2 lucio crinò medical oncology department university hospital perugia, italy the optimal...
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2
Lucio CrinòMedical Oncology Department
University Hospital Perugia, Italy
The optimal therapeutic algorithm for EML4-ALK
+ ve pts
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“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
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Timeline
Mano H Cancer Discovery 2012;2:495-502
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Clinical development of Crizotinib for ALK+ NSCLC
*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
StudyPhase
(planned accrual)
HistologyLine of therapy
Study designPrimary endpoint
PROFILE 1014III
(334 pts)Non-squamous 1st
Platinum*-Pemetrexed vs Crizotinib
PFS≠
PROFILE 1007III
(318 pts)NSCLC 2nd
2nd line chemo** vs Crizotinib
PFS
PROFILE 1005II
(400 pts)NSCLC
3rd or more∞
Crizotinib monotherapy
ORR
ORR = overall response rate; PFS = progression-free survival; pts = patients
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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
Crizotinib for ALK+ NSCLC
∞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
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Tumor responses to crizotinib by patient
Median time to response: 8 wk
1. Camidge et al., ASCO 2011; Abs #25012. Riely et al., IASLC 2011; Abs #O31.05
PROFILE 10052PROFILE 10011
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Study Design
Key entry criteria
● ALK+ by central FISH testing
● Stage IIIB/IV NSCLC
● 1 prior chemotherapy
(platinum-based)
● ECOG PS 0−2
● Measurable disease
● Treated brain metastases allowed
N=318
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)
PROFILE 1007: NCT00932893
Endpoints
● Primary– PFS (RECIST 1.1,
independent radiology review)
● Secondary– ORR, DCR, DR– OS– Safety – Patient reported
outcomes (EORTC QLQ-C30, LC13)
RANDOMIZE
CROSSOVER TO CRIZOTINIB ON PROFILE 1005
aStratification factors: ECOG PS (0/1 vs 2), brain metastases (present/absent), and prior EGFR TKI (yes/no)
a
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aRECIST v1.1
65.3
19.5OR
R (
%)
ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P<0.001
Crizotinib (n=173)
PEM/DOC (n=174)
80
60
40
20
0Treatment
65.7
29.3
6.9
Crizotinib (n=172)
PEM (n=99)
DOC (n=72)
Treatment
80
60
40
20
0
ORR in PROFILE 1007
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Crizotinib
(n=172a)
PEM
(n=99b)
DOC
(n=72b)
Events, n (%) 100 (58) 72 (73) 54 (75)
Median, mo 7.7 4.2 2.6
HRc (95% CI) 0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43)
P <0.001 <0.001
Pro
babi
lity
of s
urvi
val w
ithou
t pr
ogre
ssio
n (%
)100
80
60
40
20
0
0 5 10 15 2025 Time (months)
172 93 38 11 2 0
99 36 12 3 1 0
72 13 3 1 0
No. at riskCrizotinib
PEMDOC
aExcludes 1 patient who did not receive study treatment; bexcludes 3 patients in chemotherapy arm who did not receive study treatment; cvs crizotinib
PROFILE 1007: PFS of Crizotinib vs Pemetrexed or Docetaxel
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Shaw, et al. NEJM 2013
Survival curves from PROFILE 1007
PFS OS
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Survival in ALK-positive NSCLC with crizotinib versus crizotinib-naive controls
0
0%
20%
40%
60%
80%
100%
Overall survival (years)1 2 3 4
ALK Crizotinib(n=30)
ALK Control(n=23)
Median Survival, mo NR 6
1-yr Survival, % 70 44
WT/WT Control(n=125)
11
47
From 2nd/3rd line crizotinib
2-yr Survival, % 55 12 32
HR = 0.49, p=0.02
Camidge D R , Lancet Oncol 2012; 13: 1011–19
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PROFILE 1014 Study Design
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Primary Endpoint Met: Crizotinib Superior to Pemetrexed-based Chemotherapy in Prolonging PFSa
T. Mok –ASCO 2014
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Secondary Endpoints: ORRa and OS
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Emerging issues in management of crizotinib-treated, ALK-positive patients
Crizotinib in ALK-positive
NSCLC
Brain metastases
Therapy for crizotinib-
resistant disease
Treatment beyond
progression
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OS from Start of Initial Crizotinib Treatment
Ou et al, Ann Oncol 2014
Median OS (95% CI) CBPD: 29.6 months (23.1−NR) No CBPD: 10.8 months (8.9−14.7)
HR=0.30 (0.19−0.46)p<0.0001
Number at riskContinued 120 104 30 61Did not continue 74 40 8 0
0 5 10 15 20 25 30 35 40Time (months)
100
80
60
40
20
0
Shaded areas are 95% Hall-Wellner confidence bands
Continued crizotinib
Did not continue crizotinibP
rob
abili
ty o
f su
rviv
al (
%)
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Otterson, et al. ASCO 2012
Organ sites in which new lesions developed and/or non-target lesions progressed in the Crizotinib-Beyond-PD group
OrganPatients with new lesions and/or non-
target 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)
Other 21 (18)
aExcluding patients with target lesions only: patients could be counted more than once across organ sites
Most common sites of PD in patients continuing crizotinib beyond PD
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Study Population: ALK+ NSCLC With or Without Brain Metastases at Baseline
1. Kim D-W, et al. J Clin Oncol 2012;30(Suppl.) (abstr. 7533); 2. Shaw AT, et al. N Engl J Med 2013;368:2385–2394Crinò et al. Poster presented at European Cancer Congress 2013 (abstract 3413)
Previously untreatedfor BM (n=109)
No BM detected(n=613)
RETROSPECTIVE ANALYSIS of crizotinib-treated patients with or without asymptomatic BM at baseline (n=888)
PROFILE 10051
(open-label,single-arm phase II)
Crizotinib 250 mg BID
PROFILE 10072
(randomized phase III vs. standard chemo)
Crizotinib 250 mg BID
Previously treatedfor BM (n=166)
● 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)
12% 19% 69%
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● 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
Crizotinib Antitumor Activity in Patients With or Without Brain Metastases at Baseline
Previously untreated
for BM (n=109)
Previously treated for BM (n=166)
No BM detected
(n=613)
n Outcome n Outcome n OutcomeDCR at 12 weeks, % (95% exact 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% exact CI)
IC 109 7 (3−14) 166 7 (4−12) NA
Patients with 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)
NA, not applicable; NR, not reachedaIn patients with confirmed objective response; bKaplan−Meier method; cBrookmeyer−Crowley method
Crinò et al. Poster presented at European Cancer Congress 2013 (abstract 3413)
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Emerging issues: 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.
INTRACRANIAL DISEASE CONTROL RATE AT 12 WEEKS IN PATIENTS WITH BASELINE ASYMPTOMATIC BRAIN METASTASES4BEST PERCENTAGE CHANGE IN INTRACRANIAL TARGET LESIONS
FROM BASELINE (%)
*Patients previously treated for brain metastases.
Best objective response according to RECIST.
** *
*
* **
* **
*
*Progressive disease Stable disease
Partial response Complete response
**
40
20
0
−20
−40
−60
−80
−100
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Frequencies of crizotinib resistance mechanisms in ALK+ NSCLC
Unknown 25%
Alk mutation 22-33% L1196M G1202R S1206Y G1269A 1151Tins Others
KIT amplification 10 %
Change in driver mutations5%
Alk amplification6-16%
Increased EGFR signaling30-35%
ALK non-dominant (Bypass tracks)
ALK dominant
Camidge D. R. Nat. Rev. Clin. Oncol. 11, 473–481 (2014) ;
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2nd generation ALK-TKIs
Acquired resistance
ALK translocated Crizotinib
All of them seem to be very good
1) Better affinity for ALK2) Better affinity for crizotinib resistant second-site mutated ALK 3) Improvement in pharmacokinetics to brain tissue and CSF
Options at acquired resistance to Crizotinib
Switch to chemotherapy
Crizotinib beyond progression +
CHT or Hsp90I
Crizotinib beyond progression
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Ceritinib: Highly Active Treatment <br />Option for ALK-Positive NSCLC
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Toxicity Challenges with Ceritinib
Presented By Howard West at 2014 ASCO Annual Meeting
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AP26113 IN CRIZOTINIB-RESISTANT ALK-REARRANGED NSCLC
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Ceritinib, Alectinib and AP26113, show antitumor activity in ALK+ NSCLC with brain metastasis
Mehra et al., ASCO (2012), abstr 3007Gettinger et al., ESMO (2012), abstr 4390Nishio et al., ESMO (2012), abstr 4410
6 wksBaseline LDK378
AP26113
CH5424802Baseline
8 wksBaseline
33 wks
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Tumor Responses to Crizotinib in ROS1-rearranged NSCLC
Shaw AT et al. N Engl J Med 2014.
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)
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Efficacy of crizotinib in MET-amplified NSCLC
aConfirmed objective responses.bBased on investigator assessment.cTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment.
Best percent change from baseline in target tumor lesionsa by patient
Low METn=2
Intermediate METn=6
High METn=6
100
80
60
40
20
0
–20
–40
–60
–80
–100
100
80
60
40
20
0
–20
–40
–60
–80
–100
Disease progressionStable diseasePartial responseb
Complete responseb
% C
han
ge
Fro
m B
asel
ine
100
80
60
40
20
0
–20
–40
–60
–80
–100
Threshold for partial responsec
c
Presented By D. Camidge at 2014 ASCO Annual Meeting
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Squamous cell cancer
Non-squamous cancer
Platinum + 3rd generation agent
EGFR WT, ALK neg
EGFR mut +
ALK/ROS1 rearranged
EGFR-TKI
ALK-TKI
EGFR WT/ALK neg, clinically selected
EGFR WT/ALK neg, clinically
unselectedPlatinum + Pemetrexed
Platinum-based doublet
+ Bevacizumab
Oncogene addicted
Biologically-unselected non-squamous NSCLC
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Istituto Toscano Tumori – Livorno, Italy
First-line therapy for metastatic NSCLC in 2014
Stratification for EGFR, ALK and histology
EGFR Mut+ ALK-/EGFRwt non-squamous
ALK-/EGFRwt squamous
EGFR TKIPlatinum doublet +
bevacizumabOR
platinum + pemetrexed
+/- bevacizumab
Platinum-based doublet
ALK rearranged
Crizotinib
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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