Discussion of mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibitors in lung cancer after an initial good response.

1. How Do We Manage Acquired Resistance
to EGFR TKI Therapy?
Howard (Jack) West, MD
Swedish Cancer Institute
Seattle, WA
Challenging Cases
in Breast & Lung Cancer
Las Vegas, NV
April 21, 2012

2. Why Do We See
Acquired Resistance?

3. T790M Mutation
• Most common mechanism of resistance to EGFR
TKIs (50-68%)
• May have a better prognosis than non-T790M
mechanisms: 19 vs. 12 mo post-progression, Oxnard, CCR
2010
N = 93
• T790M more likely to show
progression in lungs/pleura
• Non-T790M more likely to
progress distantly, & worse PS

4. Rapid Progression with Discontinuation of
EGFR TKI after Prolonged PFS
Rapid acceleration of disease progression resulting
in hospitalization and/or death after discontinuation of
gefitinib or erlotinib and before initiation of study drug
(up to ~1/4 of pts in MSKCC series (Chaft, CCR,
2011)
Last day of TKI Off EGFR TKI Resumed TKI
Day 0 Day 21 Day 42
From Riely, CCR 2007

5. For Cancers with a Known Driver Mutation, Continuing
Inhibition of that Target is Beneficial after Progression
• Progression of CML on imatinib  increase dose, or dasatinib, or
nilotinib lead to consistent response
• Solid tumor example: HER2+ breast cancer
Minckwitz, JCO 2009

6. Such Patients Often Show
Slow, Modest Progression
Brakes may not be as good, but better than no brakes
No change in therapy may be needed initially

7. Combining Systemic and Local Targeted Therapies:
Radiation (or Surgery) to Isolated Area of Progression
Survival after RT to 1-2 sites of Freedom from Locoregional
metastatic disease (Lung Ca) Recurrence after Chest RT
1.0
0.9
Freedom from Locoregional Recurrence
EGFR mutation
0.8
0.7
0.6
0.5
0.4
EGFR wild type
0.3
0.2
0.1
0.0
0 12 24 36 48 60 72 84 96 108
Time (months)
Kahn, Radiotherapy & Oncology, 2006 Mak, ASCO 2010, A#7016
Perhaps extend the idea of the “precocious metastasis” to
“precocious recurrence”

8. Overcoming T790M: Irreversible TKIs

9. 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)
• PF-299804 (EGFR + Her2)
• RR 7% in TKI-resistant patients (Janne, ASCO ’09)
• BIBW-2992 (EGFR + Her2)
• RR 7% in TKI-resistant pts, 2 mo PFS increase (Miller, ESMO’10)
• Interesting ongoing study combining afatinib and cetuximab based on
a mouse model that was successfully treated w/ this combo

10. LUX Lung 1
• Does Afatinib work in patients with acquired resistance
to first generation EGFR TKI?
Patients with:
• Adenocarcinoma of the lung
• Stage IIIB/IV
• Progressed after one or two lines of chemotherapy (incl. one platinum-based regimen) and ≥12 weeks of
treatment with erlotinib or gefitinib
• ECOG 0–2
N=585
Randomization
2:1
Oral BIBW 2992 50 mg once daily Oral placebo once daily
plus best supportive care plus best supportive care
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL, safety

11. LUX Lung 1: Efficacy
Progression-Free Survival Overall Survival
Miller, ESMO 2010

12. Implication of LUX Lung1
• Lack of OS
– OS of 11.9 months in Placebo group
• Suggestive evidence of efficacy:
– RR at 13.3% and PFS (HR 0.38)
• Relationship to T790M not known
• Future implication
– Biomarker selection
– Combination with cetuximab

13. Afatinib/Cetuximab in
EGFR TKI-Resistant NSCLC
Dose escalation schema
NSCLC w/ 3-6 patients per cohort
EGFR mut’n1
and PD2
afatinib p.o. daily + escalating doses of
SD ≥ 6 mo on Stop EGFR TKI cetuximab IV q 2 weeks
erlotinib/gefitinib For ≥ 72 hours3
or Dose levels starting at:
CR or PR afatinib 40 mg +
to erlotinib/gefitinib cetuximab 250 mg/m2
Predefined maximum dose:
afatinib 40mg +
cetuximab 500 mg/m2
1
EGFR G719X, exon 19 deletion, L858R, L861Q
2
Progression of disease (RECIST v1.1) on continuous
treatment with erlotinib or gefitinib within the last 30 Expansion cohort part4
days. MTD cohort expanded
3
Amended from original 14 days interval up to 80 EGFR mutation-positive patients:
4
Acquisition of tumor tissue after the emergence of
40 T790M-positive and 40 T790M-negative
acquired resistance was mandated
Jangigian & Pao, ASCO 2011, #7525

14. Afatinib + Cetuximab at MTD:
Responses by EGFR Mutation
40% confirmed response rate and a clinical benefit rate of 90%
Jangigian & Pao, ASCO 2011, #7525

15. Afatinib + Cetuximab:
Insights & Future Directions
• Remarkable efficacy seen in EGFR TKI-
resistant tumors
– Requires further validation
• Activity not specific to common T790M mutant
• Need to further define biology and refine patient
population for phase III trial

16. MET Overexpression

17. 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 pts
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
• PF-02341066:
– Still in early phase studies

18. MetMAb is an anti-Met Monovalent
Antibody that Inhibits HGF-MediatedActivation
Rationale for targeting Met:
HGF HGF • Met is amplified, mutated,
overexpressed or uniquely activated
in many tumors
MetMAb • Met expression is associated with
worse prognosis in many cancers
including NSCLC
Met Met
• Met activation is implicated in
resistance to erlotinib/gefitinib in pts
with activating EGFR mutations
MetMAb:
Growth No
Migration activity • One-armed format designed to
Survival prevent HGF-mediated stimulation
of pathway
HGF: Hepatocyte growth factor • Preclinical activity across multiple
Spigel, ASCO 2011, #75051 tumor models

19. Randomized Phase II: Erlotinib + MetMAb
or Placebo in 2nd/3rd line NSCLC
Stage IIIB/IV NSCLC N = 69
2nd/3rd line Erlotinib 150 mg PO daily
Tissue required R MetMAb 150 mg/kg IV Q3wk
PS 0–2 A
Stratification factors: N
•Tobacco history
•Performance status
D Erlotinib 150 mg PO daily
•Histology Placebo IV Q3wk
N = 68
N = 137
PD
N = 27
Co-primary objectives: Other key objectives:
• PFS in ‘Met Diagnostic • OS in ‘Met Diagnostic positive’ add MetMAb
positive’ patients (est. 50%) patients Must be eligible to be
• PFS in overall ITT population • OS in overall ITT patients treated with MetMAb
• Overall response rate
• Safety/tolerability
Spiegel, ASCO 2011, #7505

20. Development of Met IHC for
Use as a Companion Diagnostic
• Technical metrics
– Tissue was obtained from 100% of patients.
– 93% of patients had adequate tissue for evaluation of Met by IHC
• Intensity of Met IHC staining on NSCLC tumor cells scored in 4 categories
Met Dx Met Dx Positive
1000 Negative
MET mRNA (2-∆ct)
Negative (0) Weak (1+)
100
Met Dx
Negative 10
1
Moderate (2+) Strong (3+)
Met Dx 0
Positive 0 1 2 3
MET IHC score
• Met diagnostic status was assessed after randomization and prior to unblinding
– ‘Met Diagnostic Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong staining intensity
52% patients enrolled were ‘Met Diagnostic Positive’
Spiegel, ASCO 2011, #7505

21. Erlotinib + MetMAb or Placebo
in 2nd/3rd line NSCLC: Safety
Met Diagnostic Positive Met Diagnostic Negative
No.of patients (%) MetMAb +
Placebo + erlotinib MetMAb + erlotinib Placebo + erlotinib
erlotinib
(n=31) (n=35) (n=31)
(n=31)
Any adverse event 31 (100) 35 (100) 31 (100) 31 (100)
Grade ≥3 adverse
17 (54.8) 20 (57.1) 13 (41.9) 17 (54.8)
event
Serious adverse
11 (35.5) 15 (42.9) 9 (29.0) 13 (41.9)
event
Adverse events
leading to treatment 2 (6.5) 8 (22.9) 0 (0) 2 (6.5)
discontinuation
Adverse events
4 (12.9) 1 (2.9) 0 (0) 3 (9.7)
leading to death
Spiegel, ASCO 2011, #75051

22. Erlotinib + MetMAb or Placebo:
Efficacy in ITT Population
PFS: HR=1.09 OS: HR=0.8
Placebo + MetMAb + Placebo + MetMAb +
erlotinib erlotinib erlotinib erlotinib
Median (mo) 2.6 2.2 Median (mo) 7.4 8.9
1.0 HR 1.09 1.0 HR 0.80
Probability of progression free
(95% CI) (0.73–1.62) (95% CI) (0.50–1.3)
Log-rank p-value 0.69 Log-rank p-value 0.34
Probability of survival
0.8 No. of events 56 48 0.8 No. of events 41 34
0.6 0.6
0.4 0.4
0.2 0.2
Note: + = censored value. Note: + = censored value.
0.0 0.0
0 3 6 9 12 15 18 0 3 6 9 12 15 18 21
Time to progression (months) Overall survival (months)
Control arm was consistent with previous studies in a similar population
(Br21 PFS 2.2 mo, OS 6.7 mo, ORR 8.9%)
Spigel, ASCO 2011, #75051

23. Erlotinib + MetMAb or Placebo: Efficacy
in Met Diagnostic Positive NSCLC Patients
PFS: HR=0.53 OS: HR=0.37
Placebo + MetMAb + Placebo + MetMAb +
erlotinib erlotinib erlotinib erlotinib
Median (mo) 1.5 2.9 Median (mo) 3.8 12.6
1.0 HR 0.53 1.0 HR 0.37
(95% CI) (0.28–0.99) (95% CI) (0.19–0.72)
Probability of progression free
Log-rank p-value 0.042 Log-rank p-value 0.002
0.8 No. of events 27 20 0.8 No. of events 26 16
Probability of survival
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
0 3 6 9 12 15 18 0 3 6 9 12 15 18 21
Time to progression (months) Overall survival (months)
The addition of MetMAb to erlotinib doubled the progression free survival
and nearly tripled the overall survival in this population
Spigel, ASCO 2011, #75051

24. ARQ-197: c-MET Receptor Tyrosine Kinase
• Implicated in tumor cell migration,
invasion, proliferation, and angio-
genesis1
• Only known high-affinity receptor for
hepatocyte growth factor (HGF)1
• c-MET amplification associated with:
• Poor prognosis in NSCLC2
• Resistance to EGFR TKIs3,4
1. Birchmeier C and Gherardi E. Trends Cell Biol 1998;8:404–10
2. Cappuzzo F et al. JCO 2009;27:1667–74
3. Engelman JA et al. Science 2007;316:1039–43
4. Bean J et al. PNAS 2007;104:20932–7

25. Rand Phase II: Erlotinib + Tivantinib (ARQ-197)
or Placebo in Prev Treated Adv NSCLC
Inop Loc Adv/Met NSCLC
>1 prior line of Rx N = 84 Erlotinib 150 mg PO daily
No prior EGFR TKI R ARQ-197 360 mg PO BID
PS 0–2 A
Stratification factors:
sex, age, ECOG PS, N
smoking status, histology, D Erlotinib 150 mg PO daily
prior Rx, best response, & Placebo PO BID
geography (U.S. vs. ex- N = 83
U.S.) PD
N = 167 N = 21
Endpoints
add ARQ-197
• 1° PFS
• 2° ORR, OS
• Subset analyses
Sequist, JCO 2011 • Crossover: ORR

26. Erlotinib + Tivantinib or Placebo:
Efficacy (ITT Population)
Sequist, JCO 2011

27. Erlotinib + Tivantinib or Placebo:
PFS & OS in Non-Squamous NSCLC Patients
Sequist, JCO 2011

28. Erlotinib + Tivantinib or Placebo: Time to New
Metastatic Lesions (ITT & Non-Squamous)
Sequist, JCO 2011

29. Erlotinib + Tivantinib or Placebo:
PFS in Histologic and Molecular Subgroups
Placebo/
ARQ197/erlotinib erlotinib
N Median PFS (95% CI, weeks) Unadjusted HR (95% CI)
HR=1.05
Squamous Cell 26 / 24 13.7 (8.0‒18.1) 8.4 (7.9‒21.0)
Non-Squamous Cell 58 / 59 18.9 (15.0‒31.1) 9.7 (8.0‒16.0) HR=0.71
HR=0.71
c-MET FISH >4 19 / 18 15.4 (8.1‒24.4) 15.3 (7.1‒16.3)
HR=0.45
c-MET FISH >5 8 / 11 24.1 (16.3‒NE) 15.6 (7.9‒31.4)
HR=1.23
EGFR mutant 6 / 11 24.1 (8.0‒32.1) 21.0 (8.1‒36.0)
EGFR wt 51 / 48 13.7 (8.1‒18.1) 8.1 (7.9‒9.9) HR=0.70
KRAS mutant 10 / 5 9.7 (7.9‒NE) 4.3 (1.1‒8.0) HR=0.18
HR=1.01
KRAS wt 49 / 45 15.4 (8.1‒18.1) 9.9 (8.0‒16.0)
0 0.5 1.0 1.5 2.0 5.0
Schiller, ASCO 2010 Favors Favors
ARQ 197/Erlotinib Erlotinib/placebo

30. Erlotinib + Tivantinib or Placebo:
Crossover Patients
2 PR2
34 Crossover 23 Evaluable
Patients for Response1 9 SD3
2
Pt # 24:
EGFR IND
1
Baseline + ≥1 post-baseline scan. 12 PD KRAS WT
Reasons for non-evaluable incl: c-MET > 4
- Clinical progression (n=4)
- Active but haven’t received 1st post- Pt # 58:
progression scan (n=2) EGFR MUT
- Death (n=1) KRAS WT
- Dosing delay (n=1) c-MET > 5
- Withdrew consent (n=1)
- Investigator decision (n=1) 3
3‒18+ weeks
Schiller, ASCO 2010

31. Research Efforts for
Acquired Resistance to EGFR TKIs
• Afatinib/cetuximab looks very promising
• Unexpectedly, not correlated with T790M
• Phase III trial in development
• MetMAb phase II trial encouraging in subset
• Benefit appears limited to high Met expression
(detrimental in low Met expression)
• Phase III trial in development
• Tivantinib phase II trial favorable, esp in non-squamous
• Phase III trial now ongoing
• Possibly particularly helpful for KRAS mut’n positive
• Increasing interest in post-PD biopsies, though not yet
useful outside of trial setting

32. Acquired Resistance to EGFR TKIs:
Practical Principles for the Clinic
• Patients can respond to EGFR TKI with rechallenge,
especially after long interval off of EGFR TKI (breaks
onc rule of “you can never go back”
• ?Consider local therapy to solitary area of PD
• Some patients will have a rebound rapid progression
after being taken off of an EGFR TKI
• Heterogeneous populations of cancer cells
• Is it better to continue the EGFR TKI and add an
agent/regimen, or to stop it and potentially restart it later??
• I favor continuing EGFR TKI when PD < PR, but not
when PD is very clear
• No comparison and no good data to address this