OSIM-therapy

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OSIM-therapy
OSIM-therapy
Tony Mok MD
Li Shu Fan Medical Foundation Professor of Clinical Oncology
Dept. of Clinical Oncology
The Chinese University of Hong Kong
Percentage of
patients who
attained partial
response
411
66
11
No of T790M
+ive patients
who received
osimertinib
80mg
Median number
of months of
PFS
LBA #2 by Yang et al
OSIMertinib (AZD9291) in pre-treated patients with T790M-positive
advanced NSCLC: updated Phase I and pooled Phase II results
Largest cohort of T790M +ive
population on osimertinib 80mg
Target is targeted
1.0
0.9
Probability of
progression-Free survival
Erlotinib in
EGFR +ive pts
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
Number
of patients at risk:
Osimertinib 80 mg 411
3
6
9
12
15
18
21
24
27
Month
332
271
205
161
38
0
Yang et al ELCC 2016; Rosell et al NEJM2009
Progression-free survival is most certainly better than
chemotherapy in T790M mutation-positive patients
T790M positive subgroup from IMPRESS study
Probability of PFS
1.0
0.9
Gefitinib Placebo
0.8
0.7
0.6
T790M mutationpositive (n=142)
0.5
Median PFS,
months
(n=81)
(n=61)
4.6
5.3
HRa (95% CI) = 0.97 (0.67, 1.42);
p=0.88
0.4
0.3
0.2
Gefitinib (n=81)
Placebo (n=61)
0.1
0.0
0
6
2
8
10
12
4
Time of randomization (months)
1
4
Mok et al WCLC 2015
AURA 3 Study
Thanks to James for
predicting our study to
be positive
Central
testing of
~ 1540
biopsy
samples
T790M+
(n=470)
T790M-
*Pemetrexed 500 mg/m2 + carboplatin AUC5 or
Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2
P
PI: T Mok YL Wu
AZD9291 (80 mg p.o.
qd)
Platinum-based doublet
chemotherapy* every
3 weeks
Primary
endpoint:
PFS
Not eligible for enrolment
AUC5, area under the plasma concentration–time curve 5 mg/mL−1 per minute;
EGFRm+, EGFR mutation-positive; EGFR-TKI, EGFR tyrosine kinase inhibitor;
NSCLC, non-small cell lung cancer; p.o., orally; qd, once daily;
T790M+, T790M mutation-positive; T790M-, T790M mutation-negative
Percentage of
patients who
attained partial
response
60
77
19.3
No of EGFR
+ive patients
who received
first line
osimertinib
Median number
of months of
PFS as first line
therapy
LBA #1 by Ramalingham et al
OSIMertinib as first-line treatment for EGFR mutation-positive
advanced NSCLC: updated efficacy and safety results from two
Phase I expansion cohorts
PFS of 19.3 month is impressive but
not the first time we see…
Shaw et al NEJM 2014
ASCEND 3:
Phase II study on first line ceritinib
Felips et al ASCO 2015
Best percentage change from baseline in
target lesion size (%)
Which is the right dose?
100
90
80
70
60
50
40
30
20
10
0
10
20
30
40
50
60
70
80
90
100
D
DD
DD
DDD
DD
D
D
D
1st line osimertinib 80mg capsule
Confirmed ORR
Best objective response
Complete response
Partial response
Stable disease ≥6 weeks
Progressive disease
D
DD
D
D
1st line osimertinib 160mg capsule
D
D
80 mg
N=30
160 mg
N=30
67%
(95% CI 47, 83)
87%
(95% CI 69, 96)
0
20
8
2
2
24
4
0
D
AURA manuscript – supplementary appendix
December 28, 2014
Why 160mg may be better?
Table S5. Summary of Multiple-Dose AZD9291 Pharmacokinetic Parameters after Daily Administration of Capsules for 22 Days.
20 mg
40 mg
80 mg
160 mg
240 mg
N=7
N = 46
N = 90
N = 61
N = 14
1965 [72.8]
5636 [43.9]
12120* [54.0]
19160 [61.6]
28770 [48.1]
AUCtau, nM .h
(873–4990)
(2040–14100)
(3680–38800)
(1900–55400)
(11500–51200)
106.3 [72.5]
305.1 [44.7]
635.4 [55.4]
1006 [58.7]
1510 [45.7]
Cmax, nM
AURA manuscript – supplementary appendix
28, 2014
(45.4–280)
(128–807)
(167–2110) December
(132–2930)
(722–2620)
Data are preliminary, unvalidated, and subject to change. AUC, area under the concentration–time curve; Cmax, maximum plasma
concentration.
* N=87.
Table
S6. Objective Response Rate by Dose.
20 mg
Overall population
52% (11/21)
ORR
95% CI, 30% to
74%
T790M + patients
50% (5/10)
ORR
95% CI, 19% to
81%
T790M - patients
67% (2/3)
ORR
95% CI, 9% to
99%
40 mg
80 mg
160 mg
240 mg
Total
43% (25/58)
95% CI, 30% to 57%
52% (40/77)
95% CI, 40% to
63%
58% (36/62)
95% CI, 45% to
70%
52% (11/21)
95% CI, 30% to
74%
51% (123/239)
95% CI, 45% to
58%
59% (19/32)
95% CI, 41% to 76%
70% (30/43)
95% CI, 54% to
83%
61% (17/28)
95% CI, 41% to
79%
50% (7/14)
95% CI, 23% to
77%
61% (78/127)
95% CI, 52% to
70%
6% (1/17)
95% CI, 0.1% to
29%
17% (4/23)
95% CI, 5% to
39%
33% (6/18)
95% CI, 13% to
59%
-
21% (13/61)
95% CI, 12% to
34%
Patients are eligible for confirmed response if they have two post-baseline Response Evaluation Criteria In Solid Tumors (RECIST)
assessments or patients who withdraw/die prior to the second RECIST assessment.
Janne et al NEJM 2015 (supp)
What is the MTD?
AURA manuscript – supplementary appendix
December 28, 2014
Table S4. All-Causality Serious Adverse Events
Serious adverse event (SAE),
20 mg
n (%)
(N = 21)
40 mg
(N = 58)
80 mg
(N = 90)
160 mg
(N = 63)
240 mg
(N = 21)
Total
(N = 253)
All SAEs
4 (19)
13 (22)
20 (22)
16 (25)
3 (14)
56 (22)
Pneumonia
1 (5)
3 (5)
2 (2)
0
0
6 (2)
Pulmonary embolism
1 (5)
2 (3)
1 (1)
2 (3)
0
6 (2)
Pleural effusion
1 (5)
1 (2)
1 (1)
1 (2)
0
4 (2)
Diarrhea
0
0
1 (1)
1 (2)
0
2 (1)
Dysphagia
0
0
1 (1)
1 (2)
0
2 (1)
Ischemic stroke
0
0
1 (1)
1 (2)
0
2 (1)
Pneumonitis
0
0
1 (1)
1 (2)
0
2 (1)
Tumor pain
0
0
1 (1)
1 (2)
0
2 (1)
SAEs occurring in >1 patient
Serious adverse events occurring in a single patient: bacteremia (80 mg), bacterial sepsis (40 mg), bronchitis (160 mg), lung infection
(20 mg), mediastinitis (80 mg), pneumonia pneumococcal (80 mg), post-procedural infection (80 mg), pyelonephritis acute (40 mg),
sepsis (40 mg), septic shock (80 mg), upper respiratory tract infection (160 mg), urinary tract infection (40 mg), viremia (160 mg),
hepatic cancer (80 mg), uterine leiomyoma (160 mg), anemia (80 mg), pancytopenia (80 mg), hypoglycemia (80 mg), delusion
(40 mg), depression (40 mg), insomnia (40 mg), brain injury (240 mg), convulsion (80 mg), headache (160 mg), presyncope (160 mg),
blindness (40 mg), cardiac arrest (240 mg), cardiac failure acute (160 mg), myocardial infarction (40 mg), stress cardiomyopathy
(160 mg), deep vein thrombosis (40 mg), embolism (80 mg), dyspnea (20 mg), interstitial lung disease (160 mg), lung disorder
(80 mg), pneumothorax (80 mg), pulmonary artery thrombosis (40 mg), abdominal pain upper (160 mg), intestinal obstruction
(160 mg), esophageal stenosis (80 mg), esophagitis (160 mg), nausea (20 mg), pancreatitis (240 mg), fatigue (20 mg), cholecystitis
(80 mg), skin toxicity (80 mg), musculoskeletal chest pain (160 mg), renal failure (80 mg), renal impairment (80 mg), benign prostatic
hyperplasia (40 mg), chest pain (80 mg), general physical health deterioration (80 mg), pyrexia (40 mg), alanine aminotransferase
increased (20 mg), aspartate aminotransferase increased (20 mg), blood bilirubin increased (20 mg), overdose (160 mg), thoracic
vertebral fracture (240 mg), uncoded terms (160 mg).
24
Janne et al NEJM 2015
Probability of PFS survival
PFS: 80mg = 160mg
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Number of patients at risk:
1st line 80 mg
1st line 160 mg
0
3
30
30
26
29
These are NONRANDOMIZED
data15
6
9
12
18
21
24
27
14
7
7
0
0
0
0
0
Month
Median PFS,† months
(95% CI)
Remaining alive and progressionfree,‡ % (95% CI)
12 months
18 months
23
27
22
23
20
20
16
19
80 mg
N=30
160 mg
N=30
Total
N=60
NR
(12, NR)
19.3
(11, 19)
19.3
(14, NC)
75 (55, 88)
57 (36, 73)
69 (50, 83)
53 (32, 70)
72 (59, 82)
55 (41, 67)
FLAURA study design
AZD9291
(80 mg p.o. qd)
Enrollment
by local*
or central#
EGFR
mutation
testing of
biopsy sample
Stratified by:
Asian /
non-Asian
Ex19del /
L858R
Randomize patients 1:1
Would it be better with
160mg?
EGFR-TKI standard of care##:
gefitinib (250 mg p.o. qd) or
erlotinib (150 mg p.o. qd)
RECIST 1.1
assessment
every 6 weeks
until objective
progressive
disease
Patients
randomized to
standard of
care may
receive
AZD9291 after
progression§
Primary
objective:
efficacy by
PFS
*With central laboratory assessment performed for sensitivity
#cobas™ EGFR Mutation Test (Roche Molecular Systems)
##Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation
§Patients randomized to the standard of care treatment arm may receive open-label treatment with AZD9291 on central confirmation of both objective disease progression and T790M positive tumor
OS, overall survival; PFS2, second progression-free survival (time from randomization to second progression); p.o., orally
Osimertinib
should be given
as first line
therapy for EGFR
mut+ patients
Osimertinib
should be given
as a second line
therapy for T790M
+ive patients
Gefitinib/erlotinib/afatinib
Osimertinib (11m)
Osimertinib (19.3m)
Osimertinib (?14-16m based on FLAURA)
Biology of T790M mutation
How is T790M acquired?
Pre-existing versus Evolution
Hata et al Nature Medicine 2016
Pre-existing versus Evolution
If “pre-existing” is the dominant picture…
CNS
progression
Osimertinib
SCLC
Transformation
Decrease
apototic
response to
TKI
Hata et al Nature Medicine 2016
If “evolution” is the dominant picture…
Osimertinib
What are these
others?
Hata et al Nature Medicine 2016
The danger of “persister state”
Ramirez et al Nat Comm 2016
A)
Relative Cell Number % Control
Figure 1
Gefitinib/erlotinib/afatinib
C)
Normalize of All Cells
150
121 pt - GEF
121 pt - WZ
121 Res # 1- GEF
121 Res # 1 - WZ
100
121 Pt
Res # 1
Mechanism
of
resistance
Osimertinib (11m)
- + - +
1 uM WZ
pEGFR
50
EGFR
0
-6
-4
-2
0
2
pERK
[TKI] log (uM)
B)
MGH121 pt
0
30
10
0
10
Reported Resistance Mechanisms to
Rociletinib and Osimertinib (n=34)
ERK
MGH121 Res # 1
pS6
30
Actin
100
300
1000
100
300
1000
D)
Cys 797
Gly 796
G
G
C
T
G
Leu 798
C
MGH121 pt
C
T
Cys/Ser
797
Gly 796
C
T790M
Maintained
(No
additional
resistance
mechanism
identified)
35%
C797S/T790
M
21%
S6
G
G
C
T G/C C
Leu 798
C
T
C
SCLC/T790wt
9%
Her2
Amp/T790wt
MET
3% Amp/T790wt
3%
T790M
"Lost"
29%
MGH121 Res # 1
Niederst et al CCR 2015
Osimertinib (19.3m)
NGS in patients
who fails first line
osimertinib
?
Is it good or bad to have
T790M?
SLCG: Implication of de-novo T790M
Rosell et al CCR 2011
de novoT790M detected by
MALDI-TOF MS
25.2% of EGFR mutation positive pts have T790M prior
to TKI (2.8% by direct sequencing)
Su et al JCO 2012
Survival outcomes of acquired
T790M
May not be bad to have
T790M at the time of TKI
failure
Median T790M pos = 19 months
Median T790M neg = 12 months
Median T790M pos = 39 months
Median T790M neg = 26 months
Oxnard et al CCR 17:1616, 2011
Best timing for osimertinib?
Dx of EGFR
mutation
positive lung
cancer
To be supported
by FLAURA
Presence of
T790M in
plasma
cfDNA
?
Clinical
progression
and T790M
+ive
Supported by
AURA 1/2/3
Potential study concept (AURA4??):
First versus second line osimertinib
Osimertinib
Rebiopsy at
PD and
treatment
as per
discretion
EGFR
mutation
positive
Osimertinib for
T790M +
Gefitinib/
erlotinib/afatinib
Stratified by:
-T790M
-mutation type
Primary
Endpoint:
Overall survival
Rebiopsy at
PD
Treatment as
per discretion
for T790M-
Potential study concept:
Osimertinib for molecular progression
Time to osimertinib Failure (TTF)
Monthly
cfDNA for
T790M for
patient on
first line TKI
Plasma positive for
T790M without
radiologic
progression
Continue
the same
TKI till
radiologic
progression
Osimertinib
osimertinib
Primary
endpoint:
TTF or OS
Time to osimertinib Failure (TTF)
Summary
• Second line osimertinib for T790M + disease
– N=411, RR=66%, PFS=11m
• First line osimertinib for EGFR mut+ disease
– N=60, RR=77%, PFS=19.3m
– Unclear if 160mg would be better in first line
• Best timing for the use of osimertinib remains to
be defined
– Mechanism of resistance to first line osimertinib need
to be defined
– First line TKI followed by osimertinib is still a sound
approach
An cheaper but effective OSIM-therapy
ERTINIB

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