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 A
Treatment C
Treatment B
Treatment D
The Concept of Oncogene Addiction
EGFR-Addicted
Non-addicted case
EGFR
IGFR
EGFR
gefitinib
PI3K
P42/44
MAPK
K-Ras
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
Clinical Information
Targeted Therapy
Biopsy
Routine and Molecular Pathology
Repeat Biopsies: EGFR mutants with AR to gefitinib, erlotinib
Sequist et al Sci Transl
Med 2011
8
Two General Classes of TKI Resistance
Sensitive/TKI-naïve
Target Alteration
Bypass Tracks
Receptor TK
Receptor TK
RTK mutation or amplification
P
PP
P
P
RTK1
P
RTK2
P
?
STAT
STAT
ERK
Slide courtesy of Alice Shaw
RTK2
PI3K
ERK
Specific TKI
PI3K
STAT
ERK
PI3K
P
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 nonT790M mechanisms (Oxnard, CCR 2010)
Overcoming T790M: Irreversible TKIs
Drug concentration (mM)
gefitinib
NCI-H1975 (L858R and T790M)
P-AKT
P-MAPK
Total EGFR
Total AKT
Total MAPK
120
10
1
0.1
0.01
0.001
untreated
10
1
0.1
0.01
EKB-569
HKI-272 (mM)
Relative cell viability (%)
P-EGFR
gefitinib (mM)
0.001
untreated
HKI-272
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
Maximum percentage decrease
from baseline (%)
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
Median
Estimated PFS4 probability
Afatinib + cetuximab
4.7
0.8
0.6
0.4
0.2
0.0
0
Number at risk
Afatinib + cetuximab 96
3
59
6
9
12
Time from treatment start (months)
32
12
5
15
18
3
0
MTD: Afatinib 40 mg daily + cetuximab 500 mg/m2 every 2 weeks
MTD = maximum tolerated dose; PSF4 = progression-free survival at 4 months.
www.esmo2012.org
AUY922 (Hsp90): best CT response:
EGFR-mutant patients (n=25†/35)
EGFR-mutant (n=35)
100
80
ORR (any PR)
7 (20%)‡
DCR (CR/PR or SD)
20 (57%)
PFS (18 weeks [95% CI]), %
35.2 (18.7, 52.2)
Best % change in target lesions
60
40
20
0
-20
-40
-60
*
*
*
*
*
*
-80
-100
*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
Developed
Resistance
erlotinib
1/30/08
Pre-Rx ‘08
3/31/08
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-naïve paitents
showed benefit of combo but again wasn’t designed to look at
EGFR mutants or acquired resistance to EGFR TKIs (Spigel ,
ASCO 2011)
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