically-Informed Acquired Resistance Therapy

Lecia V. Sequist, MD, MPH Associate Professor of Medicine, Harvard Medical School Mary B. Saltonstall Endowed Chair in Oncology, Massachusetts General Hospital

“The magic of EGFR inhibitors”

The promise of genotype-directed therapy

Treatment B Treatment A Treatment C Treatment D

The Concept of Oncogene Addiction

EGFR-Addicted EGFR Non-addicted case IGFR EGFR gefitinib K-Ras PI3K P42/44 MAPK Jak/Stat Apoptosis • EGFR mutant cancers are “simple”-one RTK controls all downstream signaling.

PTEN PI3K MAPK Jak/Stat

Acquired Resistance Feb 2010 Diagnosis Dec 2010 TKI max response July 2011 Acq. resist Repeat Biopsy

Biopsy Clinical Information Targeted Therapy Routine and Molecular Pathology

8 Repeat Biopsies: EGFR mutants with AR to gefitinib, erlotinib

Sequist et al Sci Transl Med 2011

Two General Classes of TKI Resistance

Target Alteration RTK mutation or amplification

P P P P

Sensitive/TKI naïve Receptor TK Bypass Tracks Receptor TK

RTK1 P RTK2 RTK2 P

STAT ERK PI3K STAT ?

ERK Specific TKI PI3K STAT ERK PI3K

Slide courtesy of Alice Shaw

Sci Transl Med; March 2011

• • 37 consecutive samples with paired pre- and post- AR tissue Comparative analyses for: – Histology with IHC – SNaPshot (most common mutations in 13 genes) – FISH for EGFR and MET amplification

Updated MGH cohort: EGFR mutants with AR, n=106

SCLC 8%

with EGFR amp 1% alone 4% with PI3K 3%

PI3K 5%

with SCLC3% alone 2%

MET amp 5% BRAF 2% No identified AR mechanism 26% T790M 52%

alone 42% with EGFR amp 10%

EGFR Amp 15%

with T790M 10% alone 4% with SCLC 1%

Waxing/waning resistance in response to TKI selective pressure Sequist et al, Sci Transl Med 2011

Waxing/waning resistance in response to TKI selective pressure Adenocarcinoma Sequist et al, Sci Transl Med 2011 High-grade neuroendocrine carcinoma

EGFR transformed to SCLC is responsive to SCLC chemo Patient received carboplatin, etoposide and erlotinib

T790M

 

Most common mechanism of resistance to EGFR TKIs (50-68%) May have a better prognosis than non T790M mechanisms

(Oxnard, CCR 2010)

Overcoming T790M: Irreversible TKIs

P-EGFR P-AKT P-MAPK Total EGFR Total AKT Total MAPK NCI-H1975 (L858R and T790M) gefitinib (

m

M) HKI-272 (

m

M) Drug concentration (

m

M)

gefitinib HKI-272 EKB-569 120 100 80 60 40 20 0 0 .02 .2 2 20 Kwak, PNAS 102:7665, 2005

Irreversible TKIs (Pan-HER Inhibitors): Not highly effective for T790M • Neratinib (HKI-272) – RR 2%, PFS 15 weeks in TKI-resistant patients ( Sequist, JCO 2010 ) • Afatinib (BIBW-2992) – RR 7%, PFS ~13 weeks in TKI-resistant pts ( Miller, Lan Onc ‘12 ) • Dacomitinib (PF-299804) – RR 7% in TKI-resistant patients ( Janne, ASCO ’09 ) ….novel T790M-specific TKIs are entering clinical trials – CO-1686 – AP26113

Afatinib + cetuximab at MTD: Responses by T790M mutation

T790M+ T790M – EGFR wt Uninformative for T790M

50 40 30 20 10 0 –10 –20 –30 –40 –50 –60 –70 –80 –90 –100 –110 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Patient index sorted by maximum % decrease

www.esmo2012.org

PFS at MTD

1.0

0.8

0.6

0.4

Afatinib + cetuximab Median 4.7

0.2

0.0

0 Number at risk Afatinib + cetuximab 96 3 6 9 12 Time from treatment start (months) 32 12 5 59 MTD: Afatinib 40 mg daily + cetuximab 500 mg/m 2 every 2 weeks MTD = maximum tolerated dose; PSF4 = progression-free survival at 4 months. 15 3 18 0

www.esmo2012.org

-20 -40 -60 -80 -100 60 40 20 0

AUY922 (Hsp90): best CT response:

EGFR

-mutant patients (n=25

†

/35)

100 80

EGFR-mutant (n=35) ORR (any PR) DCR (CR/PR or SD) PFS (18 weeks [95% CI]), %

7 (20%) ‡ 20 (57%) 35.2 (18.7, 52.2) * * * * * * *Confirmed responses; † Patients with at least one post-baseline scan; ‡ Including one PR not confirmed.

Felip, et al. ESMO ‘12

TKI Resistance via MET Amplification

EGFR HGF MET

Engelman et al., Science 2007: 316; 1040.

Proof of principle: 63 year old man with an EGFR mutant lung cancer erlotinib Developed Resistance 1/30/08 3/31/08 Pre Rx ‘08 Resistant ‘09 2/25/09 Rx on clinical trial

Met Inhibitors in Clinical Trials

ARQ-197, specific MET inhibitor  Randomized phase II of erlotinib +/- ARQ-197 in TKI naïve patients showed PFS benefit of combo but wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Sequist, JCO 2011) Met-mab  Randomized phase II of erlotinib +/- MET-Mab in TKI ASCO 2011) naïve paitents showed benefit of combo but again wasn’t designed to look at EGFR mutants or acquired resistance to EGFR TKIs (Spigel , XL-184, MET + RET + VEGF  Randomized phase II of erlotinib +/- XL-184 in TKI-resistant patients, completed but not reported yet Crizotinib:  We know it works in MET amp patients, but we don’t know about EGFR mutant,TKI resistant pts with MET amp

Treatment of MET amp pt with Crizotinib Jan 2012 March 2012

Clinical Strategies for Patients in the Clinic 1.

Repeat biopsies whenever possible 2.

Clinical trials whenever possible 3.

Treatment beyond progression and local therapy for local progression 4.

Continuing TKI beyond with other therapies

Treatment Beyond Progression: appealing if PD is slow Oxnard, et al ASCO’12

Summary and Future Directions • Genotype-directed therapy paradigm has revolutionized NSCLC landscape • Treatment of resistance has proven complicated • Repeat biopsies of patients with AR will continue to greatly supplement lab-based research • Prevention may be a potent strategy, especially since pre-disposition toward certain mechanisms may be identifiable. Need more ideal combination regimens • Need to develop less-invasive ways of assessing tumor genotype

Acknowledgments

MGH Cancer Center Jeff Engelman Alice Shaw

Daniel Haber Becca Heist Jerry Azzoli Jennifer Temel Inga Lennes Justin Gainor Panos Fidias Rachel Rosovsky Mike Lanuti Subba Digumarthy Michele Myers Marguerite Parkman

Emily Howe Engelman Lab

Tony Faber Matt Niederest Elizabeth Lockerman

MGH Pathology John Iafrate Mari Mino-Kenudson

Dora Dias-Santagata Vicente Morales

Haber/Toner Lab

Shyamala Maheswaran Shannon Stott John Walsh James Sullivan Mike Rothenberg

Yale Tom Lynch Scott Gettinger

Sarah Goldberg Katie Politi

Germans Trias i Pujol, Barcelona Teresa Moran Stanford

Joel Neal

Vanderbilt

William Pao Kadaoki Ohashi

UCSF

Belinda Waltman

Funding

Uniting Against Lung Cancer NIH/NCI (R21CA156000) MGH Thoracic Oncology MGH Pathology