Transcript Acquired Resistance to EGFR TKIs: Vincent A Miller, MD Thoracic Oncology Service

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
Disclosure Slide
Consultant
ArQule, Boehringer Ingelheim
Pharmaceuticals Inc, Genentech
BioOncology, Lilly USA LLC,
OSI Pharmaceuticals Inc, Sanofi
Grant/Research
Boehringer Ingelheim Pharmaceuticals Inc,
Lilly USA LLC, Sanofi
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.
Acquired Resistance to TKI
Pre-rx
4M
19M
21M
23M
25M
bx
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
Trials to Overcome Acquired Resistance
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.
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 TKI
100
Survival of TKI_OS: Survival proportions
OS_t790M
Percent survival
80
OS_neg
60
HR 0.46, p = 0.006
Median OS T790M-positive = 47 months
Median OS T790M-negative = 26 months
40
20
0
0
Courtesy of VA Miller.
50
100
TKI_OS
150
Survival from Progressive Disease
100
Percent survival
Survival of PPS: Survival proportions
PPS_t790M
80
PPS_neg
60
HR 0.59, p = 0.057
Post-PD survival T790M-positive = 22 months
Post-PD survival T790M-negative = 14 months
40
20
0
0
Courtesy of VA Miller.
20
40
PPS
60
80
T790M as a Biomarker
T790M-type
resistance
– Longer survival
– Later metastases
– Indolent growth
– Sensitivity to
2nd-line EGFR
inhibitors?
Non-T790M-type
resistance
– Poorer survival
– Earlier metastases
– More aggressive?
– Needs mechanisms
better elucidated and
alternate therapies?
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
F
F
S
N
N
N
O
N
O
N
Cl
N
Cl
N
N
N
O
N
O
N
O
S
N
O
O
O
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.
LUX-Lung 1: Trial Design
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
(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)
Estimated PFS probability
PFS by Independent Review
1.0
Placebo, PFS events = 133, median = 1.1 months
(95% CI: 0.95-1.68)
0.8
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
0.6
0.4
0.2
0.0
0
3
6
9
12
15
PFS time since randomization (months)
Number at risk
195
390
26
152
4
65
2
16
Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.
9
3
18
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
Estimated survival probability
1.0
0.8
0.6
0.4
0.2
0.0
0
3
Number at risk
195
390
169
344
6
9
12
15
18
21
Time to death since randomization (months)
142
283
112
217
65
122
Miller VA et al. Presentation. ASTRO Thoracic Symposium 2010.
33
69
18
32
5
12
24
Summary – HOPP Lab Animal Studies
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)
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
No response (7) No response (2)
(number in parentheses = number of mice treated and assessed)
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
Dose escalation schema
3-6 patients per cohort
Study Schema
Afatinib PO daily +
escalating doses of
intravenous (IV)
cetuximab q 2 weeks
NSCLC with
EGFR mutation
AND
Stable disease
(SD) ≥6 months on
erlotinib/gefitinib
OR
Partial or
complete response
to erlotinib/gefitinib
Disease
progression
Stop erlotinib/
gefitinib for
≥72 hours
Dose levels starting at:
afatinib 40 mg +
cetuximab 250 mg/m2
Predefined maximum dose:
afatinib 40 mg +
cetuximab 500 mg/m2
Expansion cohort part
MTD cohort expanded
up to 80 EGFR mutationpossible patients:
40 T790M-positive and
40 T790M-negative
Patient Eligibility
Inclusion 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
1 EGFR
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
G719X, exon 19 deletion, L858R, L861Q mandated in MTD expansion cohort
Patient Characteristics
Afatinib 40 mg
n (%)
Median age, years (range)
Women, n (%)
Ethnicity: White/Black/Asian/American Indian, %
Baseline ECOG 0/1/2, %
Median time on erlotinib/gefitinib, months
Prior chemotherapy, n (%)
T790M-positive*, n (%)
T790M-negative*, n (%)
EGFR deletion 19, n (%)
EGFR L858R, n (%)
Unknown/other, n (%)
Cetuximab
250 mg/m2
Cetuximab
500 mg/m2
Total
4 (8)
63 (49–76)
1 (25)
75/0/25/0
25/75/0
10
3 (75)
—
2 (50)
2 (50)
1 (25)
47 (92)
61 (41–82)
36 (77)
83/4/13/0
21/75/4
25
36 (77)
27 (57)
15 (32)
27 (58)
17 (36)
51
61 (41–82)
37 (73)
82/4/14/0
22/75/4
24
39 (77)
27 (53)
17 (33)
29 (57)
18 (35)
2 (50)
5 (11)
7 (14)
* Ongoing trial – T790M status not available in all patients
Results
• 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
Maximum percentage decrease
from baseline (%)
Afatinib + Cetuximab at MTD: Responses
by Mutation
T790M+
70
60
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100
0
4
8
12
T790M-
16
20
No mutation
24
28
32
Uninformative
36
40
Patient index sorted by maximum % decrease
With permission from Janjigian Y et al. Proc ASCO 2011;Abstract 7525.
44
48
Afatinib + Cetuximab at MTD
Responses by Mutation
T790M
positive
T790M
negative
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
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
Jackman J Clin Oncol 2009
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 Design
Randomized, placebo-controlled, double-blind clinical trial
NSCLC
• Inoperable locally
adv/metastatic dz
• ≥1 prior chemo
(no prior EGFR TKI)
Endpoints
• 1° PFS
• 2° ORR, OS
• Subset analyses
• Crossover: ORR
R
A
N
D
O
M
I
Z
E
Erlotinib 150 mg PO QD
+ ARQ 197 360 mg PO BID
28-day cycle
PD
Erlotinib 150 mg PO QD
+ placebo
28-day cycle
• 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)
With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.
ARQ 197-209: Progression-Free Survival
(ITT Population)
Proportion of patients progression-free
1.0
• 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*
0.9
0.8
0.7
Erlotinib + ARQ 197 16.1 wks
(n = 84)
0.6
0.5
0.4
0.3
0.2
Erlotinib + placebo 9.7 wks
(n = 83)
0.1
0
0
10
20
30
40
Time from randomization (weeks)
* Cox regression model
•
PFS also measured by independent radiographic review:
- median 15.6 vs 8.4 wks
- unadjusted/adjusted HR = 0.74/0.51
With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.
50
ARQ 197-209: Overall Survival
(ITT Population)
1.0
• 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*
Proportion of patients surviving
0.9
0.8
Erlotinib + ARQ 197: 36.6 wks
(n = 84)
0.7
0.6
0.5
0.4
Erlotinib + placebo: 29.4 wks
(n = 83)
0.3
0.2
0.1
0.0
0
10
20
30
40
50
60
Survival time (weeks)
* Cox regression model
With permission from Schiller JH et al. Proc ASCO 2010;Abstract LBA7502.
70
MetMAb Is an Anti-Met Monovalent Antibody
That Inhibits HGF-Mediated Activation
•
HGF
HGF
MetMAb
Met
Growth,
migration, survival
Met
No
activity
•
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
With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.
OAM4558g Study Design: Global, DoubleBlind, Placebo-Controlled, Phase II Study
n = 64
n = 128
Key eligibility:
• Stage IIIB/IV NSCLC
• 2nd/3rd-line NSCLC
• Tissue required
• PS 0-2
Co-primary objectives:
• PFS in “MET High” patients
Arm A
Erlotinib (150 qd-oral) +
MetMAb (15 mg/kg IV q3w)
1:1
R
A
N
D
O
M
I
Z
A
T
I
O
N
Stratification factors:
• Tobacco history
• Performance status
n = 64
• Histology
Arm B
Erlotinib (150 qd-oral) +
placebo (IV q3w)
• PFS in overall ITT population
Other key objectives:
PD
• OS in “MET High” patients
Addition of
MetMAb*
• OS in overall ITT patients
• Overall response rate
• Safety/tolerability
- Enrollment from 3/2009 to 3/2010
- Data cut-off: June 8, 2010
With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.
* If eligible
n = 23
PFS and OS: MET High Population
OS, HR = 0.55
Erlotinib +
Placebo
(n = 30)
1.0
0.8
Erlotinib +
MetMAb
(n = 35)
12.4
Median PFS (wk) 6.4
Hazard ratio
0.56
p-value
0.0547
# Events
25
19
0.6
0.4
0.2
7.7
Median OS (mo) 7.4
0.55
Hazard ratio
0.1113
p-value
# Events
20
13
1.0
Probability of Survival
Probability of Progression Free
PFS, HR = 0.56
Erlotinib +
MetMAb
(n = 35)
Erlotinib +
Placebo
(n = 30)
0.8
0.6
0.4
0.2
0
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
0
3
Time to Progression (weeks)
9
12
15
Overall Survival (months)
Number at Risk:
Number at Risk:
Erlotinib + 30
placebo
Erlotinib + 35
MetMAb
6
18
5
3
3
2
2
0
0
22
9
5
3
1
1
1
1
Erlotinib + 30
placebo
Erlotinib + 35
MetMAb
17
9
3
0
0
26
10
3
1
0
MetMAb + erlotinib improves both PFS and OS in
MET high NSCLC patients
With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.
PFS and OS: MET Low Population
Erlotinib + Erlotinib +
Placebo
MetMAb
(n = 29)
(n = 27)
6.0
Median PFS (wk) 11.4
2.01
Hazard ratio
0.0354
p-value
20
23
# Events
1.0
0.8
0.6
0.4
0.2
OS, HR = 3.02
1.0
Probability of Survival
Probability of Progression Free
PFS, HR = 2.01
Erlotinib + Erlotinib +
MetMAb
Placebo
(n = 27)
(n = 29)
Median OS (mo) 9.2
5.5
3.02
Hazard ratio
0.0212
p-value
14
9
# Events
0.8
0.6
0.4
0.2
0
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Number at Risk:
Erlotinib + 29
placebo
Erlotinib + 27
MetMAb
Time to Progression (weeks)
22
9
6
2
2
0
0
0
15
5
1
0
0
0
0
0
0
Number at Risk:
Erlotinib + 29
placebo
Erlotinib + 27
MetMAb
3
6
9
12
15
Overall Survival (months)
23
9
3
0
0
12
3
0
0
0
MET low NSCLC patients do worse with
MetMAb + erlotinib
With permission from Spigel DR et al. Proc ESMO 2010;Abstract LBA15.
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