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 Concept of Oncogene Addiction
EGFR
PI3K P42/44
MAPK
Jak/Stat
gefitinib
Apoptosis
EGFR-Addicted
PTEN
IGFR
K-Ras
PI3K MAPK Jak/Stat
EGFR
Non-addicted case
• EGFR mutant cancers are “simple”-one RTK controls all downstream signaling.
Specific TKI
Target Alteration
RTK mutation or amplification
PI3KERKSTAT
P PP PP P
Two General Classes of TKI Resistance
Receptor TK
PI3KERKSTAT
Sensitive/TKI-naïve
RTK2
Receptor TK
PI3KERKSTAT
RTK1
P
RTK2
P
Bypass Tracks
?
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
T790M 52%alone 42%
with EGFR amp 10%
No identified AR mechanism26%
BRAF 2%
MET amp 5%SCLC 8% with EGFR amp 1% alone 4% with PI3K 3%
Updated MGH cohort: EGFR mutants with AR, n=106
EGFR Amp 15% with T790M 10% alone 4% with SCLC 1%
PI3K 5% with SCLC3% alone 2%
Waxing/waning resistance in response to TKI selective pressure
Sequist et al, Sci Transl Med 2011
Adenocarcinoma
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)
0
20
40
60
80
100
120
gefitinib
HKI-272
EKB-569
Drug concentration (M)
0 .02 .2 2 20
Rel
ati
ve
cel
l vi
abil
ity
(%)
P-AKT
P-MAPK
Total EGFR
P-EGFR
Total AKT
Total MAPK
untreated
0.001
0.01
0.1
1 10
gefitinib (M)
untreated
0.001
0.01
0.1
1 10
HKI-272 (M)
NCI-H1975 (L858R and T790M)
Overcoming T790M: Irreversible TKIs
Kwak, PNAS 102:7665, 2005
• 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
Irreversible TKIs (Pan-HER Inhibitors): Not highly effective for T790M
www.esmo2012.org
Afatinib + cetuximab at MTD: Responses by T790M mutation
5040302010
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 100Patient index sorted by maximum % decrease
Max
imum
per
cent
age
de
cre
ase
from
ba
selin
e (%
)
T790M+ T790M– EGFR wt Uninformative for T790M
www.esmo2012.org
PFS at MTD
Number at riskAfatinib + cetuximab
MTD: Afatinib 40 mg daily + cetuximab 500 mg/m2 every 2 weeks
Est
imat
ed P
FS
4 pr
obab
ility
1.0
0.8
0.6
0.4
0.2
0.0
Time from treatment start (months)0 3 6 9 12 15 18
Median
Afatinib + cetuximab 4.7
96 59 32 12 5 3 0
MTD = maximum tolerated dose; PSF4 = progression-free survival at 4 months.
AUY922 (Hsp90): best CT response: EGFR-mutant patients (n=25†/35)
EGFR-mutant (n=35)
ORR (any PR) 7 (20%)‡
DCR (CR/PR or SD) 20 (57%)
PFS (18 weeks [95% CI]), % 35.2 (18.7, 52.2)
*Confirmed responses; †Patients with at least one post-baseline scan;‡Including one PR not confirmed.
* * * **
-100
-80
-60
-40
-20
0
20
40
60
80
100
Best
% c
hang
e in
targ
et le
sion
s
*
Felip, et al. ESMO ‘12
1/30/08 3/31/08
Pre-Rx ‘08 Resistant ‘09
Proof of principle: 63 year old man with an EGFR mutant lung cancer
erlotinib
Developed 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 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
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
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
MGH Pathology John Iafrate Mari Mino-Kenudson Dora Dias-Santagata Vicente Morales
Yale Tom Lynch Scott Gettinger Sarah Goldberg Katie Politi
Engelman Lab Tony Faber Matt Niederest Elizabeth Lockerman
Vanderbilt William Pao Kadaoki Ohashi
Funding Uniting Against Lung Cancer NIH/NCI (R21CA156000) MGH Thoracic Oncology MGH Pathology
Stanford Joel Neal
UCSF Belinda Waltman
Germans Trias i Pujol, Barcelona Teresa Moran
Haber/Toner Lab Shyamala Maheswaran Shannon Stott John Walsh James Sullivan Mike Rothenberg
Top Related