alk e meccanismi di resistenza lucio crinò s.c. di oncologia medica azienda ospedaliera di perugia
TRANSCRIPT
ALK e meccanismi di resistenza
Lucio CrinòS.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
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 2012Kim, et al. ASCO 2012
Shaw, et al. NEJM 2013Perol, et al. ECCO 2013
[TITLE]
Presented By Fabrice Barlesi, MD, PhD at 2013 ASCO Annual Meeting
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
2nd generation ALK-inhibitors in clinical development
2nd generation ALK-inhibitors in clinical development
RR with 2nd generation ALK-inhibitors in Crizotinib-naïve patients
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
ALK rearrangementProgression on
Crizotinib after response or SD > 3 mo
No prior pemetrexedN=114
Pemetrexed alone
Pemetrexed +ongoing Crizotinib
RANDOMIZE
Co-primary endpoint: progression-free survivalRespnse rate, pemetrexed alone
Chemotherapy +/- ongoing crizotinib for acquired resistance in ALK-positive NSCLC
Chemotherapy +/- ongoing crizotinib for acquired resistance in ALK-positive NSCLC
SWOG 1300 (in development)SWOG 1300 (in development)
PI: Ross CamidgePI: Ross Camidge
Crizotinib beyond progressionCrizotinib beyond progression
Ou, et al. IASLC 2013
AP26113 in ALK+ NSCLCs (N=34)
13All 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
• Response duration 8+ to 40+ weeks• 14 confirmed, 4 awaiting confirmation, 4 not confirmed
Data as of 6 Sept 2013
Be
st
Ch
an
ge
fro
m B
as
elin
e in
Ta
rge
t L
es
ion
(%
)
-100
-80
-60
-40
-20
0
20
40
Progressive Disease Stable Disease Partial Response Complete ResponseBest Overall Response:
c
b
b
a
a
a
d
• 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)
Camidge, et al. IASLC 2013
Alectinib in crizotinib-refractory patients Overall RR 54.5% across all cohorts for all patients
Waterfall plot% tumor shrinkage
Days on
study
Duration 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
• 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
The problem of CNS progression to Crizotinib in ALK+ patients
The problem of CNS progression to Crizotinib in ALK+ patients
Crizotinib antitumour activity in patients with or without brain metastasis (BM) at baseline
Previously untreatedfor BM (n=109)
Previously treated for BM (n=166)
No BM detected(n=613)
n Outcome n Outcome n Outcome
DCR at 12 weeks, % (95%CI)
IC 109 56 (46−66) 166 62 (54−70) NA
Systemic 109 63 (54−72) 166 65 (57−72) 613 71 (68−75)
ORR, % (95% CI)
IC 109 7 (3−14) 166 7 (4−12) NA
Target-lesion BM 22 18 (5−40) 18 33 (13−59) NA
Systemic 109 53 (43−63) 166 46 (39−54) 613 55 (51−59)
Median time to tumor response (range),a weeks
IC 8 6.0 (4.9−12.4) 12 6.4 (5.9−17.7) NA
Systemic 58 6.1 (2.0−31.4) 77 6.1 (3.1−35.3) 336 6.1 (3.0−49.1)
Median duration of responseb (range),a weeks
IC 8 26.4 (6.1−59.3) 12 NR (6.0−59.9) NA
Systemic 58 47.9 (5.3−55.0) 77 55.6 (4.4−95.3) 336 49.0 (4.1−96.1)
Median systemic PFS,b (95% CI),c mo 109 8.3 (6.7−14.0) 166 13.5 (6.2−16.5) 613 9.9 (8.8−12.2)
NR, not reachedaIn patients with confirmed objective response; bKaplan−Meier method; cBrookmeyer−Crowley method 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
• 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.
Brain RT > 4 wks
No brain RT91+ 203+ 42
224+
224+287+98+ 196+
294+
Days on study
CR PR SD PD
Total N=21 6 5 8 2
% 29% 24% 38% 10%
PR
Progressing CNS mets 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
Unraveling the mechanisms of resistance to EGFR-TKIs and Crizotinib
Katayama, et al. Sci Trans Med. 2012Doebele, et al. Clin Cancer Res. 2012
Unknown
Bypass tracksEGFR MTKRAS MT
Am
plifi
ed
L1196M
G1269A
S1206YG1202R1151TinsL1152RC1156Y
No ALKamp or mut
ALKamp
ALKmutALK+
IGF-1R and IRS-1 are up-regulated in ALK TKI resistant cells
pIGF-1R Y1131
IRS-1 pY941
AKT
pAKT S473
S6
pERK
ERK
IRS-1
IGF-1R
pS6
DMSO
500
5000ALK TKI [nM]
TKI sensitive
DMSO
500
5000
TKI resistant
pALK Y1604
ALK
References: Lovly, C et al 2011 Cancer Research and Lovly, C et al submitted
Generation of isogenic pairs of ALK TKI sensitive and ALK TKI resistant cells
pIGF-1R and IRS-1 are up-regulated in patient biopsy samples at the time of acquired
resistance to crizotinib
Reference: Lovly, C et al submitted
pIGF-1R and IRS-1 are up-regulated in patient biopsy samples at the time of acquired
resistance to crizotinib
Key:- X-376: ALK TKI- MAb391: IGF-1R MAb
IGF-1R inhibitors sensitize H3122 ALK TKI resistant cells
to the anti-proliferative effects of ALK inhibitors
- 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
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)
Hsp90 inhibitor AUY922: activity in ALK+ patients (n=19/22)
Felip, et al. ESMO 2012
Tumor #6transplanted
H2228R tumor xenografts treated with AT13387
• AT13387 treatment inhibits the growth of an ALK-dependent tumor xenograft with acquired resistance to crizotinib
0
100
200
300
400
500
1 8 15 22 29
Tum
or v
olum
e (m
m3 )
Day
Crizotinib 50 mg/kg po qd + cyclodextrin ip 1qw
Crizotinib 50 mg/kg po qd + AT13387 55 mg/kg ip 1qw
Wallis, IASLC 2013
The Hsp90i AT13387 overcomes acquired resistance to crizotinib
The Hsp90i AT13387 overcomes acquired resistance to crizotinib
ALK: (e.g. ALK-TKI + Hsp90 inhibitor; ALK-TKI + IGFR-1R inhibitors )
Therapy Therapy Therapy Resistance
Selection for genetic instabilitySelection for genetic instability
Selection for resistance
Rationale for the upfront use of combination regimens
Rationale for the upfront use of combination regimens
Sang et al. Cancer Discov 2013
Preclinical evidence for UPFRONT dual ALK/Hsp90 inhibition: ALK-TKI + Ganetespib
Preclinical evidence for UPFRONT dual ALK/Hsp90 inhibition: ALK-TKI + Ganetespib
0
100
200
300
400
500
600
700
1 8 15 22 29 36
Tu
mo
r v
olu
me
(m
m3 )
Day
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
0
50
100
150
200
250
300
1 8 15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120 127
Rel
ativ
e T
um
or
Vo
lum
e
Day
Crizotinib
Crizotinib+AT13387
Continuous treatment
Final tumor weight (Day 126)
Tu
mo
r w
eig
ht
(mg
)
0
25
50
75
100
125450500
Crizotinib Crizotinib+ AT13387
• 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
Preclinical evidence for UPFRONT dual ALK/Hsp90 inhibition: ALK-TKI + AT13387
Preclinical evidence for UPFRONT dual ALK/Hsp90 inhibition: ALK-TKI + AT13387
Wallis, IASLC 2013
Regimen Phase ClinicalTrials.gov Identifier
Crizotinib + AT13387 I/II NCT01712217
Crizotinib + Ganetespib I/II NCT01579994
LDK378 + AUY922 Ib NCT01772797
Clinical attempt to better Crizotinib: trials of ALK/HSP90 inhibition
Clinical attempt to better Crizotinib: trials of ALK/HSP90 inhibition
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 Crizotinib-refractory 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 ALK-TKIs + HSP90 or IGF-1R inhibitors in ALK+ advanced NSCLC
[email protected]@ospedale.perugia.it
Thanks for your attention