Jan 15, 2016
2
Lucio CrinòMedical Oncology Department
University Hospital Perugia, Italy
The optimal therapeutic algorithm for EML4-ALK
+ ve pts
“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
*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
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
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
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
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
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
Shaw, et al. NEJM 2013
Survival curves from PROFILE 1007
PFS OS
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
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
Crizotinib in ALK-positive
NSCLC
Brain metastases
Therapy for crizotinib-
resistant disease
Treatment beyond
progression
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 (
%)
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
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%
● 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)
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
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) ;
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
Ceritinib: Highly Active Treatment <br />Option for ALK-Positive NSCLC
Toxicity Challenges with Ceritinib
Presented By Howard West at 2014 ASCO Annual Meeting
AP26113 IN CRIZOTINIB-RESISTANT ALK-REARRANGED NSCLC
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
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)
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
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
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
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