ALK e meccanismi di
resistenza
Lucio Crinò
S.C. di Oncologia Medica
Azienda Ospedaliera di Perugia
Outline
• Current evidence with ALK-TKIs in naïve patients
• ALK-TKIs in crizotinib-refractory disease
• Challenging brain mets in ALK+ disease
• Resistance to crizotinib: focus on ‘unknown’ mechanisms
Outline
• Current evidence with ALK-TKIs in naïve patients
• ALK-TKIs in crizotinib-refractory disease
• Challenging brain mets in ALK+ disease
• Resistance to crizotinib: focus on ‘unknown’ mechanisms
Crizotinib for ALK+ advanced NSCLC:
RR appr. 60%, PFS 7.7-9.7 mos
Study
No. of patients
RR (%)
PFS (mos.)
A8081001
143
60.8
9.7
A8081005
261
59.8∞
8.1
A8081007
173
65*
7.7
French Temporary Authorization
for use of Crizotinib
230
56.5
Not
reported
∞259
pts evaluable for response
*Independent radiologic review
Camidge, et al. Lancet Oncol 2012
Kim, et al. ASCO 2012
Shaw, et al. NEJM 2013
Perol, et al. ECCO 2013
[TITLE]
Presented By Fabrice Barlesi, MD, PhD at 2013 ASCO Annual Meeting
Efficacy and safety data
Mean dura on of treatment (n=227): 5.01 months (range: 0.03 – 21.80)
Radiological evalua on of response (physician assessment, RECIST 1.1) for 197 evaluable pa ents
All pa ents
N=197, %
ECOG PS≥3
N=6, %
Brain metastases
N=58, %
≥3 previous
treatment lines
N=54, %
Complete response
5.6%
0
3.5%
5.5%
Par al response
59.3%
66.6%
67.2%
55.6%
64.9%
66.6%
70.7%
61.1%
Stable disease
19.3%
16.7%
13.8%
12.9%
Disease progression
15.7%
16.7%
15.5%
25.9%
ORR (95%CI)
Safety: 412 AEs related to crizo nib, of which 132 were SAEs, reported in 152 pts (49% of pts).
Most frequent AEs were transaminases increase (10.0%), vision disorders (9.7%), neutropenia
(5.3%), diarrhea (4.7%), peripheral oedema (4.9%), asthenia (4.1%) and nausea (3.9%).
Conclusion: ac vity and safety profile of crizo nib are similar in clinical prac ce to those of clinical
trials (PROFILE 1001, 1005 and 1007) with a good benefit/toxicity ra o.
2nd generation ALK-inhibitors in
clinical development
Drug
Inhibition of secondary
L1196M ‘gatekeeper’
mutation
Company
Clinical stage
AP-26113
Yes
Ariad
Pharmaceuticals
Phase I/II
LDK378
Yes
Novartis
Phase II/III
Alectinib
Yes
Chugai
Pharmaceuticals
Phase I/II
TSR-011
Yes
Tesaro
Phase I
NMS-E628
Yes
Nerviano Medical
Phase I
ASP-3026
Yes
Astellas
Phase I
X-376 and -396
Yes
Xcovery
Phase I
CEP-28122
Yes
Cephalon
Preclinical
RR with 2nd generation ALK-inhibitors
in Crizotinib-naïve patients
Author
Drug
No. of pts
RR (%)
Camidge
(ECCO 2013)
AP26113*
3
100
Shaw
(ASCO 2013)
LDK378**
35
60
Seto
(Lancet Oncol 2013)
Alectinib***
46
93.5
*60-300 mg/d
**400-750 mg/d
***300 mg x 2/d; Asiatic (Japanese) patients
Outline
• Current evidence with ALK-TKIs in naïve patients
• ALK-TKIs in crizotinib-refractory disease
• Challenging brain mets in ALK+ disease
• Resistance to crizotinib: focus on ‘unknown’ mechanisms
CHEMOTHERAPY
TKI beyond PD or 2nd generation
TKI ± local therapy
TKI beyond PD + brain RT
Chemotherapy +/- ongoing crizotinib for
acquired resistance in ALK-positive NSCLC
SWOG 1300 (in development)
PI: Ross Camidge
ALK rearrangement
Progression on
Crizotinib after response
or SD > 3 mo
No prior pemetrexed
N=114
Co-primary endpoint:
progression-free survival
Respnse rate, pemetrexed alone
R
A
N
D
O
M
I
Z
E
Pemetrexed alone
Pemetrexed +
ongoing Crizotinib
Crizotinib beyond progression
Ou, et al. IASLC 2013
AP26113 in ALK+ NSCLCs (N=34)
Best Change from Baseline in Target Lesion (%)
Best Overall Response:
•
40
20
b
Progressive Disease
Stable Disease
Partial Response
Complete Response
65% (22/34) objective response rate (95% CI: 47-80%)
• 61% (19/31) post-crizotinib (incl. 1 criz intolerant)
• 100% (3/3) in TKI-naïve (incl. 1 CR)
0
-20
-40
a
c
b
-60
a
-80
-100
d
•
a
Response duration 8+ to 40+ weeks
• 14 confirmed, 4 awaiting confirmation, 4 not confirmed
13
All patients received prior crizotinib unless otherwise indicated; Doses ranged from 60-240 mg/d (23 pts ≥180mg/d); aTKI-naïve;
bReceived prior crizotinib and LDK378; cPD by RECIST 1.1 due to 2nd primary tumor of melanoma;
dCrizotinib-intolerant
of 6 Sept2013
2013
Camidge, etData
al.as
IASLC
Alectinib in crizotinib-refractory patients
Overall RR 54.5% across all cohorts for all patients
Waterfall plot
% tumor
shrinkage
Duration on study
Days
on
study
(*: off study, data cut-off Sept. 12, 2013)
** *
*
*
*
**
** *
*
*
*
Overall RR 59.5% for cohorts of 460 mg dose or higher
24 of the 47 patients received the drug for 120 days or longer
Gadgeel, et al. IASLC 2013
Outline
• Current evidence with ALK-TKIs in naïve patients
• ALK-TKIs in crizotinib-refractory disease
• Challenging brain mets in ALK+ disease
• Resistance to crizotinib: focus on ‘unknown’ mechanisms
The problem of CNS progression to
Crizotinib in ALK+ patients
• 13/28 (46%) patients at U. of Colorado
with first progression in CNS
2/13 had synchronous systemic
progression
Weickardt et al. JTO 2013
• Decreased CSF:plasma (0.0026) ratio
suggestive of pharmacological failure of
Crizotinib
Costa et al. JCO 2011
Crizotinib antitumour activity in patients with or without
brain metastasis (BM) at baseline
Previously untreated
for BM (n=109)
n
Outcome
Previously treated
for BM (n=166)
n
Outcome
No BM detected
(n=613)
n
Outcome
DCR at 12 weeks, % (95%CI)
IC
109
56 (46−66)
166
62 (54−70)
Systemic
109
63 (54−72)
166
65 (57−72)
109
7 (3−14)
166
7 (4−12)
NA
22
18 (5−40)
18
33 (13−59)
NA
109
53 (43−63)
166
46 (39−54)
NA
613
71 (68−75)
ORR, % (95% CI)
IC
Target-lesion BM
Systemic
613
55 (51−59)
Median time to tumor response (range),a weeks
IC
Systemic
8
6.0 (4.9−12.4)
12
6.4 (5.9−17.7)
58
6.1 (2.0−31.4)
77
6.1 (3.1−35.3)
8
26.4 (6.1−59.3)
12
NR (6.0−59.9)
58
47.9 (5.3−55.0)
77
55.6 (4.4−95.3)
336
49.0 (4.1−96.1)
109
8.3 (6.7−14.0)
166
13.5 (6.2−16.5)
613
9.9 (8.8−12.2)
NA
336
6.1 (3.0−49.1)
Median duration of responseb (range),a weeks
IC
Systemic
Median systemic PFS,b (95% CI),c mo
NR, not reached
aIn patients with confirmed objective response; bKaplan−Meier method; cBrookmeyer−Crowley method
NA
Costa, et al. IASLC 2013
Example of a complete response of a brain lesion in
response to crizotinib treatment
Before initiation of crizotinib
6 weeks after crizotinib 250 mg BID
This patient presented with a brain lesion previously treated with chemotherapy and palliative IC radiation,
which was classified as a target lesion. A CR in this lesion was observed after 6 weeks of treatment and had
persisted for 54 weeks by data cutoff (courtesy of J-Y Han, National Cancer Center, Goyang, South Korea)
Systemic progression-free survival (PFS) by presence or
absence of brain metastases (BM) at baseline (BL)
The presence of BM at BL does not significantly affect systemic PFS to crizotinib
Costa, et al. IASLC 2013
CNS activity of alectinib
• ORR of the 21 patients as determined by central image review
CR
PR
SD
PD
Total N=21
6
5
8
2
%
29%
24%
38%
10%
• 9/21 patients with baseline CNS metastasis had measurable CNS
lesions and received no prior radiation within 4 weeks from first dose of
alectinib
– No CR. 5/9 achieved CNS PR (≥ 30% reduction in sum of largest dimension). 2/9
had CNS stable disease and 2/9 had CNS progression.
0.60
PR
0.40
0.20
0.00
Brain RT > 4 wks
91+
203+
No brain RT
42
-0.20
-0.40
224+
287+ 224+
-0.60
98+
196+
294+
-0.80
Progressing CNS mets
Days on study
Ou, et al. IASLC 2013
Outline
• Current evidence with ALK-TKIs in naïve patients
• ALK-TKIs in crizotinib-refractory disease
• Challenging brain mets in ALK+ disease
• Resistance to crizotinib: focus on ‘unknown’ mechanisms
Unraveling the mechanisms of resistance to
EGFR-TKIs and Crizotinib
Unknown
ALK
amp
ALK+
ALK
mut
No ALK
amp or mut
Bypass tracks
EGFR MT
KRAS MT
Katayama, et al. Sci Trans Med. 2012
Doebele, et al. Clin Cancer Res. 2012
IGF-1R and IRS-1 are up-regulated in ALK TKI resistant cells
Generation of isogenic pairs of ALK TKI
sensitive and ALK TKI resistant cells
TKI sensitive
ALK TKI [nM]
pALK Y1604
ALK
pIGF-1R Y1131
IGF-1R
pAKT S473
AKT
pS6
S6
pERK
ERK
IRS-1 pY941
References:
Lovly, C et al 2011 Cancer Research and Lovly, C et al submitted
IRS-1
TKI resistant
pIGF-1R
pIGF-1Rand
andIRS-1
IRS-1are
areup-regulated
up-regulatedininpatient
patientbiopsy
biopsysamples
samplesatat
the
thetime
timeof
ofacquired
acquiredresistance
resistanceto
tocrizotinib
crizotinib
Reference: Lovly, C et al submitted
IGF-1R inhibitors sensitize H3122 ALK TKI resistant cells
to the anti-proliferative effects of ALK inhibitors
Key:
- X-376: ALK TKI
- MAb391: IGF-1R MAb
-
Soft agar assay in H3122 X-376 resistant cells
Similar results seen in H3122 crizotinib resistant cells
Analogous results seen with IGF-1R TKIs in addition to IGF-1R MAbs
Reference: Lovly, C et al submitted
Rationale for double ALK/HSP90 inhibition
in ALK+ advanced NSCLC
From Crystal and Shaw, Clin Cancer Res 2012
Hsp90 inhibitor AUY922: activity in
ALK+ patients (n=19/22)
Felip, et al. ESMO 2012
The Hsp90i AT13387 overcomes acquired resistance to
crizotinib
H2228 tumor xenografts treated with
crizotinib
H2228R tumor xenografts treated with
AT13387
Crizotinib 50 mg/kg po qd + cyclodextrin ip 1qw
500
1400
Tumor volume (mm3)
2
1000
3
800
4
600
5
400
6
Tumor #6
transplanted
400
300
200
100
7
200
Tumor volume (mm3)
1
1200
0
0
1
29
57
85
113
141
169
Continuous daily crizotinib treatment
•
Crizotinib 50 mg/kg po qd + AT13387 55 mg/kg ip 1qw
197
Day
1
8
15
22
Day
29
AT13387 treatment inhibits the growth of an ALK-dependent tumor xenograft with acquired
resistance to crizotinib
Wallis, IASLC 2013
Rationale for the upfront use of
combination regimens
Therapy
Therapy
Therapy
Resistance
Selection for resistance
Selection for genetic instability
ALK: (e.g. ALK-TKI + Hsp90 inhibitor; ALK-TKI + IGFR-1R inhibitors )
Preclinical evidence for UPFRONT dual ALK/Hsp90 inhibition:
ALK-TKI + Ganetespib
Sang et al. Cancer Discov 2013
Preclinical evidence for UPFRONT dual ALK/Hsp90
inhibition: ALK-TKI + AT13387
Final tumor weight (Day 126)
700
Tumor weight (m g)
Vehicle (cyclodextrin) ip 1qw
AT13387 55 mg/kg ip 1qw
Crizotinib 50 mg/kg po qd
Crizotinib 50 mg/kg po qd + AT13387 55 mg/kg ip 1qw
500
75
50
25
0
Crizotinib
+ AT13387
300
400
300
200
100
Crizotinib
250
Crizotinib+AT13387
200
150
100
50
0
0
1
•
•
100
Crizotinib
Relative Tumor Volume
Tumor volume (mm3)
600
500
450
125
8
15
22
29
Day
36
1
8
15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120 127
Continuous treatment
Day
Combination of AT13387 and crizotinib shows improved inhibition of tumor growth over monotherapies
Combining crizotinib upfront with AT13387 delays the emergence of resistance in vivo
Wallis, IASLC 2013
Clinical attempt to better Crizotinib:
trials of ALK/HSP90 inhibition
Regimen
Phase
ClinicalTrials.gov Identifier
Crizotinib + AT13387
I/II
NCT01712217
Crizotinib + Ganetespib
I/II
NCT01579994
LDK378 + AUY922
Ib
NCT01772797
ALK-inhibition in ALK+ NSCLC
• Platform networks required tools for optimization of NSCLC
treatment
• 2nd generation ALK-TKIs may break the boundary of 60%
response rate observed with Crizotinib
• Appr. 60% of RR with 2nd generation ALK-TKIs in Crizotinibrefractory patients
• 2nd generation ALK-TKIs may prevent CNS pharmacological
failure
• Hsp90 activity and IGF-1R upregulation may be partly
responsible for the non-ALK dominant mechanisms of
resistance to crizotinib
• Robust preclinical evidence of anticancer efficacy with ALKTKIs + HSP90 or IGF-1R inhibitors in ALK+ advanced NSCLC
Thanks for your attention
lucio.crino@ospedale.perugia.it