Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat? Vincent A Miller, MD Thoracic Oncology Service Memorial Sloan-Kettering Cancer Center.
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Acquired Resistance to EGFR TKIs: What Is It and How Do We Treat?
Vincent A Miller, MDThoracic Oncology Service
Memorial Sloan-Kettering Cancer Center
Consultant
ArQule, Boehringer Ingelheim Pharmaceuticals Inc, Genentech BioOncology, Lilly USA LLC, OSI Pharmaceuticals Inc, Sanofi
Grant/ResearchBoehringer Ingelheim Pharmaceuticals Inc, Lilly USA LLC, Sanofi
Disclosure Slide
Background
• Patients with CML and GIST have a high rate of response to treatment with imatinib.
• These patients commonly acquire resistance after an initial response.
• There are a small number of conserved changes in the BCR-ABL tyrosine kinase domain which confer resistance in vivo.
• Other patients with acquired resistance have amplification of the BCR-ABL gene.
• Virtually all patients with response to gefitinib or erlotinib eventually have progression of disease.
21M 23M 25M
Pre-rx 4M 19M
bx
Acquired Resistance to TKI
Clinical Definition of Acquired Resistance to EGFR TKIs in Lung Adenocarcinoma
• Prior treatment with single agent TKI• Either:
– EGFR ex 19 del, L858R, G719X, L861Q– PR or CR with TKI or SD lasting ≥6 months
• PD by RECIST or WHO in previous 30 days• No therapy after TKI before start of new agent• “Washout” after stopping TKI not >5 half-lives of the
TKI (14 days for gefitinib or erlotinib)• Obtain baseline scan on day 1
Jackman J Clin Oncol 2009
Treatment RR (%) Reference
EGFR TKI + everolimus 0 Riely et al CCR ‘07
Everolimus 2 Soria et al Ann Oncol ‘09
Neratinib 3 Sequist et al JCO ‘10
IPI-504 4 Sequist et al JCO ‘10
Erlotinib + cetuximab 0 Janjigian et al CCR ‘11
Dasatinib/erlotinib + dasatinib 0/0 Johnson et al JTO in press
XL647 4 Miller et al PASCO ‘08
PF00299804 5 Campbell et al PASCO ‘10
PF00299804 15* (only 2 pts w/ EGFR mt) Park et al PASCO ‘10
Erlotinib + XL184 8 (only 1 pt w/ EGFR mt) Wakelee et al PASCO ‘10
Afatinib/placebo 7/0.5 Miller et al PESMO ‘10
* The number of patients enrolled into the trial with AR to EGFR TKIs was low.
Trials to Overcome Acquired Resistance
T790M in Acquired Resistance
• Acquired exon 20 mutation found in >50% of pts with acquired resistance to TKI
• Increases relative affinity of mutant EGFR for ATP, may also cause steric hindrance
• Less commonly detected in CNS, thought to be due to poor CNS penetrance of TKI
Overall Survival from Start of TKI100
80
60
40
20
0
100
80
60
40
20
000 5050 100100 150150
Survival of TKI_OS: Survival proportionsSurvival of TKI_OS: Survival proportions
HR 0.46, p = 0.006HR 0.46, p = 0.006
Median OS T790M-positive = 47 monthsMedian OS T790M-negative = 26 monthsMedian OS T790M-positive = 47 monthsMedian OS T790M-negative = 26 months
TKI_OSTKI_OS
Per
cen
t su
rviv
alP
erce
nt
surv
ival
OS_t790M
OS_neg
OS_t790M
OS_neg
Courtesy of VA Miller. Courtesy of VA Miller.
Survival from Progressive Disease100
80
60
40
20
0
100
80
60
40
20
000 2020 6060 8080
Survival of PPS: Survival proportionsSurvival of PPS: Survival proportions
HR 0.59, p = 0.057HR 0.59, p = 0.057
Post-PD survival T790M-positive = 22 monthsPost-PD survival T790M-negative = 14 monthsPost-PD survival T790M-positive = 22 monthsPost-PD survival T790M-negative = 14 months
PPSPPS
Per
cen
t su
rviv
alP
erce
nt
surv
ival
PPS_t790M
PPS_neg
PPS_t790M
PPS_neg
Courtesy of VA Miller. Courtesy of VA Miller.
4040
T790M as a Biomarker
T790M-typeresistance
– Longer survival– Later metastases– Indolent growth
– Sensitivity to 2nd-line EGFR inhibitors?
Non-T790M-typeresistance
– Poorer survival– Earlier metastases– More aggressive?
– Needs mechanisms better elucidated and alternate therapies?
EGFR - Cys773
HER2 - Cys805
Solca F et al. 17th EORTC-NCI-AACR Symposium on “Molecular Targets and Cancer Therapeutics” Philadelphia, PA, USA, November 14 – 18, 2005.
N
N
N
F
Cl
O
O
N
O
N N
S
O
N
S
O
N
N
N
F
Cl
O
O
N
O
N
Afatinib (BIBW 2992) — Irreversible Dual EGFR/HER2 Inhibitor• Anilino quinazoline derivative • Activity versus T790M (100 nM)• Binds covalently to Cys773 of the EGFR and Cys805 of HER2
LUX-Lung 1: Trial Design
Randomization 2:1(Double blind)
Oral afatinib 50 mg once daily plus BSC
Oral placebo once daily plus BSC
Primary endpoint: Overall survival (OS)
Secondary: PFS, RECIST response, QoL (LC13 & C30), safety
• Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter• Exploratory biomarkers:
Archival tissue testing for EGFR mutations (optional; central lab)Serum EGFR mutational analysis (all patients)
• Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter• Exploratory biomarkers:
Archival tissue testing for EGFR mutations (optional; central lab)Serum EGFR mutational analysis (all patients)
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
PFS by Independent Review
Placebo, PFS events = 133, median = 1.1 months (95% CI: 0.95-1.68)
Afatinib, PFS events = 275, median = 3.3 months (95% CI: 2.79-4.40)Hazard ratio (95% CI) = 0.38 (0.306, 0.475)Log-rank test p-value <0.0001
PFS time since randomization (months)
Est
imat
ed P
FS
pro
babi
lity
Number at riskNumber at risk
195195 26 26 4 4 2 2390390 152 152 65 65 16 16 9 9 3 3195195 26 26 4 4 2 2390390 152 152 65 65 16 16 9 9 3 3
00 33 66 99 1212 1515 1818
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.
Primary Analysis: Overall Survival
Placebo, deaths = 114 (58.5%), median = 11.96 months (95% CI: 10.15-14.26)Afatinib, deaths = 244 (62.6%), median = 10.78 months (95% CI: 9.95-11.99)Hazard ratio (afatinib vs placebo) = 1.077 (0.862, 1.346)Log-rank test p-value (one-sided) = 0.7428
Time to death since randomization (months)
Est
imat
ed s
urvi
val p
roba
bilit
y
Number at riskNumber at risk
195195 169169 142142 112 112 65 65 33 33 18 18 5 5390390 344344 283 283 217 217 122 122 69 69 32 32 12 12
00 33 66 99 1212 1515 2424
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1818 2121
Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.
Drug L858R L858R + T790M T790M
Remove dox Response (6) Response (9) Response (5)
Placebo No response (3) No response (6) No response (2)
Erlotinib Response (12) No response (6) No response (5)
Pemetrexed n/a No response (4) n/a
Paclitaxel n/a No response (5) n/a
Cetuximab Response (6) No response (7) No response (2)
Erloti/cetux n/a No response (4) n/a
BIBW 2992 Response (4) No response (6) n/a
BIBW/cetux n/a Response! (8) n/a
(number in parentheses = number of mice treated and assessed)
Summary – HOPP Lab Animal Studies
Hypothesis
We hypothesized that the combination of afatinib and cetuximab would overcome acquired resistance to erlotinib or gefitinib in patients with non-small cell lung cancer (NSCLC)
Methods: Study Design• Phase Ib, open-label, multicenter trial in the US and the
Netherlands • Primary objective: Maximum tolerated dose (MTD) and
recommended Phase II dose (RPIID) for afatinib and cetuximab in patients with acquired resistance to erlotinib and gefitinib
• Primary endpoint:– Occurrence of dose-limiting toxicity (DLT)
• Secondary endpoints include:– Safety as assessed by National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) grading system
– Objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 assessed at weeks 4, 8 and 12, and every 8 weeks thereafter
Methods
• Definitions of DLTs (CTCAE V3):• Grade ≥2 decrease in cardiac left ventricular function• Grade ≥2 diarrhea lasting for ≥7days, despite anti-diarrheal
therapy• Grade ≥3 rash or nausea/vomiting despite medical management• Grade ≥3 fatigue lasting for ≥7 days• Grade 3 or 4 hypomagnesemia with clinically significant
sequelae• All other toxicities of CTCAE Grade ≥3 (except alopecia and
allergic reaction) leading to an interruption of afatinib/cetuximab for ≥14 days until recovery
Expansion cohort part
MTD cohort expandedup to 80 EGFR mutation-
possible patients:40 T790M-positive and
40 T790M-negative
NSCLC withEGFR mutation
AND
Stable disease(SD) ≥6 months on erlotinib/gefitinib
OR
Partial orcomplete responseto erlotinib/gefitinib
Diseaseprogression
Stop erlotinib/gefitinib for≥72 hours
Dose escalation schema 3-6 patients per cohort
Afatinib PO daily + escalating doses of
intravenous (IV) cetuximab q 2 weeks
Dose levels starting at: afatinib 40 mg +
cetuximab 250 mg/m2
Predefined maximum dose: afatinib 40 mg +
cetuximab 500 mg/m2
Study Schema
1 EGFR G719X, exon 19 deletion, L858R, L861Q mandated in MTD expansion cohort
Patient EligibilityInclusion criteria:• Pathologically confirmed NSCLC • Presence of EGFR drug-sensitizing
mutations1 or RECIST response, or SD ≥6 months
• Systemic progression of disease on continuous treatment with erlotinib or gefitinib within 30 days
• No systemic therapy between cessation of gefitinib/erlotinib and initiation of the study treatment
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
• Age ≥18 years
Exclusion criteria:
• Prior treatment with EGFR targeting antibodies
• Prior severe infusion reaction to a monoclonal antibody
• Patients with disease progression only in the central nervous system
• Symptomatic brain metastases
Patient Characteristics
Afatinib 40 mg
TotalCetuximab250 mg/m2
Cetuximab500 mg/m2
n (%) 4 (8) 47 (92) 51
Median age, years (range) 63 (49–76) 61 (41–82) 61 (41–82)
Women, n (%) 1 (25) 36 (77) 37 (73)
Ethnicity: White/Black/Asian/American Indian, % 75/0/25/0 83/4/13/0 82/4/14/0
Baseline ECOG 0/1/2, % 25/75/0 21/75/4 22/75/4
Median time on erlotinib/gefitinib, months 10 25 24
Prior chemotherapy, n (%) 3 (75) 36 (77) 39 (77)
T790M-positive*, n (%) — 27 (57) 27 (53)
T790M-negative*, n (%) 2 (50) 15 (32) 17 (33)
EGFR deletion 19, n (%) 2 (50) 27 (58) 29 (57)
EGFR L858R, n (%) 1 (25) 17 (36) 18 (35)
Unknown/other, n (%) 2 (50) 5 (11) 7 (14)
* Ongoing trial – T790M status not available in all patients
• Dose cohorts tested in the dose escalation:– Afatinib 40 mg + 250 mg/m2 cetuximab (n = 4)– Afatinib 40 mg + 500 mg/m2 cetuximab (n = 6)– No DLT occurred in cycle 1 (28 days)
• Pre-defined MTD = RPIID:– Afatinib 40 mg daily + cetuximab 500 mg/m2
• 47 patients have been enrolled in the MTD expansion cohort to date out of 80 planned
– 12 (26%) patients discontinued due to progression of disease
– Six (13%) patients discontinued due to toxicity
Results
Afatinib + Cetuximab at MTD: Responses by Mutation
T790M+ T790M- No mutation Uninformative70605040302010
0-10-20-30-40-50-60-70-80-90
-1000 4 8 12 16 20 24 28 32 36 40 44 48
Patient index sorted by maximum % decrease
Max
imum
per
cent
age
decr
ease
fr
om b
asel
ine
(%)
With permission from Janjigian Y et al. Proc ASCO 2011;Abstract 7525.With permission from Janjigian Y et al. Proc ASCO 2011;Abstract 7525.
T790Mpositive
T790Mnegative
T790M unknown
No EGFR mutation Total
Total treated 27 15 3 2 47
Evaluable for efficacy* 26 14 3 2 45
Best response n (%)
Any PR 13 (50) 8 (57) 2 (67) — 23 (51)
Confirmed PR 9 (35) 7 (50) 2 (67) — 18 (40)
SD 11 (42) 5 (36) 1 (33) — 19 (42)
Clinical response (any PR + SD)
24 (92) 13 (93) 3 (100) 2 (100) 42 (93)
Progression of disease 2 (8) 1 (7) — — 3 (7)
* Two patients were not evaluable for efficacy
Afatinib + Cetuximab at MTDResponses by Mutation
Jackman J Clin Oncol 2009
Case Presentation
• Middle-aged female diagnosed with Stage III-A lung adenocarcinoma in 2004
• 10 pack-yr smoker, no symptoms• Treated with chemotherapy, lobectomy and adjuvant
RT followed by adjuvant erlotinib• May 2007 isolated bone met, treated with
bisphosphonate, analgesics• May 2008 XRT L hip• June 2008 renal metastasis
Case Presentation
• Erlotinib continued• February 2009 clinical trial with dasatinib – POD• May 2009 pemetrexed added and then bevacizumab
added – initial response then POD in October 2010• KPS 60-70%• Left hip pain, nausea, malignant pleural effusion,
nausea, hematuria• Opiates, oxygen required
Case Presentation (cont’d)
• Commenced afatinib and cetuximab• Nausea resolved; weight gain• Opiates stopped, no need for wheelchair or cane• Hematuria absent• KPS 80%• Tox – Grade 1 rash, xerosis, paronychia
9/14/10 10/11/10
What Causes Non-T790M Resistance?
• 47 of 93 patients (51%) had tissue available for MET FISH– 9 patient specimens failed testing
• 4 of 38 patients (11%) had MET:CEP7 ratio >2– 1 pt with high level amplification + T790M– 2 of 3 pts with low level amplification had T790M
• Is FISH the optimal way to test for MET amplification?
ARQ 197-209: Study DesignRandomized, placebo-controlled, double-blind clinical trial
RANDOMIZE
Erlotinib 150 mg PO QD+ placebo
28-day cycle
Erlotinib 150 mg PO QD+ placebo
28-day cycle
Erlotinib 150 mg PO QD+ ARQ 197 360 mg PO BID
28-day cycle
Erlotinib 150 mg PO QD+ ARQ 197 360 mg PO BID
28-day cycle
Endpoints • 1° PFS• 2° ORR, OS• Subset analyses• Crossover: ORR
NSCLC• Inoperable locally
adv/metastatic dz• ≥1 prior chemo
(no prior EGFR TKI)
• 33 sites in 6 countries
• Study accrual over 11 months (10/08-9/09)
• Randomization stratified by prognostic factors incl sex, age, smoking, histology, performance status, prior therapy and best response, and geography (US vs ex-US)
PD
With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.
ARQ 197-209: Progression-Free Survival (ITT Population)
5020 300 10 40
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pro
po
rtio
n o
f p
ati
en
ts p
rog
res
sio
n-f
ree
Time from randomization (weeks)
Erlotinib + ARQ 197 16.1 wks(n = 84)
Erlotinib + placebo 9.7 wks(n = 83)
* Cox regression model
• PFS also measured by independent radiographic review: - median 15.6 vs 8.4 wks- unadjusted/adjusted HR = 0.74/0.51
• HR = 0.81 (95% CI: 0.57, 1.15); p = 0.24• Adjusted HR = 0.68 (95% CI: 0.47, 0.98); p < 0.05*
With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.
ARQ 197-209: Overall Survival (ITT Population)
• HR = 0.88 (95% CI: 0.60, 1.3); p = 0.50• Adjusted HR = 0.88 (95% CI: 0.6, 1.3); p = 0.52*
Erlotinib + ARQ 197: 36.6 wks(n = 84)
Erlotinib + placebo: 29.4 wks(n = 83)
0 10 20 30 50 7040 60
Survival time (weeks)
0.0
0.2
0.4
0.6
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1.0
Pro
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f p
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urv
ivin
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0.7
0.9
* Cox regression model
With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.
MetMAb Is an Anti-Met Monovalent Antibody That Inhibits HGF-Mediated Activation
• Rationale for targeting Met:
– Met is amplified, mutated, overexpressed in many tumors
– Met expression is associated with a worse prognosis in many cancers including NSCLC
– Met activation is implicated in resistance to erlotinib/gefitinib in pts with activating EGFR mutations
• MetMAb:
– One-armed format designed to prevent HGF-mediated stimulation of pathway
– Preclinical activity across multiple tumor models
HGFHGF HGFHGF
MetMetMetMet
MetMAbMetMAb
Growth, migration, survival
Growth, migration, survival
No activity
No activity
With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.
OAM4558g Study Design: Global, Double-Blind, Placebo-Controlled, Phase II Study
Arm AErlotinib (150 qd-oral) + MetMAb (15 mg/kg IV q3w)
Addition of MetMAb*
PD
* If eligible
Co-primary objectives:
• PFS in “MET High” patients
• PFS in overall ITT population
Other key objectives:
• OS in “MET High” patients
• OS in overall ITT patients
• Overall response rate
• Safety/tolerability
Key eligibility:
• Stage IIIB/IV NSCLC
• 2nd/3rd-line NSCLC
• Tissue required
• PS 0-2
RANDOMIZATION
1:1n = 128
n = 64
n = 64
n = 23
- Enrollment from 3/2009 to 3/2010- Data cut-off: June 8, 2010
Arm BErlotinib (150 qd-oral) +placebo (IV q3w)
With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.
Stratification factors:
• Tobacco history
• Performance status
• Histology
PFS, HR = 0.56 OS, HR = 0.55
MetMAb + erlotinib improves both PFS and OS in MET high NSCLC patients
With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.
Pro
ba
bil
ity
of
Pro
gre
ss
ion
Fre
e 1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time to Progression (weeks)
Median PFS (wk)Hazard ratiop-value# Events
6.4 12.4
25 19
0.560.0547
30
35
30
35
18
22
18
22
5
9
5
9
3
5
3
5
3
3
3
3
2
1
2
1
2
1
2
1
0
1
0
1
0
1
0
1
Pro
ba
bil
ity
of
Su
rviv
al
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15
Overall Survival (months)
Median OS (mo)Hazard ratiop-value# Events
7.4 7.7
20 13
0.550.1113
30
35
30
35
17
26
17
26
9
10
9
10
3
3
3
3
0
1
0
1
0
0
0
0
Erlotinib +Placebo(n = 30)
Erlotinib + placeboErlotinib + placebo
Erlotinib + placeboErlotinib + placebo
Erlotinib +MetMAb(n = 35)
Erlotinib + MetMAbErlotinib + MetMAb
Erlotinib + MetMAbErlotinib + MetMAb
Number at Risk: Number at Risk:
PFS and OS: MET High Population Erlotinib +Placebo(n = 30)
Erlotinib +MetMAb(n = 35)
PFS and OS: MET Low PopulationPFS, HR = 2.01 OS, HR = 3.02
MET low NSCLC patients do worse with MetMAb + erlotinib
With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.
Pro
ba
bil
ity
of
Pro
gre
ss
ion
Fre
e 1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time to Progression (weeks)
11.4 6.0
20 23
2.010.0354
Number at Risk:
29
27
29
27
22
15
22
15
9
5
9
5
6
1
6
1
2
0
2
0
2
0
2
0
0
0
0
0
0
0
0
0
0
0
0
0
Pro
ba
bil
ity
of
Su
rviv
al
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15
Overall Survival (months)
9.2 5.5
9 14
3.020.0212
Number at Risk:
29
27
29
27
23
12
23
12
9
3
9
3
3
0
3
0
0
0
0
0
0
0
0
0
Erlotinib + placeboErlotinib + placebo
Erlotinib +Placebo(n = 29)
Erlotinib + placeboErlotinib + placebo
Erlotinib + MetMAbErlotinib + MetMAb
Erlotinib +MetMAb(n = 27)
Erlotinib + MetMAbErlotinib + MetMAb
Median PFS (wk)Hazard ratiop-value# Events
Median OS (mo)Hazard ratiop-value# Events
Erlotinib +Placebo(n = 29)
Erlotinib +MetMAb(n = 27)
Approach to Therapy of Acquired Resistance to EGFR TKIs• Rebiopsy the patient
– T790M prognostic and possibly predictive biomarker
– Rare transformation to small cell phenotype• Continue an EGFR TKI• “Second generation” EGFR/ErbB2 TKIs• Rational combination strategies
– BIBW 2992 + cetuximab– HSP-90 inhibitor + chemo or EGFR-TKI– Add MET inhibitor - best diagnostic unclear
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