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ALK +ive Lung Cancer: First line and
Resistance Disease
Professor Tony Mok
Li Shu Fan Medical Foundation Professor of Clinical Oncology
Dept of Clinical Oncology
The Chinese University of Hong Kong
DisclosuresAffiliation/Financial Interest Name of Organisation(s)
Grant/Research Support from: AstraZeneca, BI, BMS, Clovis Oncology, MSD, Novartis, Pfizer, Roche,
SFJ, XCovery
Lecture fees: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Novartis, BMS,
Taiho, Takeda Oncology, PrIME Oncology, Amoy Diagnostics Co., LTD.
Honoraria/Honorarium from: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD,
Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc. , Vertex
Pharmaceuticals, BMS, OncoGenex Pharmaceuticals, Inc., Celgene,
Ignyta, Inc., Fishawack Facilitate Ltd, Takeda Oncology, Janssen,
Hutchison Chi-Med, OrigiMed, Hengrui Therapeutics Inc., Sanofi-Aventis
R&D, Yuhan Corporation, PrIME Oncology, Amoy Diagnostics Co., LTD.,
Loxo-Oncology
Major Stock Shareholder in: Sanomics Ltd., Hutchison Chi-Med
Advisory Board for: AstraZeneca, BI, Roche/Genentech, Pfizer, Eli Lilly,
Merck Serono, MSD, Novartis, SFJ Pharmaceutical,
ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, geneDecode Co.,
Ltd., OncoGenex Technologies Inc., Celgene, Ignyta, Inc., Cirina,
Fishawack Facilitate Ltd., Janssen, Takeda, Hutchison Chi-Med, OrigiMed,
Hengrui Therapeutics Inc., Sanofi-Aventis R&D, Yuhan Corporation, Loxo-
Oncology
Board of Directors: IASLC, ASCO, Hutchison Chi-Med, Chinese Lung Cancer Research
Foundation Ltd., Chinese Society of Clinical Oncology (CSCO), Hong Kong
Cancer Therapy Society (HKCTS), Asian Thoracic Oncology Research
Group (ATORG), St. Stephen’s College & Prep. School
~250 kb ~300 kb
t(2;5) ALK gene
breakpoint region
2p23 regionTelomere Centromere
3’ 5’
FISH Assay for ALK Rearrangement
Break-apart FISH assay
for ALK-fusion genes1
ALK 29.3
EML4 42.3
ALK break-apart FISH assay[Courtesy John Iafrate, Massachusetts General Hospital]
1Shaw AT et al. J Clin Oncol
2009;27:4247–4253
1Shaw AT et al. J Clin Oncol
2009;27:4247–4253
q36.1
q36.3
q37.2
q34
q32.1
q32.3
q33.2
q31.3
q24.3
q24.1
q23.2q22.2
q22.1
q21.2
q14.3
q14.1
q12.3q12.1
p12
p13.2
p14
p16.1
p16.3
p22.1
p23.2
p22.3
p24.1
p24.3
p25.2
q36.1
q36.3
q37.2
q34
q32.1
q32.3
q33.2
q31.3
q24.3
q24.1
q23.2q22.2
q22.1
q21.2q14.3
q14.1
q12.3q12.1
p12
p13.2
p14
p16.1
p16.3
p22.1
p23.2
p22.3
p24.1
p24.3
p25.2
Split signal
Non-split signal
*Assay is positive if rearrangements can be detected in ≥15% of cellsFISH = fluorescence in situ hybridization
>15% cells
Concordance between FISH and IHC
Yatabe et al JTO 2015
Which biomarker to use?
FISH +ive
ALK TKI
IHC +ive
ALK TKI
IHC +ive
ALK TKI
FISH +ive
What happens to the IHC+/FISH- ive patient?
1 2 3
ALEX study: Biomarker analysis
• Patient with “ALK-positive” NSCLC will
benefit from first line ALK targeted
therapies
• Current definition of “ALK-positive” is based
on either FISH or IHC
• Discrepancy between FISH and IHC
occurs, and clinical outcomes on the
discrepant cases are not available.
• The ALEX trial provides a unique dataset to
assess ALK IHC- and FISH-based assays
regarding clinical outcome for alectinib and
crizotinib, particularly for the subset of
patients with IHC-positive/FISH-negative
(n=39) NSCLC
ALK status by IHC and FISH test in ALEX
Result, n (%) IHC FISH Total, n
Positive 303 (100) 203 (67)
Negative
-Alectinib
-Crizotinib
0 39 (12.9)
21
18
39
Uninformative
FISH result 0 33 (10.9) 33
Not done* 0 28 (9.2) 28
*Not enough adequate tissue/no tissue available for FISH test
Mok et al WCLC 2017
ALK IHC positive, FISH negative - outcomes
Crizotinib (n=18)
Alectinib (n=21)
Patients with event, n (%) 11 (61.1) 14 (66.7)
Median PFS,* months
(95% CI)
7.4
(2.7–NR)
3.8
(1.9−NR)
HR
(95% CI), P value
1.45
(0.59–3.53), 0.4132
12-month event free rate,
% (95% CI)
42.1
(17.0–67.1)
35.0
(14.1–55.9)
Difference, %
(95% CI), P value
7.1
(-25.6–39.7), 0.6715
Responders, % (95% CI) 44 (22−69) 29 (11−52)
CR, % 0 5
PR, % 44 24
SD, % 28 24
*Investigator-assessed; NR, not reached
First line therapy
PROFILE 1014 Study Design
Key entry criteria
● ALK-positive by central FISH testinga
● Locally advanced, recurrent, or metastatic non-squamous NSCLC
● No prior systemic treatment for advanced disease
● ECOG PS 0−2
● Measurable disease
● Stable treated brain metastases allowed
N=343
Crizotinib 250 mg BID PO, continuous dosing
(n=172)
Pemetrexed500 mg/m2
+ cisplatin 75 mg/m2 or carboplatin AUC 5–6
q3w for ≤6 cycles(n=171)
Solomon & Mok (co-first) et al NEJM Dec 2014
Endpoints
● Primary
– PFS (RECIST 1.1,
independent
radiologic review
[IRR])
● Secondary
– ORR
– OS
– Safety
– Patient-reported
outcomes
(EORTC QLQ-C30,
LC13)
RANDOMIZE
CROSSOVER TO CRIZOTINIB
PERMITTED AFTER PROGRESSIONc
aALK status determined using standard ALK break-apart FISH assay bStratification
factors: ECOG PS (0/1 vs. 2), Asian vs. non-Asian race, and brain metastases
(present vs. absent)cAssessed by IRR
b
PROFILE 1014
RN1
Slide 12
RN1 Can you confirm this reference is Solomon & Mok (co-first) et al NEJM Dec 2014?Rebecca Nunn, 01/09/2017
Intracranial DCR by IRR in Patients with Brain Metastases at Baseline
Solomon et al JCO 2016
Final Primary OS Analysis (ITT Population)
Median follow-up ~46
months in both arms
HR 0.760 (95%CI: 0.548 –
1.053); aP=0.0489
Crizotinib(N=172)
Chemotherapy(N=171)
Deaths, n (%) 71 (41.3) 81 (47.4)
Median OS (95% CI), months NR (45.8–NR) 47.5 (32.2–NR)
100
80
60
40
20
0
Overa
ll S
urv
ival (%
)
Months
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
172171
157150
144131
128118
111100
9889
8982
7973
6563
5146
3631
2021
811
11
00
+ Censored
No. at riskCrizotinibChemotherapy
a1-sided stratified log-rank test. P value <0.05 is not statistically significant as it was 1-sided
Mok et al ESMO 2017
15
Subsequent treatment, n (%) Crizotinib
(N=172)
Chemotherapy
(N=171)
Any ALK tyrosine kinase inhibitor (TKI)
Number of patients 57 (33.1) 145 (84.8)
Deaths, n (%) 11 (19.3) 66 (45.5)
Median OS, months (95% CI) NR (NR, NR) 49.5 (41.0, NR)
Treatment other than ALK TKI
Number of patients 37 (21.5) 3 (1.8)
Deaths, n (%) 25 (67.6) 2 (66.7)
Median OS, months (95% CI) 20.8 (14.4, 31.8) 12.1 (2.2, NR)
Impact of Subsequent Therapy on OS: ALK TKI versus Treatment Other Than ALK TKI
NR, not reached
1 2
3 4
No. at risk
Crizotinib followed by any ALK TKI
Crizotinib followed by any follow-up
therapy other than ALK TKI
Chemotherapy followed by any ALK TKI
Chemotherapy followed by any follow-
up therapy other than ALK TKI
100
80
60
40
20
0
Ove
rall
Su
rviv
al (%
)
Months
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
57
37
145
3
57
36
136
2
57
30
123
2
57
22
113
1
50
19
97
1
45
16
86
1
42
13
79
1
40
9
70
1
33
5
60
1
25
3
43
1
16
2
30
1
8
1
20
1
3
0
10
1
1
0
1
0
0
0
0
0
+ Censored
Impact of Subsequent Therapy on OS: ALK TKI versus Treatment Other Than ALK TKI
1
2
3
4
Second generation TKI
ALK
KDR
SRC
INSR
FGFR2
ABL
IGF1R
PDFGRβ
MET
RON
EGFR
HER2
KIT
CDK1
PKA
MEK1
PKCα
Raf-1
AKT1
PKCβ1
AuroraA
JAK1
CDK2
PKCβ2
110100100010000 110100100010000
ROS1
RET
ALK
KDR
SRC
INSR
FGFR2
ABL
IGF1R
PDFGRβ
MET
RON
EGFR
HER2
KIT
CDK1
PKA
MEK1
PKCα
Raf-1
AKT1
PKCβ1
AuroraA
JAK1
CDK2
PKCβ2
ROS1
RET
ROS1
IC50 (nM)
MET
Defining second generation: selectivity
RON
Cell-free kinase inhibition assay
Alectinib Crizotinib
Defining second generation: Potency
Mok et al Can Treat Report 2017
Ceritinib: Higher potency
Fribouler et al Cancer Discovery 2014
Defining second generation:
Targeting resistant mutations
• 1151T insertion – affects ATP affinity
• L1196M – gatekeeper mutation to prevent access of crizotinib into the binding pocket
• G1202R – solvent front mutation altering crizotinib binding
• C1156Y, L1152R, G1296A, F1174L –other mutations reported in the literature
Alectinib on resistant mutation
Ceritinib on resistant gene
Mok et al Can Treat Report 2017
The pump
• P-glycoproteins are ATP-driven pumps drugs out of the cells.
• Presence of P-gp in brain endothelial cell restrict permeability of hydrophobic compound.
• Prevent neurotransmitters from entering the brain (low lipid solubility and lack of specific transport carriers)
Defining second generation:
Better CNS penetration• Alectinib is a less-
effective substrate for
drug efflux proteins such
as
• Able to achieve higher
intra-CSF drug levels
• One report up to 87% of
CNS penetration rate
Baik et al JTO 2015
Ceritinib
ASCEND 4
RANDOMISE
Ceritinib 750mg
(n=174)
Pemetrexed/cisplatinOR
pemetrexed/carboplatin q3w
(n=174)
Pemetrexedq3w
Eligibility criteria:
● ALK-positive
locally
advanced/metastat
ic non-squamous
NSCLC
● No prior treatment
for advanced
disease
Primary endpoint = PFS
Soria et al Lancet 2017
ASCEND 4
Soria et al Lancet 2017
ASCEND 8: Randomized PK
study on lower dose with food
Cho et al JTO 2017
ASCEND 8
Cho et al JTO 2017
•DOR and PFS by BIRC Assessment∆
DOR Ceritinib 450 mg fed
(N = 32)
Ceritinib 600 mg fed
(N = 30)
Ceritinib 750 mg fasted
(N = 28)
Events, n (%) 6 (18.8) 6 (20.0) 11 (39.3)
Patients censored, n (%)
Ongoing without event or death
26 (81.2)
23 (71.9)
24 (80)
22 (73.3)
17 (60.7)
17 (60.7)
Median duration of response, months
(95% CI)Estimated 12-month DOR rate, % (95% CI)
16.4
(7.1-16.4)
74.6 (48.4-88.8)
NE
(6.9-NE)
72.5 (47.6-87.0)
10.4
(7.1-NE)
42.5 (18.1-65.2)
PFS Ceritinib 450 mg fed
(N = 41)
Ceritinib 600 mg fed
(N = 40)
Ceritinib 750 mg fasted
(N = 40)
Events, n (%) 12 (29.3) 13 (32.5) 17 (42.5)
Patients censored, n (%)
Ongoing without event or death
29 (70.7)
26 (63.4)
27 (67.5)
23 (57.5)
23 (57.5)
21 (52.5)
Median progression-free survival, months
(95% CI)Estimated 15-month PFS rate, % (95% CI)
17.6
(8.5-NE)
66.4 (46.5-80.4)
NE
(8.3-NE)
58.0 (35.9-74.8)
10.9
(6.3-NE)
41.0 (19.6-61.5)
ΔEfficacy-analysis
set
Cho et al ESMO Asia 2017
Should we use Ceritinib 450mg daily with food as
standard first line therapy?
Alectinib
J-ALEX Phase III Study Design
Stratification factors:
R1:1
Key Entry Criteria• Stage IIIB/IV or recurrent
ALK-positive NSCLC• ALK centralized testing
(IHC and FISH or RT-PCR)• ECOG PS 0-2• ≥1 measurable lesion
assessed by investigator• Treated/asymptomatic brain
metastases allowed• ≤1 prior chemotherapy
Alectinib 300 mg BID PO, 28-day cycle
(N=100)
Crizotinib 250 mg BID PO, 28-day cycle
(N=100)
Endpoints• Primary
- PFS assessed by IRF*
• Secondary- OS- ORR- PK- QOL- CNS PFS- Safety
Clinical stage (IIIB/IV vs. Recurrent)Prior chemotherapy (0 vs. 1)ECOG PS (0/1 vs. 2)
JapicCTI-132316
*IRF Independent Review Facility
Hiroshi Nokihara ASCO 2016
J-ALEX: PFS
Alectinib(N=103)
Crizotinib(N=104)
Events, n (%) 25 (24.3%) 58 (55.8%)
Median, mo [95% CI] NR [20.3 - NR] 10.2 [8.2 - 12.0]
P-value <0.0001
HR [99.6826% CI] 0.34 [0.17 - 0.71]
Hida et al Lancet 2017
Global ALEX study (with differences from J-ALEX)
KEY ELIGIBILITY
● Advanced or metastatic
ALK+ NSCLC
● ALK+ by central IHC
testing
● Treatment-naïve
● ECOG PS 0−2
● Measurable disease
● Asymptomatic brain
metastases allowed
Alectinib600mg BID PO
Crizotinib250mg BID PO
RANDOMIZE
NO CROSSOVER
per protocol
Stratification factors: • ECOG PS (0/1 vs 2) • Race (Asian vs non-Asian) • Brain metastases (present vs absent)
N=286
ENDPOINTS
● Primary
– PFS (RECIST 1.1) by
investigator review
● Secondary
– PFS by IRC
– Time to CNS progression
– ORR, DOR
– OS
– Safety and tolerability
– Patient-reported
outcomes
Randomized 1:1
IHC, immunohistochemistry; ECOG PS, Eastern Cooperative Oncology Group performance status; PO, by mouth; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors;
IRC, independent review committee; ORR, objective response rate; DOR, duration of response; OS, overall survival
Peter and Mok NEJM 2017
ALEX Study: PFS
Peter and Mok NEJM 2017
ALEX: Toxicity profile
Peter and Mok NEJM 2017
Highly effective systemic therapy for CNS disease
Peter and Mok et al NEJM 2017
G-ALEX: PFS of alectinib vs crizotinibin patients with and without BM
Peter and Mok NEJM 2017
*investigator-assessed; †All patients with CNS metastases at baseline, irrespective of radiotherapy
G-ALEX: Time to CNS progression by prior brain RT*
Gadgeel et al. ESMO 2017;
Stage IIIB/IV ALK+ NSCLC• Asian patients• Treatment naïve • ECOG PS 0–2• Central ALK testing
(Ventana IHC)
R2:1
Alectinib 600mg twice daily
(n=125)
Crizotinib 250mg twice daily
(n=62)
N=187
DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance
status
IHC, immunohistochemistry; IRC, Independent Review Committee; ORR, objective response
rate
OS, overall survival; RECIST, Response Evaluation Criteria in Solid Tumors
Stratification• ECOG PS (0 /1 vs 2)
• Baseline CNS metastases (yes
vs no)Primary endpoint• Investigator-assessed PFS1 Key secondary endpoints
• PFS by IRC
• Time to CNS progression (IRC
RECIST v1.1)
• Investigator-assessed ORR and DoR
• OS
2 • CNS ORR
• Safety and
tolerability
• Quality of life
• Pharmacokinetics
No crossover
permitted
ALESIA: STUDY DESIGN
Zhou et al ESMO 2018
0
20
40
60
100
Day 1 6 15 21
80
Pro
gre
ssio
n-f
ree
su
rviv
al,
%
Time (months)
PROGRESSION-FREE SURVIVAL (INVESTIGATOR)
181293
Alectinib (n=125)
Crizotinib (n=62)
Censored
Primary endpoint
Primary data cut-off: 31 May, 2018
Median duration of follow up (alectinib vs crizotinib): 16.2 vs 15.0 months
The p-values presented for the efficacy endpoints are descriptive only
NE, not estimable
Alectinib
(n=125)
Crizotinib
(n=62)
Patients with event, n (%) 26 (20.8) 37 (59.7)
Median PFS, months
(95% CI)
NE
(20.3–NE)
11.1
(9.1–13.0)
HR (95% CI)
P-value (log-rank test)
0.22(0.13–0.38)
P<0.000111.1 months
NE
TIME TO CNS PROGRESSION (IRC)
0
20
40
60
100
0 6 12 18
80
Cu
mu
lati
ve
inci
de
nce
* (
%)
Time (months)
• A competing risk analysis with CNS progression, non-CNS progression and
death as competing events was conducted; for each patient, only the first
event was counted
Alectinib
(n=125)
Crizotinib
(n=62)
Patients with event, n (%) 12 (9.6) 22 (35.5)
Cause-specific HR
(95% CI)
P-value (log-rank test)
0.14
(0.06–0.30)
P<0.0001
Primary data cut-off: 31 May, 2018; IRC by RECIST v1.1
The p-values presented for the efficacy endpoints are descriptive only
Alectinib (n=125)
Crizotinib (n=62)
*Cumulative incidence of CNS progression without prior non-CNS
progression or death
7.3%
35.5%
(95% CI 3.6–12.8)
(95% CI 23.5–47.8)
Three trials with differences in designJ-ALEX Global ALEX ALESIA
Sample size 207 303 187
Age 60 55 50
Stage IV 74% (+ 23%
recurrence)
96% 91%
Never smoker 56% 63% 69%
Prior chemo 36% 0% 8.5%
CNS met 16% 40% 36%
Randomization 1 to 1 1 to 1 2 to 1
Race All Japanese 46% Asian All Asian
Stratification Exclude CNS met Include CNS met Include CNS met
Dose 300mg bd 600mg bd 600mg bd
Prior RT to brain NA 15.5% 7%
Primary endpoint PFS by IRC PFS by investigator PFS by investigator
No difference in key outcome
0
20
40
60
100
Day 1 6 15 21
80
Pro
gre
ssio
n-f
ree
su
rviv
al,
%
Time (months)
181293
Alectinib (n=125)
Crizotinib (n=62)
Censored
Primary endpoint
11.1 months
NE
J-ALEX (HR 0.34) Global ALEX (HR 0.47)
ALESIA
(HR 0.22)
Alectinib Crizotinib
I am better than
you!
I am better than I am better than
you!
I am better than
you!
I am better than
you!
You are very
annoying
ALTA-1L: Phase 3, Open-label, Randomized, Multicenter, Study (NCT02737501)
• Primary endpoint: Blinded independent review committee (BIRC)–assessed PFS per RECIST v1.1
• Key secondary endpoints: Confirmed ORR, confirmed intracranial ORR, intracranial PFS, OS, safety, and tolerability
• Statistical considerations: ~270 total patients (198 events); 135 in each arm to detect a 6-month improvement in PFS (HR=0.625), assuming:– 10-month PFS in crizotinib arm– 2 planned interim analyses at 99 (50%) and 149 (75%) total expected events
First interim analysis:• A total of 99 PFS events are included• According to the prespecified O’Brien-Fleming Lan-DeMets alpha spending function, a 2-sided P value of 0.0031 was used
to define the threshold for significance
Stratified by:
• Brain metastases at baseline (y/n)• Prior chemotherapy for locally advanced
or metastatic disease (y/n)
Randomized1:1
Brigatinib 180 mg qd with 7-day
lead-in at 90 mg
Crizotinib 250 mg bid
• Stage IIIB/IV ALK+ NSCLC
‒ Enrollment based on local
ALK testing
• No prior ALK inhibitor
• ≤1 prior systemic therapy for
locally advanced/metastatic
NSCLC
• BIRC-assessed PD*
• Intolerable toxicity
• Other reasons for
discontinuation
Trial fully accrued in August 2017 (N=275)
*Arm B crossover to brigatinib permitted at
BIRC-assessed PD
Disease assessment every 8 weeks, including brain MRI for all patients
• Investigator-assessed median PFS was NR (95% CI, NR–NR) in the
brigatinib arm and 9.2 months (95% CI, 7.4–12.9 months) in the crizotinib arm (HR, 0.45 [95% CI, 0.30–0.68]; log-rank P=0.0001)
• 1-year OS probability: brigatinib, 85% (95% CI, 76%–91%); crizotinib, 86% (77%–91%)
Primary Endpoint: BIRC-Assessed PFS
Brigatinib met the prespecified threshold for
statistical superiority vs crizotinib
Treatment
No. (%) of Patients
With EventsMedian PFS
(95% CI)1-Year PFS, %
(95% CI)
Brigatinib (n=137)
36 (26)
NR (NR–NR)
67
(56–75)
Crizotinib (n=138)
63 (46)
9.8 months (9.0–12.9)
43
(32–53)
Intracranial PFS in Patients With Any Brain Metastases at Baseline
Treatment
Median Intracranial
PFS (95% CI)
1-Year PFS
Probability, % (95%
CI)
Brigatinib (n=43)
NR (11.0–NR) 67 (47–80)
Crizotinib (n=47)
5.6 months (4.1–9.2)
21 (6–42)
Ongoing phase III studies
Drug Sample size
Primary endpoint
Study starting date
Clinical trial number
Ensartinib
vs
crizotinib
402 PFS June
2016
NCT02767804
Lorlatinib
vs
crizotinib
280 PFS April
2017
NCT03052608
Resistance
Mechanisms of resistances ALK TKIs
ALK resistance
mutations
Bypass pathways
activation
CNS metastasisHistological
transformation
Preclinical TKI activity against ALK point mutants
1st gen 3rd genCrizotinib Alectinib Brigatinib Ceritinib Lorlatinib
G1123S Res Sens N/D Res N/D
1151Tins Res Sens Sens Res Sens
L1152P/R Res Sens N/D Res Sens
C1156Y/T Res Sens Sens Res Sens
I1171T/N Res Res Sens Sens N/D
F1174C/L/V Res Sens Sens Res Sens
V1180L Res Res N/D Sens N/D
L1196M Res Sens Sens Sens Sens
L1198F Sens Res Res Res Res
G1202R Res Res Sens Res Sens
S1206C/Y Res Sens Res Sens Sens
F1245C Res N/D Sens Sens N/D
G1269A/S Res Sens Sens Sens Sens
2nd gen
ALK Mutation Type And New ALK TKI Efficacy
Adopted from Lovly, ELCC 2016; Friboulet Cancer Disc 2014, Gainor Cancer Disc 2016, Mologni, Oncotarget 2015
b124
26
14
27
No Mutation
1 ALK Mutation
>1 ALK Mutation
Other
C1156YD1160HD1203NE1129VE1161DE1210K/QF1174C/L/VF1245CG1128AG1202R/delG1269AI1171N/S/TL1122VL1196ML1198FN1335KP1213HP1329SR1113QR1192PT1151KT1151MV1180L
139
28
176
No Mutation
1 ALK Mutation
>1 ALK Mutation
Other
Tumor tissue analysis (archival or de novo):
- 40/191 (21%) patients with 1 or more ALK
kinase domain mutations
- 58 mutations detected (used for the
frequency denominator)
cfDNA analysis:
- 45/190 patients (24%) with 1 or more ALK
kinase domain mutations
- 75 mutations detected (used for the
frequency denominator)
Spectrum of ALK resistance mutations detected from tumor or liquid biopsy in Lorlatinib phase 2 study (Shaw et al, AACR 2018)
aNo mutation includes samples with no cfDNA was detected; bOther includes samples which failed analysis, were uninformative or not analyzed.
G1202R/del27.6%
F1174C/L/V17.2%
a
b
C1156YD1160HD1203NE1129VE1161DE1210K/QF1174C/L/VF1245CG1128AG1202R/delG1269AI1171N/S/TL1122VL1196ML1198FN1335KP1213HP1329SR1113QR1192PT1151KT1151MV1180L
F1174C/L/V14.7%
G1202R/del25.0%
L1196M14.7%
Bypass pathways reported in literature as resistance to ALK TKIs
56
ALK TKI Bypass Pathway Reference
Crizotinib EGFR Activation Katayama et al 2012Doebele et al 2012
Sasaki et al 2011
cKIT amplification Katayama et al 2012
IGF-1R Signaling Lovely et al 2014
SRC Signaling Crystal et al 2014
Crizotinib/Ceritinib MAPK Pathway Activation
Doebele et al 2012Crystal et al 2014
RAS Pathway Dardaei et al 2018
Alectinib MET amplification Gouji et al 2014
ASCEND-9: phase II study, of ceritinib after alectinib (300 mg BID)
in Japanese patients
• *% change in target lesion available but contradicted by overall lesion response = PD (contradicting assessment represents the only valid post-baseline assessment)
• Ceritinib is not licenced for use post-ALECENSA
Horinouchi et al. WCLC 2017; Hida et al. Cancer Sci 2018
Ceritinib demonstrated clinical
benefit in Japanese patients
who progressed on alectinib
(alectinib only [n=16];
alectinib and crizotinib [n=4])
• Median PFS: 3.7 months
• Median DoR: 6.3 months
• ORR: 25% (5/20 patients) Be
st %
ch
an
ge
fro
m b
ase
line
(m
ea
su
rab
le le
sio
ns)
Ceritinib 750mg (n=17)
Prior therapies:
ALECENSA + crizotinib
ALECENSA
☨ Chemotherapy
* *
☨
☨ ☨
☨
☨
☨
☨
☨
☨
☨
100
80
60
40
20
0
–20
–40
–60
–80
–100
ALTA II Study
� Open-label, randomized, multicenter, international phase II study to
prospectively assess brigatinib efficacy and safety at 90 mg once daily
and 180 mg once daily (with lead-in) in patients with crizotinib-
refractory advanced ALK-positive NSCLC.
Primary Efficacy Endpoint:
�confirmed ORR per RECIST v1.1 (per investigator)
Secondary endpoints:
� confirmed ORR (per central IRC)
Results – response
Investigator Assessed IRC Assesseda
Efficacy Parameter 90 mg once daily
(n = 112)
90 mg ���� 180 mg once
daily(n = 110)
90 mg once daily
(n = 112)
90 mg ���� 180 mg once daily
(n = 110)
Confirmed ORR, n (%)
[97.5% CI]b or [95% CI], %
50 (45)[34-56]b
61 (55)[44-65]b
55 (49)[40-59]
59 (54)[44-63]
Confirmed CR, n (%) 2 (2) 6 (5) 4 (4) 6 (5)
Confirmed PR, n (%) 48 (43) 55 (50) 50 (45) 54 (49)
DCR, n (%)[95% CI]
91 (81)[73-88]
95 (86)[79-92]
87 (78)[69-85]
92 (84)[75-90]
Median DOR, months[95% CI]
12.0[7.4-NR]
13.8[9.2-NR]
13.8[7.4-NR]
15.6[9.7-NR]
The IRC-assessed confirmed ORR was 49% in the 90-mg arm and 54% in the 90-mg � 180-mg once daily arm
The IRC-assessed median DOR was 13.8 months in the 90-mg once daily arm and 15.6 months in the 90-mg � 180-mg once daily arm
PFS by Arm
Events / Total (%)
1-Year PFS Probability, %
(95% CI)
Median PFS (95% CI)
Hazard Ratio(95% CI)†
90 mg qd 50/112 (45)
39(27–52)
9.2 months(7.4–15.6)
0.55 (0.35–0.86)180 mg qd* 31/110
(28)54
(37–68)12.9 months
(11.1–notreached)
* 180 mg qd with 7-day lead-in at 90 mg† Study was not designed to compare treatment arms statistically; however, post hoc comparisons were performed to support dose selection
Pro
ba
bil
ity
of
PF
S (
%)
Median PFS exceeds 1 year (12.9 months)
with 180 mg brigatinib
Brigatinib CNS Antitumor Activity by Arm
Brigatinib Pivotal Randomized Phase 2 Trial
Presented by: Dr. Dong-Wan Kim
Dotted line at –30% indicates threshold for partial response per RECIST v1.1* Single response awaiting confirmation† Includes patients with active brain metastases at baseline (90 mg qd, n=16; 180 mg qd, n=14)‡ 180 mg qd with 7-day lead-in at 90 mgǁ Category includes single responses that were not confirmed
–20
–40
–60
–80
–100
0
20
40
Be
st
Ch
an
ge
Fro
m B
as
eli
ne
in
Ta
rge
t L
es
ion
s (
%)
90 mg qd† 180 mg qd† ‡
*
–20
–40
–60
–80
–100
0
20
40
*
*
Last scan date: February 17, 2016
Partial response Complete responseProgressive disease Stable diseaseǁ
Brigantinib: a retrospective study of brigatinib in
patients pretreated with alectinib
• *18 patients had measurable disease at
baseline
Lin et al, Lin et al, Lin et al, Lin et al, J J J J ThoracThoracThoracThorac Oncol Oncol Oncol Oncol 2018; 13: 15302018; 13: 15302018; 13: 15302018; 13: 1530----1538153815381538
Brigatinib demonstrated clinical activity in heavily pre-treated patients who had previously received ALECENSA (n=22)
Collaboration among Massachusetts General hospital, University of California Irvine, and MSKCC
Baseline characteristicsAll patients
(N=22)
Lines of systemic therapy before alectinib012≥3
3 (14%)12 (55%)6 (27%)1 (5%)
Intervening lines of therapy between alectinib andbrigatinib
015
19 (86%)2 (9%)1 (6%)
Number of ALK TKIs prior to brigatinib123
5 (23%)13 (59%)4 (18%)
• Median PFS: 4.4 months
• Median DoR: 5.7 months
• ORR: 17% (3/18 patients*)
Time (months)
Pro
gre
ss
ion
-fre
e s
urv
iva
l (%
)
1322 9 4 1 0
Number at risk
100
80
60
40
20
0
0 2 4 6 8 10
Brigatinib-2002: phase II study of brigatinib in patients
pre-treated with alectinib or ceritinib
• Clinicaltrials.gov Clinicaltrials.gov Clinicaltrials.gov Clinicaltrials.gov
(NCT03535740)(NCT03535740)(NCT03535740)(NCT03535740)
Brigatinib
180mg QD
• Locally advanced Stage IIIB
or Stage IV NSCLC
• ALK+ disease confirmed
by IHC or FISH
• Progressive disease on
prior treatment with
alectinib or ceritinib
Primary endpoint
• Confirmed ORR
1
2 Secondary endpoints
• DoR
• ORR
• PFS
• DCR
• TTR
• OS
• iORR
• Duration of intracranial
response
• iPFS
• Safety
• PROs
• 54 patients (41 ALK positive, 13 ROS1)
• 72% with CNS met
• All had prior TKIs
• MTD not reached
Shaw et al Lancet Oncology 2017
Response rate
RR 46% for ITT
RR 41% for 2 or more line of TKI
CNS response
RR 31%
Schema of Lorlatinib Phase 2 design
Solomon et al, Lancet Oncol 2018 in press
Efficacy in ALK+ Patients Previously Treated with 2G ALK TKIs (EXP3B and EXP4–5)
68
70
60
10
0
30
20
50
40
‒10
‒20
‒30
‒40
‒50
‒60
‒70
‒80
‒90
‒100
Best
Ch
an
ge F
rom
Baselin
e (
%)
Overalla,b
Off treatment or PD occurred
Complete response
Partial response
Stable disease
Progressive disease (PD)
Indeterminate
EXP3B: 1 non-crizotinib TKI ±chemo (n=27)
ORR, n/N (%) (95% CI)
9/27 (33)(16, 54)
IC ORR, n/N (%) (95% CI)
5/12 (42)(15, 72)
Median PFS, mo(95% CI)
5.5 (2.9, 9.0)
70
60
10
0
30
20
50
40
‒10
‒20
‒30
‒40
‒50
‒60
‒70
‒80
‒90
‒100B
est
Ch
an
ge F
rom
Baselin
e (
%)
Overalla,b
Complete response
Partial response
Stable disease
Progressive disease (PD)
Indeterminate Off treatment or PD occurred
EXP4–5: ≥2 prior ALK TKIs ±chemo (n=111)
ORR, n/N (%) (95% CI)
43/111 (39)(30, 49)
IC ORR, n/N (%) (95% CI)
40/83 (48)(37, 59)
Median PFS, mo(95% CI)
6.9(5.4, 9.5)
a Patients with at least one on-study target lesion assessment as per independent central review were included. If any procedure was different and not interchangeable from the procedure at screening, the percent change from baseline could not be calculated and is
not displayed.b Complete response was defined as the disappearance of all target lesions; when nodal disease was included in target lesions, reversion to normal node size (<10 mm) prevented the percent change from baseline from reaching –100%. Some patients with a total
change from baseline of –100% are shown as partial responses due to the inclusion of non-target lesions in the summary.
Solomon BJ, et al. J Thorac Oncol:2017;12:abs1756 (Data cut-off: 15 Mar 2017).
Cumulative incidence of CNS progression, non-CNS progression, and death in patients with ≥1 prior 2nd-gen ALK TKI (EXP3B–5)
Patients with baseline CNS mets(n=94)
Patients without baseline CNS mets(n=45)
For patients with baseline CNS mets, the probabilities of non-CNS PD was higher than CNS PD (35% vs 23% at 12 months).
Patients without baseline CNS mets had a higher probability of non-CNS PD than CNS PD (55% vs 12% at 12 months).
In EXP3B and EXP4–5, IC-ORR* was 46% (95% CI 19–75) and 48% (95% CI 37–60), and median IC-DOR was NR (95% CI 4 mos–NR) and 15 mos (95% CI 11–NR), respectively.
Cumulative no. of events
Cu
mu
lati
ve in
cid
en
ce f
un
cti
on
Time (months)
1.0
0.8
0.6
0.4
0.1
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 1514
0.2
0.3
0.5
0.7
0.9
0 0 6 6 8 9 12 14 15 17 18 18 20 20 22210 0 6 10 13 17 22 23 25 27 28 28 30 33 3636
0 1 3 6 6 6 6 6 6 6 6 6 6 6 66
CND PDNon-CNS PD
Death
CNS PDNon-CNS PDDeath
CNS PDNon-CNS PDDeath
Cumulative no. of events
Cu
mu
lati
ve in
cid
en
ce f
un
cti
on
Time (months)
1.0
0.8
0.6
0.4
0.1
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 1514
0.2
0.3
0.5
0.7
0.9
0 0 3 5 5 5 5 5 5 5 5 5 5 5 550 1 5 8 11 12 15 18 19 20 21 21 22 22 2323
0 0 0 1 2 2 2 3 3 3 3 3 3 3 33
CNS PD
Non-CNS PD
Death
Bauer et al, WCLC 2018
Summary• First line
– Both Alectinib and Brigatinib is superior to crizotinib in
PFS and CNS control
– Phase III studies on other second/third generation TKI
are ongoing
• Resistance
– Multiple mechanism of resistance
– Brigatinib: promising phase II data on Alectinib failure
– Loratinib: promising phase I /II data
Populated Landscape
