The optimal therapeutic
algorithm for EML4-ALK
+ ve pts
Lucio Crinò
Medical Oncology Department
University Hospital Perugia, Italy
2
“Anaplastic Lymphoma kinase”(ALK)rearrangment
• 3-5% of lung adenocarcinomas
ALK signal transduction¹
ALK fusions²
1. Roskoski jr. Pharma research 2013
2. Peters et al. Lung Cancer 2013
Timeline
Mano H Cancer Discovery 2012;2:495-502
Clinical development of Crizotinib for
ALK+ NSCLC
Study
Phase
(planned
accrual)
Histology
Line of
therapy
Study design
Primary
endpoint
PROFILE 1014
III
(334 pts)
Non-squamous
1st
Platinum*-Pemetrexed
vs Crizotinib
PFS≠
PROFILE 1007
III
(318 pts)
NSCLC
2nd
2nd line chemo**
vs Crizotinib
PFS
PROFILE 1005
II
(400 pts)
NSCLC
3rd or
more∞
Crizotinib
monotherapy
ORR
ORR = overall response rate; PFS = progression-free survival; pts = patients
*Cisplatin or carboplatin according to investigator’s choice
≠Cross-over to crizotinib allowed at PD in the standard arm
**Pemetrexed or docetaxel; prior chemo must have been platinum-based chemotherapy
∞May have received Pemetrexed or Docetaxel from previous phase III PROFILE 1007 trial and discontinued
treatment due to RECIST-defined progression
Crizotinib for ALK+ NSCLC
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
Tumor responses to crizotinib by patient
PROFILE 10011
PROFILE 10052
Median time to response: 8 wk
1. Camidge et al., ASCO 2011; Abs #2501
2. Riely et al., IASLC 2011; Abs #O31.05
Study Design
Endpoints
Key entry criteria
● ALK+ by central
FISH testing
● Measurable disease
R
A
N
D
O
M
I
Z
Ea
● Treated brain
metastases allowed
N=318
● Stage IIIB/IV NSCLC
● 1 prior chemotherapy
(platinum-based)
● ECOG PS 0−2
Crizotinib 250 mg BID
PO, 21-day cycle
(n=159)
Pemetrexed 500 mg/m2
or
Docetaxel 75 mg/m2
IV, day 1, 21-day cycle
(n=159)
● Primary
– PFS (RECIST 1.1,
independent
radiology review)
● Secondary
– ORR, DCR, DR
– OS
– Safety
– Patient reported
outcomes
(EORTC QLQ-C30,
LC13)
CROSSOVER TO CRIZOTINIB
ON PROFILE 1005
a
Stratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and
prior EGFR TKI (yes/no)
PROFILE 1007: NCT00932893
ORR in PROFILE 1007
ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P<0.001
Crizotinib (n=173)
PEM/DOC (n=174)
80
80
65.3
ORR (%)
60
DOC (n=72)
65.7
60
40
40
29.3
19.5
0
RECIST v1.1
6.9
20
20
a
Crizotinib (n=172)
PEM (n=99)
Treatment
0
Treatment
PROFILE 1007: PFS of Crizotinib vs
Pemetrexed or Docetaxel
Probability of survival without
progression (%)
100
Events, n (%)
80
Median, mo
Crizotinib
(n=172a)
PEM
(n=99b)
DOC
(n=72b)
100 (58)
72 (73)
54 (75)
7.7
4.2
2.6
HRc (95% CI)
60
0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43)
P
<0.001
<0.001
40
20
0
No. at risk
Crizotinib
PEM
DOC
a
0
5
10
15
Time (months)
20
25
172
93
38
11
2
0
99
36
12
3
1
0
Excludes 1 patient who72
did not receive study treatment; bexcludes
3 patients in3chemotherapy arm
13
1 who did not receive
0 study
treatment; cvs crizotinib
Survival curves from PROFILE 1007
PFS
OS
Shaw, et al. NEJM 2013
Survival in ALK-positive NSCLC with crizotinib versus
crizotinib-naive controls
ALK
Crizotinib
(n=30)
100%
80%
ALK
Control
(n=23)
WT/WT
Control
(n=125)
Median Survival, mo
NR
6
11
1-yr Survival, %
70
44
47
2-yr Survival, %
55
12
32
60%
From 2nd/3rd line crizotinib
HR = 0.49, p=0.02
40%
20%
0%
0
1
2
3
4
Overall survival (years)
Camidge D R , Lancet Oncol 2012; 13: 1011–19
PROFILE 1014 Study Design
Primary Endpoint Met: Crizotinib Superior to Pemetrexed-based Chemotherapy in Prolonging PFSa
T. Mok –ASCO 2014
Secondary Endpoints: ORRa and OS
Emerging issues in management of
crizotinib-treated, ALK-positive patients
Brain metastases
Crizotinib in
ALK-positive
NSCLC
Treatment
beyond
progression
Therapy for
crizotinibresistant disease
OS from Start of Initial Crizotinib Treatment
Continued crizotinib
Did not continue crizotinib
Probability of survival (%)
100
80
60
40
Median OS (95% CI)
CBPD: 29.6 months (23.1−NR)
No CBPD: 10.8 months (8.9−14.7)
20
HR=0.30 (0.19−0.46)
p<0.0001
0
0
Number at risk
Continued
Did not continue
120
74
5
10
15
20
25
Time (months)
30
104
40
30
8
6
0
35
40
1
Shaded areas are 95% Hall-Wellner confidence bands
Ou et al, Ann Oncol 2014
Most common sites of PD in patients
continuing crizotinib beyond PD
Organ sites in which new lesions developed and/or non-target lesions
progressed in the Crizotinib-Beyond-PD group
Organ
Patients with new lesions and/or nontarget lesions (n=115)
No. of patients (%)a
Brain
53 (46)
Liver
30 (26)
Lung
23 (20)
Bone
20 (17)
Pleural effusion
16 (14)
Lymph node
12 (10)
Adrenal
1 (1)
Chest wall
1 (1)
Pelvis
1 (1)
Soft tissue
1 (1)
Spine
1 (1)
aExcluding
Other
patients with target lesions only: patients could be counted more than once across organ sites
21 (18) Otterson, et al. ASCO 2012
Study Population: ALK+ NSCLC With or
Without Brain Metastases at Baseline
PROFILE 10051
(open-label,
single-arm phase II)
Crizotinib 250 mg BID
PROFILE 10072
(randomized phase III
vs. standard chemo)
Crizotinib 250 mg BID
RETROSPECTIVE ANALYSIS of crizotinib-treated patients with
or without asymptomatic BM at baseline (n=888)
Previously untreated
for BM (n=109)
●
●
12%
Previously treated
for BM (n=166)
19%
No BM detected
(n=613)
69%
Among evaluable patients:
–
20% of patients (22/109) with previously untreated asymptomatic BM had BM classified as
target lesions
–
11% of patients (18/166) with previously treated asymptomatic BM had BM classified as
target lesions
–
9% of patients (55/613) with no detectable BM at baseline developed symptomatic BM after
the start of crizotinib treatment
Median duration of crizotinib treatment similar in the three groups (22.0–29.3 weeks)
1. Kim D-W, et al. J Clin Oncol 2012;30(Suppl.) (abstr. 7533); 2. Shaw AT, et al. N Engl J Med 2013;368:2385–2394
Crinò et al. Poster presented at European Cancer Congress 2013 (abstract 3413)
Crizotinib Antitumor Activity in Patients With
or Without Brain Metastases at Baseline
●
IC and systemic DCR at 12 weeks: 56–65% in patients with BM at baseline
●
IC ORR: 25% in 40 patients with BM classified as target lesions
●
Systemic ORR: 46–55% across the three groups
Previously untreated
for BM (n=109)
n
Outcome
DCR at 12 weeks, % (95% exact CI)
IC
109
Systemic
109
ORR, % (95% exact CI)
IC
109
Patients with target-lesion BM
22
Systemic
109
a
Median time to tumor response (range), weeks
IC
8
Systemic
58
b
a
Median duration of response (range), weeks
IC
8
Systemic
58
b
c
Median systemic PFS, (95% CI), mo
109
Previously treated
for BM (n=166)
n
Outcome
56 (46−66)
63 (54−72)
166
166
62 (54−70)
65 (57−72)
7 (3−14)
18 (5−40)
53 (43−63)
166
18
166
7 (4−12)
33 (13−59)
46 (39−54)
6.0 (4.9−12.4)
6.1 (2.0−31.4)
12
77
6.4 (5.9−17.7)
6.1 (3.1−35.3)
26.4 (6.1−59.3)
47.9 (5.3−55.0)
8.3 (6.7−14.0)
12
77
166
NR (6.0−59.9)
55.6 (4.4−95.3)
13.5 (6.2−16.5)
No BM detected
(n=613)
n
Outcome
613
NA
71 (68−75)
613
NA
NA
55 (51−59)
336
NA
6.1 (3.0−49.1)
336
613
NA
49.0 (4.1−96.1)
9.9 (8.8−12.2)
NA, not applicable; NR, not reached
aIn patients with confirmed objective response; bKaplan−Meier method; cBrookmeyer−Crowley method
Crinò et al. Poster presented at European Cancer Congress 2013 (abstract 3413)
Emerging issues: brain metastases
INTRACRANIAL DISEASE CONTROL RATE AT 12 WEEKS IN PATIENTS WITH
BEST PERCENTAGE
CHANGE IN INTRACRANIAL TARGET LESIONS
BASELINE ASYMPTOMATIC BRAIN METASTASES4
FROM BASELINE (%)
40
20
0
* * *
−20
*
−40
*
* * *
−60
*
*
*
*
*
−80
Best objective response according to RECIST.
−100
Progressive disease
Stable disease
Partial response
Complete response
*
*Patients previously treated for brain metastases.
aPatients
with one intracranial target lesion at baseline (n=33, 7 patients with early death/indeterminate response excluded).
Costa DB, et al. Oral presentation at World Congress on Lung Cancer, October 27–30, 2013, Sydney, Australia: Abstract 2932.
Frequencies of crizotinib resistance mechanisms
in ALK+ NSCLC
ALK non-dominant
Unknown 25%
ALK dominant
(Bypass tracks)
KIT amplification
10 %
Change in driver
mutations
5%
Increased EGFR
signaling
30-35%
Alk mutation
22-33%






L1196M
G1202R
S1206Y
G1269A
1151Tins
Others
Alk amplification
6-16%
Camidge D. R. Nat. Rev. Clin. Oncol. 11, 473–481 (2014) ;
Options at acquired resistance to Crizotinib
All of them seem
to be very good
2nd generation ALK-TKIs
Crizotinib beyond progression
ALK
translocated
Crizotinib
Acquired
resistance
Switch to chemotherapy
Crizotinib beyond progression
+
CHT or Hsp90I
1) Better affinity for ALK
2) Better affinity for crizotinib resistant second-site mutated ALK
3) Improvement in pharmacokinetics to brain tissue and CSF
Ceritinib: Highly Active Treatment <br />Option for ALK-Positive NSCLC
Toxicity Challenges with Ceritinib
AP26113 IN CRIZOTINIB-RESISTANT ALK-REARRANGED NSCLC
Ceritinib, Alectinib and AP26113, show antitumor activity
in ALK+ NSCLC with brain metastasis
Baseline
LDK378
6 wks
Baseline
Baseline
AP26113
CH5424802
8 wks
33 wks
Mehra et al., ASCO (2012), abstr 3007
Gettinger et al., ESMO (2012), abstr 4390
Nishio et al., ESMO (2012), abstr 4410
Tumor Responses to
Crizotinib in ROS1rearranged NSCLC
ORR = 72% (95% CI, 58 to 84)
DOR= 17.6 mos (95% CI, 14.5-not reached)
PFS= 19.2 mos (95% CI, 14.4-not reached)
Shaw AT et al. N Engl J Med 2014.
Efficacy of crizotinib in MET-amplified NSCLC
Best percent change from baseline in target tumor lesionsa by patient
% Change From Baseline
Low MET
n=2
Intermediate MET
n=6
High MET
n=6
100
100
100
80
80
80
60
60
60
40
40
40
20
20
20
0
0
0
–20
–20
–20
–40
–40
–60
–60
–80
–80
–80
–100
–100
–100
c
–40
c
Disease progression
Stable disease
Partial responseb
Complete responseb
Threshold
for partial
response
–60
aConfirmed
objective responses.
on investigator assessment.
cTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment.
bBased
Presented By D. Camidge at 2014 ASCO Annual Meeting
Biologically-unselected non-squamous
NSCLC
Squamous
cell cancer
Platinum + 3rd generation agent
EGFR WT/ALK neg,
clinically selected
Platinum-based doublet
+ Bevacizumab
EGFR WT,
ALK neg
EGFR WT/ALK neg,
clinically
unselected
Non-squamous
cancer
Platinum + Pemetrexed
EGFR mut +
EGFR-TKI
ALK/ROS1
rearranged
ALK-TKI
Oncogene
addicted
First-line therapy for metastatic NSCLC in 2014
Stratification for EGFR, ALK and histology
EGFR Mut+
ALK rearranged
EGFR TKI
Crizotinib
ALK-/EGFRwt
non-squamous
ALK-/EGFRwt
squamous
Platinum doublet +
bevacizumab
OR
platinum
+ pemetrexed
+/- bevacizumab
Platinum-based
doublet
Istituto Toscano Tumori – Livorno, Italy
SUMMARY
• Crizotinib is the first-in-class ALK-TKI inhibitor
fully approved worldwide
• Consistent response rate, PFS >60% over
8 months, very favourable toxicity profile
• Evidence of clinical benefit in continuous
treatment beyond smouldering progression and
in brain metastases in selected patients with or
without radiotherapy
• Significant activity in ROS1 rearranged patients