year in review: therapeutic advances in treating …...– asco chicago 2017 – esmo madrid 2017...
TRANSCRIPT
Year in Review: Therapeutic Advances in Treating Advanced NSCLC
2017 Conversations in Oncology in Shanghai, China
Barbara Melosky
BI Symposium
2
• Discuss the current treatment algorithms in non-squamous NSCLC
• Provide an overview of recent advances: review updates from
– ELCC Geneva 2017
– ASCO Chicago 2017
– ESMO Madrid 2017
– WCLC Japan 2017
Outline
3
Molecular Classification of NSCLC: 2017
Rosell and Karachaliou. Lancet. 2016;387:154-155.
Mutations in Adenocarcinoma
4
Driver Mutations in Adenocarcinoma
1. Barlesi F et al. Lancet. 2016;387:1415-1426; 2. Kris MG et al. JAMA. 2014;311:1998-2006; 3. Zheng D Oncotarget. 2016;7:41691-41702.
China3
5
EGFR Mutations
6
Del19 and L858R: Most Common Mutations in
the Tyrosine Kinase Domain of EGFR in NSCLC
Sharma et al. Nat Rev Cancer. 2007;7:169.
Del19 = exon 19 deletions; EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; L858R = exon 21 L858R point mutation;
NSCLC = non–small cell lung cancer.
7
IPASS: PFS1 EURTAC: PFS2
1. Mok et al. N Engl J Med. 2009;361:947; 2. Rosell et al. Lancet Oncol. 2012;13:239.
9.5 months 10.4 months
• Gefitinib: 9.5 months
• Chemotherapy: 6.3 months
– HR 0.48; 95% CI 0.36-0.64; P<0.001
• Erlotinib: 10.4 months
• Chemotherapy: 5.2 months
– HR 0.34; 95% CI 0.23, 0.49; P<0.001
8
Sub-group analyses of progression-free survival in the
intention-to-treat population2
Exon 19 Del
L858R
L858R
HR = 0.43
HR = 0.81
1. Wu et al. Lung Cancer. 2017;104:119-125; 2. Rosell et al. Lancet Oncol. 2012;13:239.
IPASS: PFS1 EURTAC: PFS2
9
IPASS1: OS EGFR Mutation + EURTAC2 Overall Survival
Overall Survival
1. Wu et al. Lung Cancer. 2017;104:119-125; 2. Rosell et al. Lancet Oncol. 2012;13:239.
10
LUX-Lung 3 and LUX-Lung 6:
Significant Improvement in PFS
1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213; 3. Data on file. Boehringer Ingelheim.
Time of Progression Free Survival (Months)
Es
tim
ate
d P
FS
Pro
ba
bilit
y
Afatinib LUX-Lung 3
Cis/Pem LUX-Lung 3
Afatinib LUX-Lung 6
Cis/Gem LUX-Lung 6
No. at risk:
LL3 Afatinib 204 169 143 115 75 49 30 10 3 0
LL3 Cis/Pem 104 62 35 17 9 6 2 2 0 0
LL6 Afatinib 216 186 152 116 82 55 33 11 4 0
LL6 Cis/Gem 62 21 7 1 0 0 0 0 0 0
0 3 6 9 12 15 18 21 24 27
0.0
0.2
0.4
0.6
0.8
1.0 LUX-Lung 31 (n=308)
Afatinib vs Cis/Pem
LUX-Lung 62,3 (n=324)
Afatinib vs Cis/Gem
Median PFS 13.6 mo vs 6.9 mo 11.0 mo vs 5.6 mo
HR for PFS 0.47, P<0.0001 0.25, P<0.0001
*Exon 19 deletions or exon 21 [L858R] substitutions.
PFS = progression-free survival.
13.6 mo. in LL3
11.0 mo in LL6
Patients with common mutations*
11
LUX-Lung 6
LUX-Lung 3 and LUX-Lung 6:
OS in Del19 Subgroup
Yang et al. Lancet Oncol. 2015;16:141.
112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 0
57 55 50 46 43 37 33 27 25 22 20 16 10 6 1 1 0 0
Afatinib
Cis/Pem
No. at risk:
124 122 118 115 106 99 90 80 73 69 59 39 16 8 1 0
62 58 53 49 44 35 30 28 26 21 18 11 4 3 0 0
1.0
0.8
0.6
0.4
0.2
0
Esti
mate
d O
S P
rob
ab
ilit
y
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (Months)
1.0
0.8
0.6
0.4
0.2
0
Esti
mate
d O
S P
rob
ab
ilit
y
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Time (Months)
Afatinib
Cis/Gem
No. at risk:
Afatinib
Cis/Pem
Afatinib
Cis/Gem
IMPRESSIVE
33.3 months 31.4 months
Prespecified Endpoint
LUX-Lung 3
Afatinib
(n=112)
Cis/Pem
(n=57)
Median,
months 33.3 21.1
HR (95% CI)
P-value
0.54 (0.36–0.79)
P=0.0015
Afatinib
(n=124)
Cis/Gem
(n=62)
Median,
months 31.4 18.4
HR (95% CI)
P-value
0.64 (0.44–0.94)
P=0.0229
12
The Impact of 1st-line TKIs on OS: Meta-Analysis of
Phase III Trials by Mutation Type – Del19
Kato et al. ISPOR 2015. PCN40.
Agent Study Hazard Ratio
(95% CI)
Afatinib
LUX-Lung 3 0.53 (0.36-0.79)
LUX-Lung 6 0.64 (0.44-0.94)
Total 0.59 (0.45-0.77)
Erlotinib
ENSURE 0.79 (0.48-1.30)
EURTAC 0.94 (0.57-1.54)
OPTIMAL 1.52 (0.91-2.52)
Total 1.04 (0.71-1.51)
Gefitinib
IPASS 0.86 (0.61-1.22)
NEJ002 0.83 (0.52-1.34)
WJTOG3405 1.19 (0.65-2.18)
Total 0.90 (0.70-1.17)
13
LUX-Lung 7
Park et al. ESMO Asia. December 2015.
ESMO ASIA 2015
*Central or local test. †Dose modification to 50, 30, 20 mg permitted in line with prescribing information.
Co-primary endpoints:
• PFS
(independent review)
• TTF
• OS
Secondary endpoints:
• ORR
• Time to response
• Duration of response
• Tumour shrinkage
• HRQoL
• Stage IIIB/IV
adenocarcinoma of
the lung
• EGFR mutation
(Del19 and/or L858R)
in the tumour tissue*
• No prior treatment for
advanced/metastatic
disease
• ECOG PS 0/1
Stratified by:
• Mutation type (Del19/L858R)
• Brain metastases
(present/absent)
• Treatment beyond progression allowed if deemed beneficial by investigator
• RECIST assessment performed at Weeks 4 and 8, and every 8 weeks thereafter until Week 64, and
every 12 weeks thereafter
1:1
Afatinib
40 mg QD†
Gefitinib
250 mg QD
14
Afatinib Gefitinib
Median, mo 11.0 10.9
HR (95% CI)
P-value
0.74 (0.57-0.95)
0.0178
Afatinib vs Gefitinib: Updated Outcomes – PFS
Paz-Ares L et al. Ann Oncol. 2017, epub ahead of print.
Es
tim
ate
d P
FS
pro
bab
ilit
y
0 3 6 9 12 18 15 21 24 27 30 33 36 39 42 45 48 51
1.0
0.8
0.6
0.4
0.2
0
Time (months)
160 142 113 94 67 47 34 26 20 13 10 8 4 3 0 0 0 0
159 132 105 82 51 21 15 10 7 5 5 3 3 3 0 0 0 0
No. at risk: Afatinib
Gefitinib
16%
7%
Afatinib
Gefitinib HR .74
15 *P=0.0067; †P=0.0029.
TTF = time from randomization to discontinuation for any reason.
Afatinib vs Gefitinib: Updated Outcomes – TTF
Park K et al. Lancet Oncol. 2016;17(5):577-89.
No. at risk:
Afatinib 160 148 133 113 91 68 56 48 40 25 18 9 5 0 0
Gefitinib 159 144 120 103 74 59 43 30 21 11 6 6 2 2 0
Afatinib Gefitinib
Median, mo 13.7 11.5
HR (95% CI)
P-value
0.73 (0.58-0.92)
0.0073
Time to treatment failure (months)
Es
tim
ate
d p
rob
ab
ilit
y o
f b
ein
g
free
of
trea
tmen
t fa
ilu
re
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
25%*
13%
Afatinib
Gefitinib
13.7 vs 11.5 months
16
0%
20%
40%
60%
80%
ITT Del19 L858R
OR
R
Afatinib vs Gefitinib: Objective Response and
Disease Control Rate by Independent Review
Paz-Ares L et al. Ann Oncol. 2017, epub ahead of print.
P=0.002
73%
56%
69%
42%
75%
66%
Afatinib Gefitinib
Median DoR , months
(95% CI)
10.1
(8.2, 11.1)
8.3
(7.3 – 10.2)
Disease control rate (N) 91.3% (146) 87.4% (139)
P=0.150 P=0.003
Afatinib
Gefitinib
69% vs 42% 73% vs 56%
17
Updated Overall Survival From LUX-Lung 7
Corral J et al. ELCC 2017; #93PD.
No. at risk:
Afatinib 160 153 139 111 94 74 59 41 23 2 0
Gefitinib 159 148 133 105 80 62 53 39 22 2 0
Afatinib Gefitinib
Median, mo 27.9 24.5
HR (95% CI)
P-value
0.85 (0.66, 1.09)
0.1950
0.8
1.0
0.6
0.4
0.2
0
0 6 12 18 24 54 48 42 36 30 60
61%
51%
28%
20%
Time to death (months)
Es
tim
ate
d o
ve
rall
su
rviv
al
pro
bab
ilit
y
Afatinib
Gefitinib
ELCC 2017
27.9 vs 24.5 months
18
OS By EGFR Mutation Subtype
Corral J et al. ELCC 2017; #93PD.
Del19 L858R
Afatinib
Gefitinib
0 6 12 18 24 30 36 42 48
93 88 82 68 61 50 40 27 17
93 86 79 66 52 39 33 24 15
0
Es
tim
ate
d O
S p
rob
ab
ilit
y
Time (months)
Afatinib
Gefitinib
No. at risk:
1.0
0.8
0.6
0.4
0.2
54
1
1
0 6 12 18 24 30 36 42 48
67 65 57 43 33 24 19 14 6
66 62 54 39 28 23 20 15 7
0
Time (months)
1.0
0.8
0.6
0.4
0.2
54
1
1
Afatinib Gefitinib
Median, mo 30.7 26.4
HR (95% CI)
P-value
0.82 (0.58-1.15)
0.242
Afatinib Gefitinib
Median, mo 25.0 21.2
HR (95% CI)
P-value
0.89 (0.61-1.31)
0.566
ELCC 2017
19
LUX-Lung 7: Side Effects
Park et al. ESMO Asia, 2015. Abstract LBA2_PR.
Four cases of ILD
three of them ≥ grade 3 No case of ILD
20
0
5
10
15
20
25
30
< ≥ < ≥ < ≥ < ≥
60 years 65 years 70 years 75 years
Me
dia
n O
S
OS Outcome With Afatinib Depending On Age Group
Paz-Ares L et al. Ann Oncol. 2017, epub ahead of print.
Total randomized 62 98 88 72 123 37 141 19
Patients died 41 68 65 53 82 27 95 14
21
Long-term Responders (LTRs), Defined by
Receiving Afatinib ≥3 Years1
1.Schuler M et al. 2017, ECCO; #1991; 2. Wu Y-L et al. ESMO 2014. Poster 1251P; 3. Paz-Ares L et al. ESMO 2016. Abstract 2988.
LTR = long-term responder.
• Post-hoc analysis identified 24 (LL3), 23 (LL6) and 19 (LL7) patients (LTRs) who received ≥3 years of afatinib
Es
tim
ate
d P
FS
pro
bab
ilit
y
Time (months)
LL3 PFS
LL6 PFS
LL7 TTF
PFS in LL3/LL62 and TTF in LL73
1.0
0.8
0.6
0.4
0.2
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
0.0
22
Tumour Volume Change in LL3/6/7
Schuler M et al. 2017, ECCO; #1991.
CR† (n=5; 8%)
PR† (n=47; 71%)
SD† (n=9; 14%)
NN† (n=5; 8%)
Ma
xim
um
tu
mo
ur
vo
lum
e c
ha
ng
e (
%)
-100
-80
-60
-40
-20
0
20
*Patients were ordered by maximum percentage decrease in tumour volume from baseline; †Tumour volume change not available for seven patients (two patients with NN
in LL3, one patient with a CR and three patients with NN in LL6, and one patient with SD in LL7). CR = complete response; PR = partial response; SD = stable disease;
NN = non-CR, non-progressive disease.
Long term responder (n=66)*†
23
What about adding Bevacizumab?
Kato T et al. ASCO 2014. Abstract 8005.
24
Afatinib plus Bevacizumab (ABC Trial)
Hata A et al. ASCO 2017, abstract 9034.
ASCO 2017
ORR 18.2 % SD 72%
25
• Advanced NSCLC with
EGFR-activating
mutation(s)
• No prior systematic
treatment of advanced
NSCLC
• No CNS metastasis
• No prior EGFR TKI or
other TKI
• ECOG PS 0, 1
Dacomitinib
45 mg PO QD
(N=227)
Gefitinib
250 mg PO QD
(N=225)
Primary endpoint
PFS by blinded
independent review R 1:1
(N=452)
Secondary endpoints
PFS (investigator
assessed), ORR, DOR,
TTF, OS, safety, PROs Stratify
Race (Asian vs non)
EGFR M+(exon 19 vs 21)
ARCHER 1050: Dacomitinib
Mok TS et al. ASCO 2017, abstract LBA9007.
ASCO 2017
26
ORR
Mok TS et al. ASCO 2017, abstract LBA9007.
ORR 74.9% ORR 71.6%
27
Daco (N=227) Gef (N=225)
Number of events, n (%) 136 (59.9%) 179 (79.6%)
Median PFS (95% Cl) 14.7 (11.1,
16.6)
9.2 (9.1,
11.0)
HR (95% Cl) 0.59 (0.47–0.74)
P<0.0001
Dacomitinib
225
227
0 42 36 30 24 18 12 6
0.0
0.2
0.4
0.6
0.8
1.0
155
154
69
106
34
73
7
20
1
6
0
0
0
0
Pro
ba
bilit
y o
f P
FS
Months
++Censored.
PFS rate
30.6% vs
9.6%
Gefitinib
No. at risk
Progression-Free Survival
Mok TS et al. ASCO 2017, abstract LBA9007.
14.7 mo vs 9.2 mo
Dacomitinib
Gefitinib
28
Dose Modification
Presented by Tony Mok at 2017 ASCO Annual Meeting.
• Dacomitinib
– First dose reduction: 30 mg/day
– Second reduction: 15 mg/day
• Gefitinib
– 250 mg every two days
30% 40%
29
Molecular Mechanisms of Acquired Resistance
to First-/Second-Generation EGFR TKIs
Yu HA et al. Clin Cancer Res. 2013;19:2240-47.
30
.
AURA 3: PFS1
1. Mok TS et al. N Engl J Med. 2017;376:629-40; 2. Papadimitrakopoulou VA et al. IASLC 2016. Abstract 4452.
CNS PFS in AURA 32
Osimertinib
(n=279)
Platinum-
pemetrexed
(n=140)
Median progressive-free
survival, mo 10.1 (8.3-12.3) 4.4 (4.2-5.6)
HR for disease progression
or death (95% CI)
P-value
0.82 (0.58-1.15)
0.242
Pro
ba
bilit
y o
f
pro
gre
ss
ion
-fre
e s
urv
iva
l
Month
No. at risk 0
0
100
80
60
40
20
0 3 6 9 12 15
0
1.0
0.8
0.6
0.4
0.2
18 Intracranial Response Rate: 70%
CNS PFS 11.7 months vs 5.6 months
Osimertinib
Platinum-pemetrexed
Osimertinib 80 mg (n=75)
Chemotherapy (n=41)
Median follow-up: Chemotherapy, 4.1 months
Osimertinib, 5.5 months
10.1 months vs 4.4 months
31
FLAURA
Soria J-C, et al. N Engl J Med. Nov 18, 2017 [Epub]. DOI: 10.1056/NEJMoa1713137.
ESMO 2017
Stratification
Exon 19 del/ L858R
Asian/non-Asian
Crossover was allowed for
patients in the SoC arm,
Patients with locally advanced or
metastatic NSCLC
• PS 0 / 1
• Exon 19 deletion / L858R
• No prior systemic anti-cancer /
EGFR-TKI therapy
• Stable CNS mets allowed
Endpoints
• Primary endpoint: PFS
Randomised 1:1
Gefitinib, erlotinib not stratified
No afatinib or dacomitinib
No uncommon mutations
Brain mets not stratified
If no brain mets: followup in CNS not specified
N = 556
EGFR-TKI;
Gefitinib or Erlotinib
(n=277)
Osimertinib (n=279)
32
FLAURA Primary Endpoint: PFS
Soria J-C, et al. N Engl J Med. Nov 18, 2017 [Epub]. DOI: 10.1056/NEJMoa1713137.
1.0
0.8
0.6
0.4
0.2
0.0 0 3 6 9 12 15 18 21 24 27
Osimertinib
Erlotinib/gefitinib
Pro
ba
bilit
y o
f
pro
gre
ss
ion
-fre
e s
urv
iva
l
Time from randomisation (months)
Osimertinib Erlotinib/
gefitinib
Median PFS, months
(95% CI)
18.9
(15.2, 21.4)
10.2
(9.6, 11.1)
HR (95% CI)
P-value
0.46 (0.37-0.57)
<0.001 18.9 vs 10.2 months
ESMO 2017
Osimertinib Erlotinib/
gefitinib
Median PFS, months
(95% CI)
17.7
(15.1, 21.4)
9.7
(8.5, 11.0)
HR (95% CI)
P-value
0.45 (0.36-0.57)
<0.001
PFS Assessed by Investigator
PFS Assessed by Independent Review
33
Does Sequence Matter?
OS in Patients Treated With 3rd-gen TKIs in LUX-Lung 7
Corral J et al. ELCC 2017; #93PD.
Afatinib
N=30
Gefitinib
N=26
Median, mo NE 48.3
HR (95% CI)
p-value
0.49 (0.20–1.19)
0.107
20% / 17% who discontinued afatinib/gefitinib received 3rd-generation TKIs
(osimertinib, olmutinib, rociletinib) E
sti
ma
ted
ove
rall
su
rviv
al
pro
ba
bil
ity
No. at risk:
Afatinib 30 30 30 30 30 30 29 29 29 29 28 28 26 21 17 14 8 1 0
Gefitinib 26 26 25 25 25 24 23 23 23 22 22 22 20 17 17 10 4 1 0
Time to death (months)
0.8
1.0
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
ELCC 2017
4 years
4 years+
34
EGFR: Advanced NSCLC
Melosky B et al. Clinical Lung Cancer. In Press.
*Dacomitinib will soon be included in the algorithm.
EGFR mutation
testing L858R 19Del
Uncommon
mutations
Plasma cfDNA
testing
Tumour rebiopsy
(T790M only)
4th Line Immunotherapy
1st Line EGFR TKI: afatinib, dacomitinib,*
gefitinib, erlotinib EGFR TKI: afatinib
preferred
EGFR TKI: afatinib
preferred
3rd Line Immunotherapy Chemotherapy Doublet
2nd Line Chemotherapy Doublet Osimertinib
T790M-
T790M- T790M+
T790M+
Brain Mets
Osimertinib
35
ALK Mutations
36
PROFILE 1014:
First-line Crizotinib vs Pem/Cis PFS
Solomon BJ et al. N Engl J Med. 2014;371:2167-2177.
Crizotinib
(N=172)
Chemotherapy
(N=172)
Events, n (%) 100 (58) 137 (80)
Median, months 10.9 7.0
HR (95% CI) 0.45 (0.35−0.60)
<0.0001
0
Time (Months) 172 120 65 38 19 7 1 0
171 105 36 12 2 1 0 0
No. at risk
Crizotinib
Chemotherapy
100
80
60
40
20
0
5 10 15 20 25 30 35
PF
S P
rob
ab
ilit
y (
%)
Crizotinib
Chemotherapy
37
ALEX
• Advanced or metastatic
ALK+ NSCLC
• Treatment-naive
• ECOG PS 0−2
• Asymptomatic brain
metastases allowed
R
A
N
D
O
M
I
Z
E
ENDPOINTS
• Primary
‒ PFS by investigator review
• Secondary
‒ PFS by IRC
‒ Time to CNS progression
‒ ORR, DOR
‒ OS
‒ Safety and tolerability
‒ Patient-reported outcomes
Stratify:
• ECOG PS (0/1 vs 2)
• Race (Asian vs non-Asian)
• Brain metastases (present vs
absent)
Alectinib vs Crizotinib: Global ALEX Trial
Shaw et al. ASCO 2017. Abstract LBA9008.
ASCO 2017
38
PFS 25.7 months
Shaw et al. ASCO 2017. Abstract LBA9008.
ASCO 2017
Alectinib vs Crizotinib
NR vs 11.1 months HR .47
PFS Independent Review PFS Investigator
25.7 vs 10.4 months HR .50
39
CNS Prevention
Shaw et al. ASCO 2017. Abstract LBA9008.
ASCO 2017
Crizotinib
(N=151)
Alectinib
(N=152)
CNS metastases
by IRC (%)
Present 58 (38) 64 (42)
Absent 93 (62) 88 (58)
CNS metastases
treatment (%)
n 58 64
None 36 (62) 37 (58)
Whole brain
RT
16 (28) 17 (27)
Brain surgery 1 (2) 1 (2)
38% vs 42%
40
ASCEND 4: Phase 3 Randomized Global
Open-label Study
Castro Jr G. WCLC 2016. Oral Presentation PL03.07
Inclusion criteria
• Stage IIIB/IV ALK+ NSCLC
• Treatment-naive
• WHO PS 0-2
• Neurologically stable brain
metastases (symptomatic or
not)
Chemotherapy
Four cycles
Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2
or
Pemetrexed 500 mg/m2 + carboplatin AUC 5–6
R
1:1
Ceritinib 750 mg/day†
• Daily oral dosing in fasted state
41
Immature but favors ceritinib
ASCEND-4 Outcomes
Castro Jr G. WCLC 2016. Oral Presentation PL03.07
42
Castro Jr G. WCLC 2016. Oral Presentation PL03.07
ASCEND-4 Outcomes
72.7 CNS Response
43
Efficacy and Updated Safety of Ceritinib
(450 mg or 600 mg) With Low-Fat Meal vs
750 mg Fasted in ALK+ Metastatic NSCLC Authors: Cho BC,1 Obermannova R,2 Bearz A,3 Kim DW,4 Orlov S,5 Borra G,6 Kim SW,7 Postmus P,8
Laurie S,9 Park K,10 Geater SL,11 Bettini A,12 Osborne K,13 Passos VQ,14 Chen Z,14 Dziadziuszko R15
WCLC 2017
Cho BC. WCLC 2017. Abstract 9366.
44
ASCEND-8: Phase 1, Randomized, Global, Open-label,
Parallel Design Study
Cho BC. WCLC 2017. Abstract 9366.
Inclusion criteria
• Stage IIIB/IV ALK+ NSCLC
• Treatment-naive* (efficacy analysis)
or previously treated with ≥1 systemic
therapy (PK analysis included both)
• ALK+ status was assessed by
Ventana IHC (treatment-naive) or
FDA approved FISH (previously
treated)
• WHO PS 0-2
• Neurologically stable brain
metastases (symptomatic or not)
R
1:1:1
Ceritinib 450 mg/day with low-fat meal
Ceritinib 600 mg/day with low-fat meal
Ceritinib 750 mg/day under fasted conditions
WCLC 2017
45
ASCEND-8 Efficacy
Cho BC. WCLC 2017. Abstract 9366.
Ceritinib 450 mg fed
(N = 41)
Ceritinib 600 mg fed
(N = 40)
Ceritinib 750 mg fasted
(N = 40)
Overall response rate (CR+PR), n (%)
(95% CI)
32 (78.0)
(62.4-89.4)
30 (75.0)
(58.8-87.3)
28 (70.0)
(53.5-83.4)
Disease control rate (CR+PR+SD+non-
CR/non-PD), n (%) (95% CI)
38 (92.7)
(80.1-98.5)
37 (92.5)
(79.6-98.4)
36 (90.0)
(76.3-97.2)
Median time to response, weeks
(95% CI)
6.3
(6.0-6.9)
6.3
(6.1-12.1)
6.3
(6.0-12.3)
ORR and DCR are clinically relevant and consistent among the 3 treatment arms.
WCLC 2017
46
Overview of GI Toxicities
Cho BC. WCLC 2017. Abstract 9366.
No. of patients (%)
Ceritinib 450 mg fed
(N = 89)
Ceritinib 600 mg fed
(N = 86)
Ceritinib 750 mg fasted
(N = 90)
Preferred term Grade 1 Grade 2 Grade 3/4 Grade 1 Grade 2 Grade 3/4 Grade 1 Grade 2 Grade 3/4
Diarrhea, n (%) 41 (46.1) 8 (9.0) 1 (1.1) 38 (44.2) 13 (15.1) 2 (2.3) 43 (47.8) 18 (20.0) 7 (7.8)
Nausea, n (%) 30 (33.7) 10 (11.2) 0 30 (34.9) 13 (15.1) 5 (5.8) 28 (31.1) 12 (13.3) 5 (5.6)
Vomiting, n (%) 27 (30.3) 4 (4.5) 0 35 (40.7) 10 (11.6) 1 (1.2) 37 (41.1) 9 (10.0) 4 (4.4)
WCLC 2017
47
ALTA: Randomized Dose Evaluation of
Brigatinib
Kim DW. ASCO 2016. Abstract 9007.
48
ALTA: Tumor Response and PFS
Kim DW. ASCO 2016. Abstract 9007.
49
Lorlatinib – Covers ALK Resistance Mutations
Presented by Ignatius Ou at ASCO 2017.
Breakthrough Therapy designation from the
FDA for use in patients with ALK-positive
metastatic NSCLC previously treated with at
least one ALK TKI
ASCO 2017
50
Lorlatinib Can Cross the Blood–Brain Barrier
Presented by Sai-Hong Ignatiusou at 2017 ASCO Annual Meeting.
ASCO 2017
51
ALK+ Patients Previously Treated With ≥1 ALK TKI
Presented by Sai-Hong Ignatiusou at 2017 ASCO Annual Meeting.
ASCO 2017
3 previous treatments
52
Treatment Algorithm for Advanced NSCLC
Non-Squamous: ALK Rearrangement
Lorlatinib
53
BRAF Mutations
54
Pre-treated patients1 Treatment-naive patients2
Never Smokers 28%
BRAF Mutations
1. Planchard 2016. Lancet Oncol. 2016;17:984-93; 2. Planchard 2017. Lancet Oncol. 2017; Published Online September 11, 2017; 3. Barlesi F et al. Lancet. 2016;387:1415-
1426.
55
Synergism to block both BRAF and MEK
Abrogation of Feedback Loop of Raf by Erk
Friday et al. Cancer Res. 2008; Zhao Y & Adjei AA. Nature.
56
Dabrafenib and Trametinib Second Line:
BRAF V600E ASCO 2017
Planchard 2016. Lancet Oncol. 2016;17:984-93.
ORR 67%
PFS 10.2 months
OS 18.2 months
N=57
57
ORR 64%
N=36
PFS 10.9 months
OS 24.6 months
ESMO 2017
Dabrafenib and Trametinib First Line: BRAF V600E
1. Planchard 2017. Lancet Oncol. 2017; Published Online September 11, 2017.
58
MET Mutations
59
Emibetuzumab (Anti-MET mAB)
Scagliotti G et al. ASCO 2017, abstract 9019.
PFS in Patients with
the Highest MET
Expression (≥90%
cells MET 3+)
60
12 13 15
12 13 14 15
MET X14 Skipped
Exon 14
(regulatory domain)
Mechanism of MET Exon 14 Skipping
61
Drug Phase Clinicaltrials.gov
Crizotinib Ib NCT00585195
Mersetinib I NCT02920996
Savolitinib I NCT02897479
Cabozantinib II NCT01639508
Capmantinib II NCT02750215
Tepotinib II NCT02864992
c-Met Inhibitors in Development
Clinicaltrials.gov
62
ASCO 2017
Impact of MET Inhibitors on Survival Among Patients With
MET Exon 14 Mutant Non-Small Cell Lung Cancer
Awad M et al. ASCO 2017 Abstract 8511.
63
ASCO 2017
Outcomes in Patients with MET Exon 14 Mutations
Awad M et al. ASCO 2017 Abstract 8511.
64
ASCO 2017
PD-L1 Expression and Response to Immunotherapy in Patients With
MET Exon 14 Altered Non-Small Cell Lung Cancer
Sebari J et al. ASCO 2017 Abstract 8512.
65
ASCO 2017
Sebari J et al. ASCO 2017 Abstract 8512.
66
PD-1/L1 mAB
68
Targeting PD-1 Pathway
Wolchock J et al. J Clin Oncol. 2013;31(Issue 15_suppl); abstr 9012. ^
T cell Tumour cell PD-L1 PD-1
Tumour microenvironment
- - -
PD-L1
Durvalumab
69
15% alive 5 years
70
PACIFIC: Stage lll
Paz-Ares et al. ESMO 2017, abstract LBA_PR.
• Patients with stage III, locally
advanced, unresectable
NSCLC who have not
progressed following
definitive platinum-based
cCRT (≥2 cycles)
• PS score 0, 1
• PD-L1 not necessary
Durvalumab
10 mg/kg q2w for
up to 12 months
N=476
Placebo
10 mg/kg q2w for
up to 12 months
N=237
2:1,
stratified by age, sex,
and smoking history R
1–42 days
post-cCRT Planned sample size: N=702 patients
Co-primary endpoints: PFS and OS
ESMO 2017
71
PACIFIC: Antitumor Activity
Paz-Ares et al. ESMO 2017, abstract LBA_PR.
Durvalumab
(N=443)*
Placebo
(N=213)*
Treatment effect
(HR [95% CI])¶
Best overall response, n (%)†
Complete response 6 (1.4) 1 (0.5)
Partial response 120 (27.1) 33 (15.5)
Stable disease 233 (52.6) 119 (55.9)
Progressive disease 73 (16.5) 59 (27.7)
Non-evaluable 10 (2.3) 1 (0.5)
Duration of response, months
Median (95% Cl) NR 13.8 (6.0–NR) 0.43 (0.22–0.84) 28.4 16.0 0
5
10
15
20
25
30
35
Durvalumab(N=443)*
Placebo(N=213)*
% P
ati
en
ts (
95
% C
I)
Objective Response
P<0.001
(24.28–32.89)
(11.31–21.59)
Treatment effect (RR [95% CI])¶:
1.78 (1.27–2.51)
28.4%
16%
ESMO 2017
72
PACIFIC: PFS
Paz-Ares et al. ESMO 2017, abstract LBA_PR.
PF
S p
rob
ab
ilit
y
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27
Time from randomization (months)
Placebo
Durvalumab
476 377 301 264 159 86 44 21 4
237 163 106 87 52 28 15 4 3
1
0
No. at risk
Durvalumab
Placebo
HR 0.52 P<0.0001
16.8 vs 5.6 months
11 month difference!
50%
25%
ESMO 2017
Durvalumab
(N=476)
Placebo
(N=237)
Median PFS (95% CI), months 16.8 (13.0–18.1) 5.6 (4.6–7.8)
73
PACIFIC: Time to Distant Metastasis or Death
Paz-Ares et al. ESMO 2017, abstract LBA_PR.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
1 3 6 9 12 15 18 21 24 27 30
Placebo
Durvalumab
476 407 336 288 173 91 46 22 4 1 0
237 184 129 106 63 32 16 5 4 0 0
HR 0.52 P<0.0001
23.2 vs 14.6
9 month difference
ESMO 2017
No. at risk
Durvalumab
Placebo
Pro
ba
bilit
y o
f d
ea
th o
r
dis
tan
t m
eta
sta
sis
Time from randomization (months)
Durvalumab Placebo
Median time (95% CI), months 23.2 (23.2–NR) 14.6 (10.6–18.6)
74
Pneumonitis or Radiation Pneumonitis
Paz-Ares et al. ESMO 2017, abstract LBA_PR.
Pneumonitis (grouped terms) or radiation
pneumonitis, n (%)*
Durvalumab
(N=475)
Placebo
(N=234)
Any grade 161 (33.9) 58 (24.8)
Grade 3/4 16 (3.4) 6 (2.6)
Grade 5 5 (1.1) 4 (1.7)
Leading to discontinuation 30 (6.3) 10 (4.3)
ESMO 2017
75 Surgery vs Durvalumab
25%
ESMO 2017
Practice Changing
Albain, Kathy S et al. The Lancet. 2009,9687; Paz-Ares et al. ESMO 2017, abstract LBA_PR.
50%
76
OAK: Treatment Beyond Progression
Wolchock J et al. J Clin Oncol. 2013;31(Issue 15_suppl); abstr 9012. ^
T cell Tumour cell PD-L1 PD-1
- - -
PD-L1
ASCO 2017
Atezolizumab
77
HR, 0.73
a
(95% CI, 0.62, 0.87)
P=0.0003
Atezolizumab
Docetaxel
Median 9.6 mo
Median 13.8 mo (95% CI, 8.6, 11.2)
(95% CI, 11.8, 15.7)
Months
168/332 = 50% Treated Beyond Progression
ESMO 2016
OAK: Overall Survival, ITT (N=850)
425 382 363 342 326 305 279 260 248 234 54
No. at risk
Atezolizumab
Placebo
407 223 218 205 198 188 175 163 157 141 115 74 41 28 15 4 1
425 385 336 311 286 263 236 219 195 179 37 390 168 151 140 132 123 116 104 98 90 70 51 28 16 6 3
78
ASCO 2017
Presented by David Gandara at 2017 ASCO Annual Meeting.
79
Non-randomized Comparisons Introduce Biases for OS Analysis
Presented by Solange Peters at 2017 ASCO Annual Meeting.
.
Selection Bias and not randomized
Discussant Dr. Solange Peters
ASCO 2017
80
KEYNOTE-024: Updated Analysis
Pembrolizumab Versus Platinum-based Chemotherapy
for Advanced NSCLC With PD-L1 TPS ≥50%
Julie R. Brahmer,1 Delvys Rodríguez-Abreu,2 Andrew G. Robinson,3 Rina Hui,4
Tibor Csőszi,5 Andrea Fülöp,6 Maya Gottfried,7 Nir Peled,8 Ali Tafreshi,9 Sinead Cuffe,10
Mary O’Brien,11 Suman Rao,12 Katsuyuki Hotta,13 Antonio Riccio,14 Jing Yang,14
M. Catherine Pietanza,14 Martin Reck15
WCLC 2017
81
Targeting PD-1 Pathway
Wolchock J et al. J Clin Oncol. 2013;31(Issue 15_suppl); abstr 9012.
Tumour Microenvironment
T cell Tumour cell PD-L1 PD-1
- - -
PD-L1
Pembrolizumab
82
PD-L1 Expression and Pembrolizumab
25% 30% 45%
83
Both Non Squamous and Squamous
ESMO 2016
KEYNOTE-024 Study Design (NCT02142738)
84
45%
28%
KEYNOTE-024: Tumor Response and PFS
Reck M et al. ESMO 2016. Abstract 437O
ESMO 2016
85
HR 0.60
50% Crossover
KEYNOTE-024: Overall Survival
Reck M et al. ESMO 2016. Abstract 437O
ESMO 2016
86
Overall Survival: Updated Analysis
Brahmer JR et al. WCLC 2017. Abstract OA 17.06
0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
T im e , m o n th s
OS
, %
P e m b r o 1 5 4 1 3 6 1 2 1 1 1 2 1 0 6 9 6 8 9 8 3 5 2 2 2 5 0
C h e m o 1 5 1 1 2 3 1 0 7 8 8 8 0 7 0 6 1 5 5 3 1 1 6 5 0
N o . a t r is k
Median (95% CI)
30.0 mo (18.3 mo–NR)
14.2 mo (9.8 mo–19.0 mo)
70.3%
54.8% 51.5%
34.5%
Events, n HR (95% CI)
Pembrolizumaba 73 0.63
(0.47–0.86)
P=0.002b Chemotherapy 96
30 months vs 14.2 months
HR 0.63
62% Crossover
WCLC 2017
87
First Line Second Line
20% 45%
WCLC 2017
KEYNOTE-024: Tumor Responses
Brahmer JR et al. WCLC 2017. Abstract OA 17.06
88
KEYNOTE-021 COHORT G: Updated Analysis
Pemetrexed/Carboplatin +/- Pembrolizumab for
Advanced NSCLC Non Squamous
WCLC 2017
89
60 pts
60 pts
ESMO 2016
Phase ll
90
Approved by the FDA!
April 2017 First line
Pem/Carbo + Pembrolizumab
ESMO 20171 WCLC 20172
56.7%
31.7%
WCLC 2017
KEYNOTE-021: Tumor Responses
1. Borghaei H et al. ESMO 2017. Abstract LBA49; 2. Borghaei H et al. WCLC 2017. Abstract OA 17.01
91
HR .54
HR .54
WCLC 2017
ESMO 20171 WCLC 20171 KEYNOTE-021: PFS
1. Borghaei H et al. ESMO 2017. Abstract LBA49; 2. Borghaei H et al. WCLC 2017. Abstract OA 17.01
92
HR .69
HR .59
HR .90
WCLC 2017
KEYNOTE-021: OS
aP value is descriptive (one sided P < 0.025). B24 additional deaths since primary analysis (pembro + PC, n=7; PC alone, n=17)
1. Langer CJ et al. Lancet Oncol. 2016;17(11):1497-1508. 2. Papadimitrakopoulou VA et al. 2017. J Clin Oncol. 35(suppl): abstract 9094.
93
WCLC 2017
94
WCLC 2017
PFS 1.7 months OS 3.4 months
Efficacy of Nivolumab: PS ≥2 Patients
95
Advanced NSCLC: Wild Type
1. Ettinger DS, et al. J Natl Compr Canc Netw 2017;15:504-535; 2. NCCN Guidelines Version 1.2018 Non-Small Cell Lung Cancer. Version 1.2018, 11/17/17.
PD-L1 Testing
1st Line
Maintenance
2nd Line
3rd Line
PD-L1
≥ 50%
PD-L1
< 50%
Pembrolizumab
Q3 w
Pembrolizumab
Q3 w
Nivolumab
Q2 w
Atezolizumab
Q3 w
Platinum
doublet
Pemetrexed/
Platinum doublet
Pemetrexed
(Non-squamous)
Based on results
of initial testing PD-L1
≥ 1%
PD-L1
> 0%
Afatinib (squamous), Erlotinib (non squamous), Docetaxel +/- Ramicirumab
96
• EGFR:
– Dacomitinib, Osimertinib, T790 testing
• ALK:
– Alectinib first line, Ceritinib, Brigatinib, Lorlatinib
• BRAF:
– Dabrafenib and Trametinib
• cMET Exon 14 Skip:
– Crizotinib
• Immunotherapy:
– PACIFIC, KN 024, KN 21G
– PD-L1, TMB and Microenvironment
Year in Review 2017
SC-CRP-00851
For more information about other BI events and collaborations, please visit www.inOncology.com