Download AZD5363, a catalytic pan-AKT inhibitor, in AKT1 E17K

AZD5363, a catalytic pan-AKT inhibitor, in AKT1 E17K mutation positive advanced solid tumors
DM Hyman,1 L Smyth,1 PL Bedard,2 A Oza,2 E Dean,3 A Armstrong,3 J Lima,4 H Bando,5 P Kabos,6 JA Perez-Fidalgo,7 K Moore,8 SN Westin,9 B You,10 S Chandarlapaty,1 L Alland,11 H Ambrose,12 A Foxley,12 J Lindemann,12 M Pass,12 P Rugman,12 S Salim,12 G Schiavon,12 K Tamura,13 J Baselga,1 U Banerji4
1
Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2The Princess Margaret Cancer Centre, Toronto, Canada; 3University of Manchester and The Christie NHS Foundation Trust, Manchester, UK; 4Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK; 5National Cancer Center Hospital East, Chiba, Japan;
6
University of Colorado Cancer Center, Aurora, CO, USA; 7INCLIVA Biomedical Research Institute, Hospital Clínico Universitario of Valencia, Valencia, Spain; 8Stephenson Oklahoma Cancer Center at the University of Oklahoma, Oklahoma City, OK, USA; 9The University of Texas MD Anderson Cancer Center, Houston, TX, USA;
10
Institut de Cancérologie des Hospices Civils de Lyon, CITOHL, Université Lyon 1, Lyon, France; 11AstraZeneca, Waltham, MA, USA; 12AstraZeneca, Cambridge, UK; 13National Cancer Center Hospital, Tokyo, Japan
L52R
Total (N=45*)
Q79K
D323Y/G
Mean age (SD), years
0
PH
Pkinase
100
0
200
(b)
Pkinase_C
300
400
Tumors in which no AKT1
E17K mutations were
detected are not shown
2
1
AKT1 mutation
frequency (%)
3
5
Bre
ast
(
TC
GA
Pro pub 2
0
sta
te ( 15)
Pro Cervi SU2C
cal
sta
)
Lun te (TC (TCG
gs
GA A)
qu
201
(T
Th
5)
Lun yroid CGA
ga
(TC pub
d
)
He
GA
ad eno (
TC pub)
&n
G
e
Sto ck (T A pu
b
C
ma
ch GA p )
Me (TCG ub)
lan
Ap
om
a (T ub)
CG
A)
0
4
3
Tumors in which no AKT1
missense mutations were
detected are not shown
3 (6.7)
42 (93.3)
1
0
5
• AZD5363 is a potent, catalytic inhibitor of all three AKT isoforms (AKT1, 2 and 3).
• Preclinical data5 demonstrate inhibition of:
– Phosphorylation of AKT substrates (PRAS40 and GSK3β)
– Tumor cell proliferation
– Tumor growth in xenograft models.
• In a previous Phase 1 study of AZD5363 in Japanese patients with advanced solid tumors, confirmed partial
responses (PRs) were observed in two patients whose tumors harbored the AKT1 E17K mutation.6
• In this analysis, we present data from a Phase 1 study in patients with advanced solid tumors and an AKT1
E17K mutation.
Objectives
• Obtain a preliminary assessment of the antitumor activity of AZD5363.
• Assess the safety and tolerability of AZD5363.
• Explore the relationship between serial measurements of AKT1 E17K in circulating tumor-derived cell-free
DNA (cfDNA) and the antitumor activity of AZD5363.
Methods
Study design
• Phase 1, open-label, multicenter, four-part (A–D) study in patients aged ≥18 years with advanced solid
tumors (NCT01226316).
• In Part A, increasing doses of AZD5363 were given orally, twice daily (bid) in three different schedules until
the maximum-tolerated dose was achieved.7
• In Part B, additional patients were enrolled and treated with AZD5363 at the dose and schedule identified in
Part A.7
• The recommended dose was carried forward into Parts C7 and D:
– 480 mg bid on a ‘4 days on/3 days off’ schedule.
• Part D enrolled patients with tumors harboring AKT1 mutations (Figure 2).
Figure 2. Study design: Part D
Gynecological tumor
with AKT1 mutation
n=20
Any other advanced solid
tumor with AKT1 mutation
n=20
Interim analysis
Interim analysis
40
40
120
120
120
Patients and dosing
• Eligibility:
– Advanced solid tumor with an AKT1 mutation
– Tumors with known RAS/RAF mutations were excluded
– Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• AKT1 E17K mutation status was identified through local screening and confirmed retrospectively by
central assay.
cfDNA decline
No
50
0
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
12
0
24
36
48
60
100
80
Figure 10. Combination of fulvestrant and AZD5363 (clinical)
60
40
20
0
0
10
1.8
2.8
4.9
0.8
4.7
0.7
8.4
3.5
8.1
3.7
22 (48.9)
21 (46.7)
2 (4.4)
5.9 (3.5)
Figure 3. Best percentage change in tumor size in patients with E17K-mutated tumors treated with
AZD5363
ER+ breast
TNBC
Cervix
Colon
Lung
Other**
Ovary
Endometrial
Prostate
Thyroid
20
10
0
–10
–20
–30
39.2
Discontinued
0
• RECIST data are available for 18 patients with ER+ breast cancer.
• 14/18 patients demonstrated target lesion shrinkage (Figure 4):
– Three had confirmed PR (including a Japanese study patient)
– Two had unconfirmed PR
• One patient is ongoing (awaiting 12-week scan)
• One patient discontinued treatment before 12 weeks because of central nervous system disease
progression (whole body autoradiography studies in rats indicate that AZD5363 has limited
permeability across the blood–brain barrier).
Patients with gynecological tumors
(a)
0.8
–30
–40
–50
–60
*
Ea
A
A
Ed
A
Pa
Gc
E
Sc
E
Ed
Histology
O
E
E
O
E
O
O
E
C
E
O
Tumor type
1
2
3
4
5
6
7
8
9
10
11
2.7
2.6
4.4
5.6
1.5
7.0
2.3
11.2
0.2
S33F
P=0.96
P value = 5x10–15
0.2
0.4
0.6
SOX17
• RECIST data are available for 12 patients with other advanced solid tumors.
• 10/12 patients demonstrated target lesion shrinkage (Figure 6):
– One had confirmed PR (ongoing)
– Two had unconfirmed PR (a further patient with shrinkage of target lesions >30% had progression of nontarget lesions and new lesions at same visit)
• One patient is ongoing
• One patient discontinued treatment before 12 weeks because of disease progression.
Pre-treatment tumor
Pre-treatment cfDNA
Post-treatment tumor
Post-treatment cfDNA
S403I
0.8
SPEN
ddPCR
R2342Q
(c)
Post-progression
Pre-treatment
AKT1
NKX2-1
NCOR1
KEAP1
ESR1
E17K
A102V
Splice
L153dup
D538G
cfDNA
10
Discontinued
Combination of fulvestrant and AZD5363: preclinical data
• A preclinical study assessed the effect of AZD5363 alone or in combination with fulvestrant on biomarker
changes and tumor growth in a panel of ER+ breast cancer cell lines.9
• Following treatment withdrawal, tumor growth was significantly delayed with AZD5363 + fulvestrant
compared with AZD5363 alone (Figure 9).
0
–10
–20
–30
–70
A
Ma
L
P
C
1
2
3
Id
U
A
Id
Id
A
Sc
B
T
P
B
B
Sa
Aa
4
5
6
7
8
9
10
An
A
Histology
L
b
Tumor type
11
12
Patient
• Serial cfDNA assessments were available in 23/47 patients by allele-specific droplet digital polymerase chain
reaction (ddPCR).
• The AKT1 E17K mutation was detectable in cfDNA in 21/23 patients (91%) at baseline.
• AKT1 cfDNA declined in 20/21 (95%) patients and became entirely undetectable in 7/20 (35%) patients, four
of whom attained a PR.
• Declines in AKT1 cfDNA were transient in non-responders, while persistent (≥21 days) cfDNA clearance
correlated with durable RECIST response (P=0.0049) [Figure 7].
• First rise in AKT1 cfDNA from nadir preceded radiological progression by a median of 67 days
(range 17–147) in 14/15 (93%) assessable patients.
20
0
20
40
10
9
8
7
6
5
4
3
2
1
0
10
20
30
40
50
60
70
Treatment
stopped
20
18
16
14
12
10
8
6
4
2
0
140
160
180
Patients (n=45*)
40 (88.9)
Any AE CTC grade ≥3
30 (66.7)
Any AE CTC grade ≥3, causally related to AZD5363
22 (48.9)
Any AE leading to dose reduction
13 (28.9)
Any AE leading to discontinuation of AZD5363
6 (13.3)
Any AE leading to discontinuation of AZD5363, causally related to AZD5363
4 (8.9)
Any SAE
19 (42.2)
Any SAE, causally related to AZD5363
7 (15.6)
80
• AKT1 E17K appears to be an actionable mutation in several solid tumors.
• AZD5363 monotherapy shows promising clinical activity in various heavily pre treated AKT1 E17K
mutant solid tumors, including in patients with ER+ breast, cervical and ovarian cancer, and lung
adenocarcinoma.
• Serial cfDNA monitoring provides an additional tool to monitor response to targeted therapy.
• Combination of AZD5363 plus fulvestrant in ER+ breast cancer may delay/overcome resistance to
AZD5363 monotherapy.
• This study is ongoing.
90
References
AZD5363 + fulvestrant
Treatment
stopped
1.
2.
3.
4.
5.
Lindsley CW. Curr Top Med Chem 2010;10:458–477.
Hennessy BT et al. Nat Rev Drug Discov 2005;4:988–1004.
Liu P et al. Nat Rev Drug Discov 2009;8:627–644.
Bellacosa A et al. Adv Cancer Res 2005;94:29–86.
Davies BR et al. Mol Cancer Ther 2012;11:873–887.
6.
7.
8.
9.
10.
Esaki T et al. Ann Oncol 2014;25(Suppl):iv146–iv164.
Banerji U et al. J Clin Oncol 2015;33(Suppl):abst 2500.
Cheng DT et al. J Mol Diagn 2015;17:251–264.
Ribas R et al. Mol Cancer Ther 2015;14:2035–2048.
Toy W et al. Nat Genet 2013;45:1439–1445.
Acknowledgments
This study was sponsored by AstraZeneca. AZD5363 was discovered by AstraZeneca subsequent to a collaboration with Astex
Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).
We thank all of the investigators and site staff, with special thanks to the patients and families.
Medical writing assistance was provided by Andrew Jones PhD from Mudskipper Business Ltd, funded by AstraZeneca.
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150
Time after start of treatment (days)
Time after start of treatment (days)
Presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, Hynes Convention Center, Boston, Massachusetts, November 5–9, 2015
120
Conclusions
(b) Changes in tumor volume during withdrawal9
AZD5363
100
Any AE causally related to AZD5363
Time after start of treatment (days)
20
18
16
14
12
10
8
6
4
2
0
80
n (%)
Control (vehicle)
Ovariectomy (vehicle)
Fulvestrant
AZD5363
AZD5363 + fulvestrant
0
60
Table 2. Frequency of AEs and SAEs during treatment with AZD5363
(a) Changes in tumor volume during treatment9
An
40
*Does not include the two patients from the Japanese study; SAEs, serious adverse events
Figure 9. Combination of fulvestrant and AZD5363 (preclinical)
–50
RECIST progression:
Fulvestrant added to AZD5363
60
0
–40
–60
80
• The safety profile of AZD5363 was consistent with previous reports (Table 2)
– Most common AEs of CTC grade ≥3 were: hyperglycemia (n=8), diarrhea (n=7), maculopapular rash (n=7)
and hypertension (n=2); all other events were reported in one patient.
CTNNB1
2.4
Ongoing
AKT1 E17K
ESR1 D538G
Safety and tolerability of AZD5363
Q497*
Figure 6. Best percentage change in tumor size in patients with other E17K-mutated advanced solid
tumors treated with AZD5363
2.5
100
Days on AZD5363 treatment
ARID1A
0.4
Plots are based on patients with available RECIST data at baseline and at least one follow-up assessment. Histology terms were not centrally
reviewed and are detailed verbatim as per investigator reports; *Patient from the Japanese study
Histology: A, adenocarcinoma; Ea, endometrial adenocarcinoma; Ed, endometroid; Gc, granulosa cell tumor; Pa, papillary carcinoma;
Sc, squamous cell carcinoma; Tumor type: C, cervical; E, endometrial; O, ovarian
4.7
Mut. allele freq.
0.0 0.2 0.4 0.6 0.8
E17K
0.0
cfDNA assessments
Patients with other advanced solid tumors
AZD5363 + fulvestrant:
Follow-up scan
AKT1
0.6
0.0
Patient
(b)
AKT1 cfDNA mutant
allele frequencies
Plots are based on patients with available RECIST data at baseline and one follow-up assessment. Histology terms were not centrally
reviewed and are detailed verbatim as per investigator reports
Histology: A, adenocarcinoma; An, adenocarcinoma (NOS); Id, invasive ductal; Ma, mucinous adenocarcinoma; Sc, squamous cell
carcinoma; U, undifferentiated (anaplastic) carcinoma; Tumor type: Aa, apocrine anal; B, TNBC; C, colon; L, lung; P, prostate;
Sa, squamous anal; T, thyroid
• RECIST data are available for 11 patients with gynecological tumors.
• 9/11 patients demonstrated target lesion shrinkage (Figure 5):
– Three had confirmed PR (including a Japanese study patient)
• Two patients are ongoing.
AZD5363 monotherapy:
Progression scan
–20
2.7
Patients with ER+ breast cancer
70
• Exon capture next-generation sequencing (NGS) of 410 genes (MSK-IMPACT) from cfDNA was performed
in a subset of patients.8
• AKT1 E17K cfDNA mutant allele fraction, as determined by ddPCR and MSK-IMPACT, was highly
concordant (P=0.96, Figure 8a).
• Mutant allele frequencies in tumor and cfDNA were highly concordant both pre- and post-treatment
(Figure 8b).
• Pre-treatment cfDNA NGS recapitulated the mutational profile of genetically heterogeneous tumors more
completely than did NGS in pre- or post-progression tumor tissue (Figure 8c).
20
Plots are based on patients with available RECIST data at baseline and at least one follow-up assessment
*Patients from the Japanese study; **Comprises ‘squamous anal’ and ‘apocrine anal’
60
Next-generation sequencing on cfDNA
On-study duration from start of study drug to discontinuation or data cut-off (months)
*
50
Figure 8. Next-generation sequencing on cfDNA
–40
*
40
–10
–70
–50
30
AKT1 E17K cfDNA decline* at day 21 predicts for improved progression-free survival
*cfDNA decline is defined as reduction of AKT1 E17K mutant allele fraction (MAF) to levels ≤50% vs baseline. MAF baseline set at 100%
Ongoing
10
20
Days since AZD5363 initiation
18
On-study duration from start of study drug to discontinuation or data cut-off (months)
Analyses are based on emerging, unvalidated clinical data
*Does not include the two patients from the Japanese study; **Endometrial, n=6; ovarian, n=5; cervical, n=2
†
Triple-negative breast (TNBC), n=4; lung, n=2; prostate, n=2; colon, n=1; thyroid, n=1; squamous anal, n=1; apocrine anal, n=1
–60
2
Figure 5. Best percentage change in tumor size in patients with E17K-mutated gynecological tumors
treated with AZD5363
–70
40
*
20
WHO performance status, n (%)
0
1
Missing
Change in sum of target lesion diameter
(best assessment, %)
AZD5363
Interim analysis
–60
Plots are based on patients with available RECIST data at baseline and at least one follow-up assessment
*Patient from the Japanese study
20 (44.5)
13 (28.9)
12 (26.6)
Number of prior anticancer regimens
Mean number of regimens (SD)
Pan-cancer human clinical data from cBioPortal (October 6 2015 release) accessed October 13 2015
n=20
–50
Patient
Tumor type (cohort or publication)
ER + breast cancer with AKT1 mutation
–40
1
Primary tumor location, n (%)
ER+ breast
Gynecological**
Other†
2
P=0.004
HR (log rank) 0.2535
(95% CI 0.03731 to 0.5066)
100
Weeks
Gender
Males
Females
C
Bre SCC
ast
(
(TC DFCI
201
G
5
Ute A pu
b2 )
rine
(TC 015)
GA
Ce
rvic
p
al ( ub)
P
Sto rosta TCGA
ma
te (
)
Pro ch (T SU2
C
st
CG
Ap )
Co ate (T
ub
lore
C
cta GA 2 )
015
l (T
)
Lun Melan CGA
p
o
ga
den ma (T ub)
C
o
G
(T
T
He hyroi CGA A)
ad
d
& n (TCG pub)
eck
A
(TC pub
)
G
Lun pRC A pu
b
gs
C(
qu
TC )
G
(TC
GA A)
pub
cR MM
(Br )
CC
GB (TCG oad)
M(
TC A pub
GA
)
201
3)
4
(b)
–30
–70
480 aa
(c)
5
56.8 (9.7)
–20
Relative tumor volume
N128S
–10
MSK-IMPACT
20
0
Relative tumor volume
40
Discontinued
Change in MAF (%)
Table 1. Patient demographics
Change in sum of target lesion diameter
(best assessment, %)
Number of
mutations
• Data are presented from the cut-off point of October 5, 2015.
• Forty-five patients are included in this analysis (Table 1).
E17K
66
AKT1 E17K
frequency (%)
Patient demographics
Change in sum of target lesion diameter
(best assessment, %)
(a)
Results
Ongoing
10
PD at <12 weeks
Yes
No
130
120
110
100
90
80
70
60
50
40
30
20
10
0
Change in AKT1 E17K
MAF (%)
Figure 1. (a) Mutations in AKT1; (b) E17K mutations in AKT1; (c) Missense mutations in AKT1
1.3 1.3 5.5 2.8 4.9 4.5 4.3 7.8 3.1 2.1 4.2 2.1 0.9 1.9 7.6 14.3 3.7 2.7
20
• Following a protocol amendment, two patients with E17K-mutated ER+ breast cancer received
fulvestrant + AZD5363 following disease progression on AZD5363 monotherapy. Both patients had
previously been treated with fulvestrant and developed resistance
– One patient discontinued treatment following further disease progression
– One patient is ongoing
• Patient was previously treated with 10 lines of therapy, including fulvestrant
• AKT1 E17K and ESR1 D538G10 present in pre-treatment cfDNA
• Experienced RECIST progression on AZD5363 monotherapy on day 121; fulvestrant added
• Follow-up scan shows shrinkage of primary breast cancer and resolution of liver metastasis
enhancement, concordant with declines in AKT1 E17K and ESR D538G mutant allele fraction in
cfDNA (Figure 10).
(c)
Relative tumor volume
• The PI3K/AKT/mTOR pathway is frequently dysregulated in human cancer and drives tumor growth and cell
survival;1 it is therefore a promising target for the development of new therapies.2,3
• AKT is a key part of the signaling network that mediates processes such as cell proliferation and resistance
to apoptosis, and it is activated in a wide range of solid and hematological malignancies.4
• E17K is the most common mutation in AKT1 (Figure 1).
On-study duration from start of study drug to discontinuation or data cut-off (months)
(a)
Change in AKT1 E17K
MAF at day 21 (%)
AKT1 E17K mutation
• Antitumor activity was assessed using RECIST every 6 weeks for 6 months, then every 12 weeks.
• Serial plasma samples were collected in a subset of patients for detection and tracking of AKT1 E17K
mutation in cfDNA.
• Safety was assessed throughout.
Combination of fulvestrant and AZD5363: clinical data
Figure 7. Changes in AKT1 cfDNA during AZD5363 treatment (ddPCR analysis)
Progression-free
survival
Introduction
Figure 4. Best percentage change in tumor size in patients with E17K-mutated ER+ breast cancer
treated with AZD5363
Change in sum of target lesion diameter
(best assessment, %)
Assessments
B109
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