1. No category

Management of EGFR-Mutant NSCLC Resistant to
EGFR-TKI therapy
Anne S. Tsao, M.D.
Director, Mesothelioma Program
Director, Thoracic Chemo-XRT Program
Associate Professor
The University of Texas
MD ANDERSON
CANCER CENTER
Department of Thoracic/Head & Neck
Medical Oncology
Outline: Long-term management EGFR mutated
NSCLC patients
EGFR
mutations
Current EGFR
TKI Resistance
Management
Common mutations
Mechanisms of resistance to EGFR TKIs
Oligo-metastatic disease resistance
Options: chemo
chemo + EGFR TKI combination
chemo then EGFR TKI
chemo with intermittent EGFR TKI
Novel agents
that target
EGFR pathway
Afatinib
Afatinib-cetuximab for T790M
CO-1686
Met inhibition
MetMAb (onartuzumab)
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. 2005;23:2556-2568; Wu et al. J Thorac Oncol. 2007;2:430-439.
Patient with EGFR mutation deletion exon 19
12-00
12-02
Patient with L858 EGFR mutation
Newly diagnosed
3-16-07
3 months of erlotinib
6-18-07
The relative frequencies of the various
mechanisms of acquired resistance.
Yu H A et al. Clin Cancer Res 2013;19:2240-2247
EGFR T790M: Frequently Found in
Tumor Cells From Patients With Acquired Resistance
to EGFR TKIs
Pao W, et al. PLoS Med. 2005;2:e73; Balak MN, et al. Clin Cancer Res. 2006;12:6494-6501.
T790M blocks erlotinib binding and leads to a
resistant phenotype
Michalczyk et al. Bioorganic & Medicinal Chemistry 16 (7): 3482; April 2008
Outline: Long-term management EGFR mutated
NSCLC patients
EGFR
mutations
Current EGFR
TKI Resistance
Management
Common mutations
Mechanisms of resistance to EGFR TKIs
Oligo-metastatic disease resistance
Options: chemo
chemo + EGFR TKI combination
chemo then EGFR TKI
chemo with intermittent EGFR TKI
Novel agents
that target
EGFR pathway
Afatinib
Afatinib-cetuximab for T790M
CO-1686
Met inhibition
MetMAb (onartuzumab)
EGFR mutant on TKI develops oligometastatic PD
• Continue EGFR TKI
• Utilize radiation therapy or surgical resection
• Close monitoring
• Several studies demonstrate additional PFS benefit (6.210 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
EGFR mutation and ALK mutation patients with oligoprogressive disease + local therapy have PFS benefit
Weickhardt et al. JTO 7: 1807-1814, 2012
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
- HER2
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% (n=14) of patients in
MSKCC series (n=61).
Riely et al. Clinical Cancer Research 2007, Chaft et al. CCR 17 (19): 6298-6303, 2011
Current Options in EGFR TKI resistant patient with
EGFR mutation
Chemotherapy
Chemotherapy
EGFR TKI
Chemotherapy + EGFR TKI combination
Chemotherapy with intermittent EGFR TKI
Chemo is safe
Chemo then maintenance erlotinib is safe
Chemo + EGFR TKIs are safe
Chemotherapy
Chemotherapy
EGFR TKI
Chemotherapy + EGFR TKI combination
Chemotherapy with intermittent EGFR TKI
SATURN
INTACT I, II
TRIBUTE,
TALENT
FAST ACT
SATURN: Treatment Schema
Chemotherapynaïve advanced
NSCLC
N=1949
4 cycles of
first-line
platinum
doublet
chemotherapy*
Erlotinib
150 mg/day
No PD
N=889
PD
1:1
Placebo
PD
Mandatory tumor
sampling
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
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
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine;
carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxel.
Cappuzzo. ASCO. 2009 (abstr 8001).
SATURN: PFS by EGFR Mutation Status
PFS: Mutated EGFR
100
HR=0.78 (0.63-0.96)
P=0.0185
80
60
Erlotinib (N=199)
40
Placebo (N=189)
20
0
0
8
16 24 32 40 48
Time (Weeks)
56 64
Patients Without Progression (%)
Patients Without Progression (%)
PFS: Wild-Type EGFR
100
HR=0.10 (0.04-0.25)
P<0.0001
80
60
Erlotinib (N=22)
40
Placebo (N=27)
20
0
0
8
16 24 32 40 48
Time (Weeks)
56 64
• About 50% of all tumors were able to be sequenced for EGFR mutation
Cappuzzo. ASCO. 2009 (abstr 8001).
Chemo is safe
Chemo then maintenance erlotinib is safe
Chemo + EGFR TKIs are safe
Chemotherapy
Chemotherapy
EGFR TKI
Chemotherapy + EGFR TKI combination
Chemotherapy with intermittent EGFR TKI
SATURN
INTACT I, II
TRIBUTE,
TALENT
FAST ACT
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% > 3 months
19% > 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
2 Trials to compare ongoing EGFR TKI for Acquired
Resistance
Chemo is safe
Chemo then maintenance erlotinib is safe
Chemo + EGFR TKIs are safe
Chemotherapy
Chemotherapy
EGFR TKI
Chemotherapy + EGFR TKI combination
Chemotherapy with intermittent EGFR TKI
SATURN
INTACT I, II
TRIBUTE,
TALENT
FAST ACT
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/encyclopedia/C/cell_cycle.html
First-Line Asian Sequential Erlotinib plus chemo
Trial (FASTACT)
Untreated
NSCLC IIIB/IV
No prior EGFR
TKI
Platinum (d1)
Gemcitabine (d1, 8)
+ Erlotinib
D15-28 Q4weeks
x 6 cycles
1:1
Placebo
n=154
Platinum (d1)
Gemcitabine (d1, 8)
+ Placebo
D15-28 Q4weeks
x 6 cycles
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
Erlotinib
FAST ACT 1 PFS favored GC-erlotinib
Lee J et al. ASCO 2012 Abstract 8031
FAST ACT-2
Mok T et al. ASCO 2012
FAST ACT II: 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
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
Outline: Long-term management EGFR mutated
NSCLC patients
EGFR
mutations
Current EGFR
TKI Resistance
Management
Common mutations
Mechanisms of resistance to EGFR TKIs
Oligo-metastatic disease resistance
Options: chemo
chemo + EGFR TKI combination
chemo then EGFR TKI
chemo with intermittent EGFR TKI
Novel agents
that target
EGFR pathway
Afatinib
Afatinib-cetuximab for T790M
CO-1686
Met inhibition
MetMAb (onartuzumab)
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)
AZD9291
Irreversible TKI to
mutant EGFR
yes
I
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
[TITLE]
Yang et al. ASCO 2012 Abstract LBA7500
Phase III Lung LUX-3 Trial
1269 screened, 452 EGFR mutation (+) => 345 randomized
Yang et al. ASCO 2012 Abstract LBA7500
[TITLE]
Yang et al. ASCO 2012 Abstract LBA7500
ORR favored afatinib
Yang et al. ASCO 2012 Abstract LBA7500
PFS favored afatinib
Yang et al. ASCO 2012 Abstract LBA7500
PFS Independent Review Subgroup Analysis
Yang et al. ASCO 2012 Abstract LBA7500
PFS Common Mutants (Del 19/L858R)
Yang et al. ASCO 2012 Abstract LBA7500
QOL: EORTC QLQ C-30
Yang et al. ASCO 2012 Abstract LBA7500
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
Summary Afatinib
•
•
•
•
•
Afatinib was approved July 12, 2013 by the FDA for firstline NSCLC patients with EGFR mutations (del exon 19
and exon 21 L858R) as detected by an FDA-approved
assay.
It remains unknown which EGFR TKI (erlotinib, gefitinib, or
afatinib) should be used first or whether these agents can
be sequenced in the EGFR mutation population.
Additional studies are needed to clarify this issue.
Afatinib is currently under development in combination with
cetuximab for resistant EGFR T790 mutant patients.
Future more broad application of afatinib is anticipated.
Combination of Afatinib and Cetuximab is effective against
EGFR T790M
Regales et al. JCI 2009
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
Responses at MTD by T790M mutation
Lynch, T. IASLC Targeted Therapies Meeting Feb 2013; Janjigian, et al. ESMO 2012
•Recurrent or advanced NSCLC
•Sensitizing EGFR mutation (i.e.,
exon 19 deletion, L858R)
•Chemotherapy and TKI-naïve
•PS 0-2
Afatinib PO
40mg daily
+
Cetuximab
IV 500mg/m2
Q2 weeks
N=138
Afatinib PO
40mg daily
N=138
Initial Evaluation:
PET-CT
Brain CT or MRI
ECG, Echo/MUGA
Tumor molecular analysis
Lynch, T. IASLC Targeted Therapies Meeting Feb 2013
Repeat Biopsy at Progression
Eligibility:
RANDOMIZE
A randomized phase II/III trial of afatinib plus
cetuximab versus afatinib alone in treatment-naïve
patients with advanced, EGFR mutation positive NSCLC
CT scans q8 wks
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
CO-1686 is a novel TKI specifically
targeting mutated EGFR
• Novel, oral, selective covalent inhibitor of EGFR mutations in NSCLC
• Inhibits key activating and T790M resistance mutations
• Minimal activity against wild type EGFR
• First-in-human study ongoing in EGFR-mutation positive pts with
recurrent advanced NSCLC, started with free base capsule
formulation, hydrobromide salt form of CO-1686 with improved drug
availability and reduced variability completed dose escalation.
• Early evidence of efficacy presented at ASCO 2013, WCLC 2013, free
base dosed to 900 mg BID
• Roche Molecular Systems companion diagnostic collaboration
• Potential for use as first-line therapy
Modified from Soria WCLC 2013
Phase I Schema
92 patients will be enrolled into Phase 1 (57 on
CO-1686 free base and approximately 35 on CO1686 HBr).
Dose 6 (n=6)
Dose 5
(n=3-6); MTD
Target Exposure
Dose 4 (n=3)
Phase II
Expansion Phase
40 T790M pts
Dose 3 (n=3)
Dose 2 (n=3)
Dose 1 (n=3)
Phase 2 Cohort A-T790M : 1. Disease
progression while on treatment with EGFRdirected therapy. Prior CT including intervening
CT before planned initiation of CO-1686, is
allowed (washout for EGFR TKI min 3 days,
chemo 14 d)
Phase 2 Cohort B-T790M 1. Disease
progression while on treatment with the first
single agent EGFR-directed therapy within the
last 30 days, with no intervening treatment
before planned initiation45
of CO-1686 .
CO-1686 freebase demonstrated limited and
low-grade adverse events in patients
AEs attributed to CO-1686,
occurring in > 10% Patients
(n=56 patients total)
Nausea
Diarrhea
Fatigue
GRADE 1
Vomiting
GRADE 2
Decreased Appetite
GRADE 3
0
20
40
60
% patients with event
Soria WCLC 2013
80
100
67% RECIST response rate in evaluable
T790M+ patients treated at 900mg BID
8 of 9 patients progressed on TKI immediately prior to CO-1686
Number of
Previous EGFR TKI
lines
1
2
2
2
4
2
2
1
1
*
6
*
Soria WCLC 2013
*
*
*
*
*
*
*
22
15
24
18
11
8
EGFRi immediately before CO-1686
*
21
30
Weeks on
treatment
Promising clinical activity observed with
CO-1686 – no evidence of WT inhibition
• 67% RECIST response rate in evaluable T790M+
patients treated at 900mg BID (free base)
• A hydrobromide (HBr) formulation of CO-1686 with improved
exposure has been introduced and a RP2D of 750mg BID has
been identified
• CO-1686 is well tolerated with no acneiform rash, consistent
with absence of WT-EGFR inhibition
• AEs all grades: nausea-25%, fatigue-21%, impaired glucose
tolerance/hyperglycemia 21%
• The pivotal phase 2/3 TIGER program starts 1H14
• Efficacy updates at ELCC2014 and ASCO2014
Modified from Soria WCLC 2013
CO-1686 phase 2/3 development:
TIGER program
TIGER: Third-generation Inhibitor of mutant EGFR in lung cancER
 All are global studies in mutant EGFR NSCLC:
− TIGER1: Phase 2/3 randomized registration study in newlydiagnosed patients (vs. erlotinib)
− TIGER2: Phase 2 registration study in 2nd line T790M+ patients
directly progressing on first TKI
− TIGER3: Phase 2 registration study in later-line T790M+ patients,
progressing on second or later TKI or subsequent chemotherapy
− TIGER4: Phase 2 study in 2nd or later-line patients with T790M
detected with a blood/plasma assay
− TIGER5: Phase 3 randomized confirmatory study in 2nd or laterline patients (vs. chemo)
Outline: Long-term management EGFR mutated
NSCLC patients
EGFR
mutations
Current EGFR
TKI Resistance
Management
Common mutations
Mechanisms of resistance to EGFR TKIs
Oligo-metastatic disease resistance
Options: chemo
chemo + EGFR TKI combination
chemo then EGFR TKI
chemo with intermittent EGFR TKI
Novel agents
that target
EGFR pathway
Afatinib
Afatinib-cetuximab for T790M
CO-1686
Met inhibition
MetMAb (onartuzumab)
ASCO 2011 Abstract #7505 MetMab
Onartuzumab
HGF
Met activation is implicated in
resistance to erlotinib/gefitinib in pts
with activating EGFR mutations.
HGF
MetMAb
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
Met
Met
Growth
Migration
Survival
No
activity
Spigel et al. ASCO 2011 Abstract 7505
Abstract #7505 Phase II Onartuzumab
Spigel et al. ASCO 2011 Abstract 7505
Met IHC Biomarker
“Met Diagnostic Positive” = >50% 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
MetMAb + erlotinib in ITT
OS HR 0.8
PFS HR 1.09
Spigel et al. ASCO 2011 Abstract 7505
MetMAb + erlotinib in Met Dx+ pts
PFS HR 0.53
OS HR 0.37
Spigel et al. ASCO 2011 Abstract 7505
MetMAb + erlotinib in Met Dx- pts
OS HR 1.78
PFS HR 1.82
Spigel et al. ASCO 2011 Abstract 7505
MetMAb benefit is not driven by EGFR
mutation nor FISH status
Spigel et al. ASCO 2011 Abstract 7505
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
Most commonly reported AE frequency > 10%
Spigel et al. ASCO 2011 Abstract 7505
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 and has completed accrual.
Tsao Conclusions on Clinical Management for
EGFR mutation patients with Acquired Resistance
Feb 2013
Oligo-PD
Global PD
Continue EGFR TKI +
localized therapy
Chemo
Chemo then EGFR TKI
Chemo + EGFR TKI
Chemo intercalated with EGFR TKI
Tsao Conclusions: Molecular Age Will Come
Molecular Rebiopsy:
- Unknown
(other pathways)
- MET
- PIK3CA
- SCLC
- HER2
Sequist L et al. Sci Transl Med 2011;3:75ra26-75ra26
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)
AZD9291
Irreversible TKI to
mutant EGFR
yes
I
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