A cancer that begins in the lungs and most often occurs in people who smoke. Two major types of lung cancer are non-small cell lung cancer and small cell lung cancer. Causes of lung cancer include smoking, second-hand smoke, exposure to certain toxins and family history. Symptoms include a cough (often with blood), chest pain, wheezing and weight loss. These symptoms often don't appear until the cancer is advanced. Treatments vary but may include surgery, chemotherapy, radiation therapy, targeted drug therapy and immunotherapy.

1. 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

2. “The magic of EGFR inhibitors”

3. The promise of genotype-directed therapy
Treatment B
Treatment C
Treatment D
Treatment A

5. 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.

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

7. Clinical Information
Biopsy
Routine and Molecular Pathology
Targeted Therapy

8. Repeat Biopsies: EGFR mutants with AR to gefitinib, erlotinib
8
Sequist et al Sci Transl
Med 2011

9. Specific TKI
Target Alteration
RTK mutation or amplification
PI3K
ERK
STAT
P P
P P
P P
Two General Classes of TKI Resistance
Receptor TK
PI3K
ERK
STAT
Sensitive/TKI-naïve
RTK2
Receptor TK
PI3K
ERK
STAT
RTK1
P
RTK2
P
Bypass Tracks
?
Slide courtesy of Alice Shaw

10. 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

11. T790M 52%
alone 42%
with EGFR amp 10%
No identified AR mechanism
26%
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%

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

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

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

15. T790M
 Most common mechanism of resistance to
EGFR TKIs (50-68%)
 May have a better prognosis than non-T790M
mechanisms (Oxnard, CCR 2010)

16. 0
20
40
60
80
100
120
gefitinib
HKI-272
EKB-569
Drug concentration (mM)
0 .02 .2 2 20
Relative
cell
viability
(%)
P-AKT
P-MAPK
Total EGFR
P-EGFR
Total AKT
Total MAPK
untreated
0.001
0.01
0.1
1
10
gefitinib (mM)
untreated
0.001
0.01
0.1
1
10
HKI-272 (mM)
NCI-H1975 (L858R and T790M)
Overcoming T790M: Irreversible TKIs
Kwak, PNAS 102:7665, 2005

17. • 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

18. www.esmo2012.org
Afatinib + cetuximab at MTD:
Responses by T790M mutation
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
Maximum
percentage
decrease
from
baseline
(%)
T790M+ T790M– EGFR wt Uninformative for T790M

19. www.esmo2012.org
PFS at MTD
Number at risk
Afatinib + cetuximab
MTD: Afatinib 40 mg daily + cetuximab 500 mg/m2 every 2 weeks
Estimated
PFS4
probability
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.

20. 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
%
change
in
target
lesions
*
Felip, et al. ESMO ‘12

21. EGFR
HGF
MET
TKI Resistance via MET Amplification
Engelman et al., Science 2007: 316; 1040.

23. 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

24. 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

25. Treatment of MET amp pt with Crizotinib
Jan 2012 March 2012

26. 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

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

28. 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

29. 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