Department of Thoracic/Head

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Long-term management EGFR mutant NSCLC patients
Anne S. Tsao, M.D.
Director, Mesothelioma Program Director, Thoracic
Chemo-XRT Program
Associate Professor
The University of Texas
Department of Thoracic/Head Neck
MD ANDERSON
Medical Oncology
CANCER CENTER
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Outline Long-term management EGFR mutated NSCLC
patients
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EGFR mutations

• Found in 10 - 15 of all lung cancer patients
  and 85 who clinically respond to EGFR TKIs
• Found more commonly in never-smokers,
  adenocarcinomas, BAC, women, Asians
• Predominantly located in EGFR exons 19 - 21
• EGFR mutations are not the same. There are
  sensitive mutations and acquired resistance
  mutations (T790M).
• 85 of EGFR mutations are either deletion exon 19
  or L858 mutation.

Pao, Miller. J Clin Oncol. 2005232556-2568 Wu
et al. J Thorac Oncol. 20072430-439.
4
Patient with EGFR mutation deletion exon 19
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Patient with L858 EGFR mutation
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Causes of EGFR TKI Resistance in 37 EGFR mutated
NSCLC patients
Sequist L et al. Sci Transl Med
2011375ra26-75ra26
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EGFR T790M Frequently Found inTumor Cells From
Patients With Acquired Resistance to EGFR TKIs
Pao W, et al. PLoS Med. 20052e73 Balak MN, et
al. Clin Cancer Res. 2006126494-6501.
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T790M blocks erlotinib binding and leads to a
resistant phenotype
Michalczyk et al. Bioorganic Medicinal
Chemistry 16 (7) 3482 April 2008
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Outline Long-term management EGFR mutated NSCLC
patients
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EGFR mutant on TKI develops oligometastatic PD

• Continue EGFR TKI
• Utilize radiation therapy or surgical resection
• Close monitoring
• Several studies demonstrate additional PFS
  benefit (6.2-10 months) and possibly OS (41
  months) benefit with this strategy.

Weickhardt et al. JTO 7 1807-1814, 2012 Yu et
al. ASCO 2012 abstract 7527, JCO 30 , 2012
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EGFR mutation and ALK mutation patients with
oligo-progressive disease local therapy have
PFS benefit
Weickhardt et al. JTO 7 1807-1814, 2012
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Flare of Disease after EGFR TKI discontinuation
in acquired resistance

• Rapid disease acceleration leading to
  hospitalization and/or death after EGFR TKI
  cessation occurs in up to 23 (n14) of patients
  in MSKCC series (n61).

Riely et al. Clinical Cancer Research 2007, Chaft
et al. CCR 17 (19) 6298-6303, 2011
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EGFR Mutant Disease Progression on EGFR TKI

• Clinical PD appearance
• - Rapid disease PD globally
• Slow growth globally
• Growth in several areas, but not all

• Molecular
• Unknown
• (other pathways)
• MET
• PIK3CA
• SCLC

Sequist L et al. Sci Transl Med
2011375ra26-75ra26
14
Current Options in EGFR TKI resistant patient
with EGFR mutation
Chemotherapy
Chemotherapy
EGFR TKI
Chemotherapy EGFR TKI combination
Chemotherapy with intermittent EGFR TKI
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Chemo is safe Chemo then maintenance erlotinib is
safe Chemo EGFR TKIs are safe
Chemotherapy
Chemotherapy
EGFR TKI
SATURN
INTACT I, II TRIBUTE, TALENT
Chemotherapy EGFR TKI combination
Chemotherapy with intermittent EGFR TKI
FAST ACT
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SATURN Treatment Schema
Erlotinib 150 mg/day
PD
Chemotherapy-naïve advanced NSCLC N1949
4 cycles of first-line platinum doublet
chemotherapy
No PD N889
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Placebo
PD
Mandatory tumor sampling

• Co-primary endpoints
• PFS in all patients
• PFS in patients with EGFR IHC tumors
• Secondary endpoints
• OS in all patients and those with EGFR IHC
  tumors, OS and PFS in EGFR IHC tumors, biomarker
  analyses, safety, time to symptom progression,
  and QOL

• Stratification factors
• EGFR IHC (positive vs negative vs indeterminate)
• Stage (IIIB vs IV)
• ECOG PS (0 vs 1)
• Chemotherapy regimen (cisplatin/gemcitabine vs
  carboplatin/docetaxel vs others)
• Smoking history (current vs former vs never)
• Region

Cisplatin/paclitaxel cisplatin/gemcitabine
cisplatin/docetaxel cisplatin/vinorelbine
carboplatin/gemcitabine carboplatin/docetaxel
carboplatin/paclitaxel.
Cappuzzo. ASCO. 2009 (abstr 8001).
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SATURN PFS by EGFR Mutation Status
PFS Mutated EGFR
PFS Wild-Type EGFR
100
100
HR0.78 (0.63-0.96) P0.0185
HR0.10 (0.04-0.25) Plt0.0001
80
80
60
60
Patients Without Progression ()
Patients Without Progression ()
Erlotinib (N199)
40
40
Erlotinib (N22)
Placebo (N189)
Placebo (N27)
20
20
0
0
0
0
8
8
48
16
48
64
16
24
64
24
32
40
56
32
40
56
Time (Weeks)
Time (Weeks)

• About 50 of all tumors were able to be sequenced
  for EGFR mutation

Cappuzzo. ASCO. 2009 (abstr 8001).
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Current options after Acquired Resistance to EGFR
TKI
Chemotherapy
Chemotherapy
EGFR TKI
SATURN
INTACT I, II TRIBUTE, TALENT
Chemotherapy EGFR TKI combination
Chemotherapy with intermittent EGFR TKI
FAST ACT
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Continuing EGFR TKI /- Chemo may have benefit
Trial Patients Continued EGFR TKI chemo
Goldberg et al. 34 chemo E 44 chemo RR improved No PFS or OS difference
Faehling et al. 27 chemo EGFR TKI 14 chemo Improved OS
Yoshimura et al. 27 pemetrexed EGFR TKI ORR 26, DCR 78 Median PFS 7 months Median OS 11.4 months
Delayed additional therapy
Oxnard et al. 42 EGFR TKI 45 gt 3 months 19 gt 12 months
ASPIRATION Phase II Asian multicenter trial for
NSCLC EGFR mutation patients using continuation
erlotinib beyond PD1 Enrollment April 2011 Dec
2014 Plan 207 patients
Goldberg et al. ASCO 2012 Abstract 7524,
Yoshimura N. et al. JTO 8 (1)96-101, 2013
Faehling et al. ASCO 2012 Abstract 7572 Oxnard
et al. ASCO 2012 Abstract 7547
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2 Trials to compare ongoing EGFR TKI for Acquired
Resistance
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Current options after Acquired Resistance to EGFR
TKI
Chemotherapy
Chemotherapy
EGFR TKI
SATURN
INTACT I, II TRIBUTE, TALENT
Chemotherapy EGFR TKI combination
Chemotherapy with intermittent EGFR TKI
FAST ACT
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Potential Antagonism Chemo EGFR TKI

• There are concerns over combining erlotinib-chemo
  as erlotinib arrests the cancer cells in the G1
  checkpoint and chemo usually works best in the
  mitotic phase.

Solit et al, Clin Can Res 2005 Davies A et al.
CLC 7 (6) 385-388, 2006 Encyclopedia of Science
Cell Biology http//www.daviddarling.info/encyclop
edia/C/cell_cycle.html
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First-Line Asian Sequential Tarceva plus chemo
Trial (FASTACT)
Platinum (d1) Gemcitabine (d1, 8)
Erlotinib D15-28 Q4weeks x 6 cycles
Erlotinib
Untreated NSCLC IIIB/IV No prior EGFR TKI
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Placebo
Platinum (d1) Gemcitabine (d1, 8)
Placebo D15-28 Q4weeks x 6 cycles
n154
1o endpoint 8-week non-PD rate 2nd PFS,
16-week non-PD rate, ORR, TTP, OS
Lee J et al. ASCO 2012 Abstract 8031
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FAST ACT 1 PFS favored GC-erlotinib
Lee J et al. ASCO 2012 Abstract 8031
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FAST ACT-2
Mok T et al. ASCO 2012
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FAST ACT 2 ITT PFS favors erlotinib-GC

• Critique
• FAST ACT 2 has a maintenance portion with the
  EGFR TKI and this affects clinical outcomes
• SATURN maintenance trial proves PFS benefit in
  EGFR mutant patients

Mok T et al. ASCO 2012
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Tsao Summary on Acquired Resistance

• For local oligo-PD, continue EGFR TKI and apply
  local therapy.
• For more global PD 4 options until future trials
  elaborate on acquired resistance
• Chemo
• Chemo EGFR TKI
• Chemo then EGFR TKI
• Chemo intercalated with EGFR TKI
• Ultimately Re-biopsy and molecular profile will
  determine the optimal therapy

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Outline Long-term management EGFR mutated NSCLC
patients
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Novel agents targeting EGFR TKI resistant disease
Agent Inhibitor type Preclinical benefit against T790M Clinical Trial phase
Dacomitinib (Pfizer) Irreversible TKI of EGFR, HER2, HER 4 yes II, III
Afatinib (Boehringer Ingelheim) Irreversible TKI of EGFR, HER2, HER4 yes II, III
CO-1686 (Clovis) Selective covalent inhibitor EGFR mutations yes I/II (T790M selection)
Onartuzumab (Genentech) Monoclonal antibody that targets MET receptor n/a II, III
Tivantinib (ArQule) MET-R TKI n/a II, III
Volitinib (AZ) cMET TKI n/a I
Ariad 26113 EGFR, ALK, ROS1 I
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Dacomitinib

• Irreversible pan-Her inhibitor that binds to
  EGFR, HER2, HER4
• Side effects diarrhea, rash, stomatitis, mucosal
  inflammation, paronychia
• Preclinical studies show high potency HER kinase
  inhibition
• Phase I/II trials showed antitumor activity in
  NSCLC patients who progressed on EGFR TKI
• Phase II trial compared dacomitinib vs erlotinib
  in 2nd/3rd line NSCLC

Median PFS (months) Median OS (months) ORR Duration of response (months)
dacomitinib 2.86 9.53 17 16.56
erlotinib 1.91 7.44 5.3 9.23
P-value HR 0.66, p0.012 HR 0.8, p0.205 P0.011
Ramalingam S, et al. JCO. 2012 30 (27)
3337-3344.
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ARCHER Phase 3 Trial Dacomitinib  vs. Erlotinib
in 2/3rd Line NSCLC unselected
Trial design Endpoints Co-primary patient populations
Double-blind, randomized, Phase 3, global Primary PFS SecondaryOS, safety, PROs All patients with advanced NSCLC Patients with NSCLC that is confirmed KRAS WT Global (Asia, EU, NA, SA) First subject June 2012
Based on IRC reviewThe study is adequately
powered to show difference in OS
Advanced NSCLC 1/2 prior CTs ECOG PS 0?2 Tissue
available (determination of molecular markers
not required prior to dosing)
Dacomitinib 45 mg QD

• Stratification
• Non-smokers vs. smokers
• Adenocarcinoma vs. nonadenocarcinoma
• East Asian vs. non-East Asian/Indian
• ECOG PS 0/1 vs. 2

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N800
Erlotinib150 mg QD
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Phase IIA Pulse Dosing for T790M
Trial Design Endpoints Study Sites
Open label, Intermittent dosing Primary BOR in Cohort A Secondary QTc, PK, DR and PFS (Cohorts A and B), Safety, tolerability (Cohort B) US, HK, Korea
E N R O L L M E N T n30
NSCLC with T790M mutation PD after EGFR-targeted
tx within 6 weeks prior to study 1-2 prior
chemo regimen 15 patients
A
Lead-In cycle 45 mg q12 hrs d1-4 60mg q12 hrs
d1-4 q2 Wks Further dose escalation allowed in
Cohort A patients only
NSCLC 0-1 prior chemo regimens 15 patients
B
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TITLE
Yang et al. ASCO 2012 Abstract LBA7500
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Phase III Lung LUX-3 Trial
1269 screened, 452 EGFR mutation () gt 345
randomized
Yang et al. ASCO 2012 Abstract LBA7500
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TITLE
Yang et al. ASCO 2012 Abstract LBA7500
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ORR favored Afatinib
Yang et al. ASCO 2012 Abstract LBA7500
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PFS favored Afatinib
Yang et al. ASCO 2012 Abstract LBA7500
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PFS Independent Review Subgroup Analysis
Yang et al. ASCO 2012 Abstract LBA7500
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PFS Common Mutants (Del 19/L858R)
Yang et al. ASCO 2012 Abstract LBA7500
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QOL EORTC QLQ C-30
Yang et al. ASCO 2012 Abstract LBA7500
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Summary LUNG LUX-3

• Front-line afatinib improved QOL, RR, DCR, and
  median PFS over cisplatin-pemetrexed in both the
  overall EGFR mutation population and in the
  common EGFR mutation (del19/L858) patients.
• Subgroup analysis showed benefit across most of
  the subgroups.
• No new safety signals with diarrhea and rash as
  the most frequent AEs.

Yang et al. ASCO 2012 Abstract LBA7500
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Combination of Afatinib and Cetuximab is
effective against EGFR T790M
Regales et al. JCI 2009
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Phase I Afatanib/Cetuximab

• No DLTs at afatinib 40mg po daily plus cetuximab
  250 mg/m2 or 500mg/m2 IV q2 weeks
• Expansion cohort dosing afatinib 40mg po daily
  cetuximab 500mg/m2 IV q2 weeks
• Data on the first 100 patients available

Lynch, T. IASLC Targeted Therapies Meeting Feb
2013 Janjigian, et al. ESMO 2012
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Responses at MTD by T790M mutation
Lynch, T. IASLC Targeted Therapies Meeting Feb
2013 Janjigian, et al. ESMO 2012
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A randomized phase II/III trial of afatinib plus
cetuximab versus afatinib alone in
treatment-naïve patients with advanced, EGFR
mutation positive NSCLC
Afatinib PO 40mg daily Cetuximab IV 500mg/m2
Q2 weeks N138
Repeat Biopsy at Progression
Primary Endpoint Progression-Free
Survival Secondary Endpoints ORR, OS, Safety,
Tolerability, QOL Exploratory Biomarkers Pre-and
post-Rx T790M testing, whole exome sequencing,
HER2 and MET FISH
RANDOMIZE

• Eligibility
• Recurrent or advanced NSCLC
• Sensitizing EGFR mutation (i.e., exon 19
  deletion, L858R)
• Chemotherapy and TKI-naïve
• PS 0-2

Afatinib PO 40mg daily N138
Initial Evaluation PET-CT Brain CT or MRI ECG,
Echo/MUGA Tumor molecular analysis
CT scans q8 wks
Lynch, T. IASLC Targeted Therapies Meeting Feb
2013
46
Outline Long-term management EGFR mutated NSCLC
patients
47
ASCO 2011 Abstract 7505 MetMab Onartuzumab
Met activation is implicated in resistance to
erlotinib/gefitinib in pts with activating EGFR
mutations. Met expression is associated with a
worse prognosis in NSCLC MetMab is an anti-Met
one-armed antibody that inhibits hepatocyte
growth factor (HGF)-mediated activation
Spigel et al. ASCO 2011 Abstract 7505
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Abstract 7505 Phase II Onartuzumab
Spigel et al. ASCO 2011 Abstract 7505
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Met IHC Biomarker
Met Diagnostic Positive gt50 tumor cells with
moderate or strong staining intensity 93 had
adequate tissue for analysis and 52 were Met
Diagnostic Positive
Spigel et al. ASCO 2011 Abstract 7505
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MetMAb erlotinib in ITT
OS HR 0.8
PFS HR 1.09
Spigel et al. ASCO 2011 Abstract 7505
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MetMAb erlotinib in Met Dx pts
OS HR 0.37
PFS HR 0.53
Spigel et al. ASCO 2011 Abstract 7505
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MetMAb erlotinib in Met Dx- pts
OS HR 1.78
PFS HR 1.82
Spigel et al. ASCO 2011 Abstract 7505
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MetMAb benefit is not driven by EGFR mutation nor
FISH status
Spigel et al. ASCO 2011 Abstract 7505
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Met expression correlates to worse outcome in
erlotinib placebo treated pts.
PFS HR 1.71
OS HR 2.61
Spigel et al. ASCO 2011 Abstract 7505
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Most commonly reported AE frequency gt 10
Spigel et al. ASCO 2011 Abstract 7505
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Phase II

• Met IHC expression inversely correlates with
  prognosis.
• MetMAb erlotinib was well-tolerated with no new
  safety signals.
• MetMAb erlotinib improved PFS and OS in Met
  Diagnostic Positive patients.
• A phase III study of MetMAb erlotinib in Met
  Diagnostic positive patients started enrollment
  January 2012.

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Tsao Conclusions on Clinical Management for EGFR
mutation patients with Acquired Resistance Feb
2013
Continue EGFR TKI localized therapy

• Oligo-PD

Chemo Chemo then EGFR TKI Chemo EGFR TKI Chemo
intercalated with EGFR TKI
Global PD
58
Tsao Conclusions Molecular Age Will Come

• Molecular Rebiopsy
• Unknown
• (other pathways)
• MET
• PIK3CA
• SCLC

Sequist L et al. Sci Transl Med
2011375ra26-75ra26
59
Future Clinical Options for T790M or Met pathway
acquired resistance
Agent Inhibitor type Preclinical benefit against T790M Clinical Trial phase
Dacomitinib (Pfizer) Irreversible TKI of EGFR, HER2, HER 4 yes II, III
Afatinib (Boehringer Ingelheim) Irreversible TKI of EGFR, HER2, HER4 yes II, III
CO-1686 (Clovis) Selective covalent inhibitor EGFR mutations yes I/II (T790M selection)
Onartuzumab (Genentech) Monoclonal antibody that targets MET receptor n/a II, III
Tivantinib (ArQule) MET-R TKI n/a II, III
Volitinib (AZ) cMET TKI n/a I
Ariad 26113 EGFR, ALK, ROS1 I
60
Tsao Algorithm Histology and Molecular Profiling
NSCLC PATIENT
Platinum-doublet-bevacizumab Platinum-pemetrexed
bevacizumab Non-platinum or platinum based
doublet Switch Maintenance pemetrexed,
erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)
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Potential Future of NSCLC - Molecular Profiling
Adenocarcinoma
KRAS mutant
Met inhibition
crizotinib
MEK inhibitor combination
Resistance rebiopsy Novel Agent
Platinum-doublet-bevacizumab Platinum-pemetrexed
bevacizumab Non-platinum or platinum based
doublet Switch Maintenance pemetrexed,
erlotinib (E4599, AVAiL, Pointbreak, SATURN, JMEN)