presentación de powerpoint · esmo 2016 socinski et al esmo 2016 . checkmate 026: nivolumab vs...
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Inmunoterapia: Nuevo paradigma de tratamiento en
primera línea de CPNCP avanzado
Delvys Rodríguez Abreu, MD
Medical Oncology Dept.
Hospital Universitario Insular de Gran Canaria. Spain
What we have in November 2017?
Monotherapy and Combinations.
• Monotherapy
Eberhardt – J Thorac Oncol 2015 Eberhardt – J Thorac Oncol 2015
Eberhardt – J Thorac Oncol 2015
Eberhardt – J Thorac Oncol 2015
Pembrolizumab and long-term survivors 1st line
8th TNM IASLC Classification, 3-y OS M1c: ~8%
PD-L1 > 50% (N=138) 3yOS: 29.7%
3-y
OS
ph
as
e I K
EY
NO
TE
00
1 T
ria
l
Leighl– ASCO 2017
Pembrolizumab up to PD
Leighl– ASCO 2017
PD-L1 >50%--58% N-27
3-y OS phase I KEYNOTE 001 Trial
Two „similar“ trials..
...but completely different outcomes! Carbone D et al, NEJM 2017; 376 (25): 2415-2426; Reck M et al, NEJM 2016; 375 (19):
1823-1833
KEYNOTE-024 Study Design (NCT02142738)
aOptional pemetrexed maintenance therapy for nonsquamous disease. bPermitted for nonsquamous disease only. cTPrior to the DMC recommendation and amendment 6, which permitted those in the chemotherapy arm to be offered pembrolizumab (based on interim analysis 2 data), patients were eligible for crossover when PD was confirmed by blinded, independent central radiology review.
Key Eligibility Criteria
• Untreated stage IV NSCLC
• PD-L1 TPS ≥50%
• ECOG PS 0–1
• No activating EGFR mutation or
ALK translocation
• No untreated brain metastases
• No active autoimmune disease
requiring systemic therapy
Pembrolizumab
200 mg IV Q3W (2 years)
R (1:1)
N = 305
Pembrolizumab
200 mg Q3W
for 2 years
Platinum-Doublet
Chemotherapya (4–6 cycles)
• Pemetrexed + carboplatinb
• Pemetrexed + cisplatinb
• Paclitaxel + carboplatin
• Gemcitabine + carboplatin
• Gemcitabine + cisplatin
End Points
Primary: PFS (RECIST v1.1, blinded
independent central review)
Key secondary: OS
Secondary: ORR, safety
Exploratory: DOR
PDc
Reck M, et al. NEJM 2016
Confirmed Objective Response Rate
Assessed per RECIST v1.1 by blinded, independent central review. Data cut-off: May 9, 2016.
0
10
20
30
40
50
60
Pembrolizumab Chemotherapy
OR
R, %
(95%
CI)
Δ17%
P = 0.0011
45%
28%
PR
CR
n = 6
n = 63
n = 41
n = 1
Reck M, et al. NEJM 2016
10,3 vs 6 months
Kaplan-Meier Estimate of OS: Updated Analysis
aNominal P value. NR, not reached. Data cutoff: July 10, 2017.
Events, n HR (95% CI)
Pembrolizumab 73 0.63
(0.47–0.86)
P = 0.002a Chemotherapy 96
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%
2 ys OS 51.5% vs 34.5%
HR 0.63 62.3% Crossover
Brahmer et al. WCLC 2017
Efficacy of 2nd line chemo post IO?
10
mPFS2 on second-line therapy
21.5 (87.5% platinum-based)
versus 8.5 (94.4% IO)
Rina Hui et al, COSA 2017
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 sP
FS
2,
%
P e m b r o 1 5 4 1 3 4 1 1 7 1 0 8 9 6 8 0 7 3 6 4 3 8 1 2 3 0
C h e m o 1 5 1 1 2 2 1 0 0 6 4 5 7 4 2 3 5 2 5 1 3 7 2 0
N o . a t r is k
67.6% 41.8%
49.7% 19.0%
Events, n HR (95% CI)
Pembrolizumab 73 0.46 (0.34–0.62)
Chemotherapy 113
Median (95% CI) 21.5 mo (14.8 mo–NR) 8.5 mo (7.2–11.4 mo)
11
Phase 3 CheckMate 026 Study Design:
Nivolumab vs Chemotherapy in First-line NSCLC
Primary endpoint: PFS (≥5% PD-L1+)d
Secondary endpoints:
• PFS (≥1% PD-L1+)d
• OS
• ORRd
Nivolumab 3 mg/kg IV Q2W
n = 271
Randomize 1:1
Key eligibility criteria:
• Stage IV or recurrent NSCLC
• No prior systemic therapy for
advanced disease
• No EGFR/ALK mutations sensitive to
available targeted inhibitor therapy
• ≥1% PD-L1 expressiona
• CNS metastases permitted if
adequately treated at least 2 weeks
prior to randomization
Chemotherapy (histology dependent)b
Maximum of 6 cycles
n = 270
Disease progression or
unacceptable toxicity
Disease
progression
Crossover
nivolumabc
(optional)
Tumor scans Q6W until
wk 48 then Q12W
aDako 28-8 validated; archival tumor samples obtained ≤6 months before enrollment were permitted; PD-L1 testing was centralized
bSquamous: gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2; gemcitabine 1000 mg/m2 + carboplatin AUC 5; paclitaxel 200 mg/m2 + carboplatin AUC 6;
Non-squamous: pemetrexed 500 mg/m2 + cisplatin 75 mg/m2; pemetrexed 500 mg/m2 + carboplatin AUC 6; option for pemetrexed maintenance therapy cPermitted if crossover eligibility criteria met, including progression confirmed by independent radiology review dTumor response assessment for PFS and ORR per RECIST v1.1 as determined by independent central review
Stratification factors at randomization:
• PD-L1 expression (<5% vs ≥5%)a
• Histology (squamous vs non-squamous)
ESMO 2016 Socinski et al ESMO 2016
CheckMate 026: Nivolumab vs Chemotherapy in First-line NSCLC
12
PFS and OS (≥5% PD-L1+)
Median OS,
months
14.4
Nivo
13.2
Chemo
Median PFS 4.2
Nivo
5.9
Chemo
Months
OS
(%
)
24 21 18 15 12 9 6 3 30
100
80
60
40
0
20
0 27
Nivolu
mab
Chemothe
rapy
HR = 1.02
Nivolumab is not better than chemotherapy in 1st line treatment of patients with PDL1 >/= 5%
Also not better among those with PDL1 >/= 50%
Socinski et al ESMO 2016
13
ORR by Tumor Mutation Burden Subgroup CheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC
111 94 47 60 n =
47
2328
33
0
10
20
30
40
50
60
70
80
90
100
High Low/medium
ORR
(%)
TMB Subgroup
Nivolumab
Chemotherapy
Nivolumab Chemotherapy
47 30 26 21 16 12 4 1 60 42 22 15 9 7 4 1
111 54 30 15 9 7 2 1 1 94 65 37 23 15 12 5 0 0
Nivolumab n = 47 n = 60
9.7 (5.5, NA)
5.8 (4.4, 9.1)
Chemotherapy
Median PFS, months (95% CI)
High TMB
PF
S (
%)
3 6 9 12 15 18 21
No. at Risk by Time Months
100
90
80
70
60
50
40
30
20
10
0
0
Nivolumab
Chemotherapy
0 3 6 9 12
Months
15 18 21 24
Nivolumab
Chemotherapy
100
90
80
70
60
50
40
30
20
10
0
n = 111 n = 94
4.1 (2.8, 5.4)
6.9 (5.6, 8.8)
HR = 1.82 (95% CI: 1.30, 2.55)
Nivolumab Chemotherapy
(95% CI) Median PFS, months
Low/Medium TMB
HR = 0.62 (95% CI: 0.38, 1.00)
Carbone et al. NEJM 2017
Mutational burden will be a predictive factor
• Atezolizumab was dosed at 1200 mg IV q3w in all cohorts
• Primary endpoint: Independent review facility (IRF)-assessed objective response rate (ORR) per RECIST v1.1
• Secondary endpoints:
• IRF-assessed progression-free survival (PFS) and
duration of response (DOR) per RECIST v1.1
• Investigator (INV)-assessed ORR, PFS and DOR
per RECIST v1.1 and modified RECIST
• Overall survival (OS)
• Safety
BIRCH: Phase II Trial of Atezolizumab Monotherapy
in PD-L1–Selected Advanced NSCLC1
a PD-L1 expression evaluated by IHC using the VENTANA SP142 assay.
IHC, immunohistochemistry; PD, progressive disease.
1. Peters S, et al. J Clin Oncol. 2017. Carcereny et al., BIRCH. WCLC 2017 16
Cohort 1 (1L) No prior chemo
n = 138
Cohort 2 (2L) 1 prior platinum chemo
n = 271
Cohort 3 (3L+) ≥ 2 prior chemos (including 1 platinum)
n = 254
PD
Until loss of clinical benefit
• Locally advanced or
metastatic NSCLC
• Tumor PD-L1
expression by IHCa
(TC2/3 and/or IC2/3)
• ECOG PS 0 or 1
• No brain metastases
N = 667
• Baseline PD-L1 expression was scored by IHC
in tumor cells (TC) as percentage of PD-L1
expressing TC and in tumor-infiltrating immune
cells (IC) as percentage of tumor area
• TC2/3 or IC2/3 = TC or IC ≥ 5%
Response Rates and Drug Exposure
CR, complete response; PR, partial response; SD, stable disease.
TC2/3 or IC2/3 = TC or IC ≥ 5% PD-L1–expressing cells, respectively;
TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells; TC2 or IC2 = TC2/3 or IC2/3 excluding TC3 or IC3.
Investigator assessment. Error bars correspond to 95% CIs.
Data cutoff date: August 7, 2017. Carcereny et al., BIRCH. WCLC 2017 17
Atezolizumab
Exposure Mean (SD)
Treatment duration, mo 9.8 (10.8)
Dose intensity, % 98.5 (7.0)
No. of doses 14.6 (15.1) 0
20
40
60
80
100
CR/PR SD
TC2/3 or IC2/3
TC3 or IC3
TC2 or IC2
Fre
qu
en
cy,
%
n = 23 n = 36 n = 13 n = 21 n = 57 n = 36
32% 35%
26%
41%
18%
49%
• Durable survival was observed in all PD-L1 subgroups
Overall Survival – PD-L1 Subgroups
Carcereny et al., BIRCH. WCLC 2017 18
Median duration of survival follow-up = 34.3 months
Phase I/II study of Durvalumab in advanced NSCLC
Durvalumab 0.1–10 mg/kg q2w
15 mg/kg q3w x 1 year
Dose escalation
Dose expansion* 10 mg/kg q2w x 1 year
Squamous NSCLC
First line (n=29)
Second line (n=33)
Second line (n=56)
Third line + (n=75)
Non-squamous NSCLC
First line (n=30)
Third line + (n=81)
•Tumour assessments were conducted at weeks 6, 12, 16, then every 8 weeks during the treatment period.
•After 1 year of treatment, patients entered follow-up.
•Treatment beyond disease progression was permitted in the absence of clinical deterioration and if the investigator considered that the patient would continue to receive benefit.
•Upon progression during the follow-up period, retreatment was offered for up to an additional 12 months.
Antonia et al ASCO 2017
Tumor response rate by PDL1 expression only
n/N (%)
95% CI
High PD-L1
expression*
(n=154)
Low PD-L1
expression*
(n=116) Total
(n=287)†
RECIST response (ORR)‡ 39/154 (25.3%)
18.7–33.0
7/115 (6.1%)
2.5–12.1
50/285 (17.5%)
13.3–22.5
Treatment setting
First line 14/49 (28.6%)
16.6–43.3
1/9 (11.1%)
0.3–48.2
16/59 (27.1%)
16.4–40.3
Second line 12/46 (26.1%)
14.3–41.1
1/24 (4.2%)
0.1–21.1
15/80 (18.8%)
10.9–29.0
≥Third line 13/59 (22.0%)
12.3–34.7
5/82 (6.1%)
2.0–13.7
19/146 (13.0%)
8.0–19.6 Pembrolizumab
RR 45% in PDL1
expression >50%
Antonia et al ASCO 2017
More trials to come...
NCCN guidelines 1st line- version 9. 2017
• Combinations
Stromal PD-L1 modulation of T
cells
Immune cell modulation
of T cells
PD-L1/PD-1-mediated
inhibition of
tumor cell killing
IFNg-mediated
upregulation of tumor
PD-L1
Priming and activation
of T cells
PD-L2-mediated inhibition of
TH2 T cells
receptor
B7.1
Chen DS, Irving BA, Hodi FS.
Clin Cancer Res. 2012;18:6580.
As Good as Immunotherapy is… it only works this well for about 20-30%
of patients: So what about the other 80% of patients?
Multiple Factors Determine Sensitivity and Resistance in the Immune Microenvironment
Potential for benefit in all
cancers!
Unmet medical need remains: combination therapies are likely to be requiro improve patient outcomes
Targeted therapy
Immune checkpoint
monotherapy
Chemotherapy
Hypothetical KM curve
Time
Perc
en
t su
rviv
al
Combinations with
immunotherapy
Combinations
IO-IO IO-CT
Combined inhibition of tumor angiogenesis and the immune checkpoint
Manegold C, et al. JTO 12: 194, 2016 27
Hossein Borghaei, et al. WCLC 2017
0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
T i m e , m o n t h s
Pr
og
re
ss
io
n-
Fr
ee
S
ur
viv
al, %
60 51 43 32 24 22 17 9 1 0 63 42 35 25 18 13 8 5 1 0
N o . a t r i s k
Median (95% CI)
19.0 (8.5–NR)
8.9 (6.2–11.8)
57%
37%
52%
29%
Events,
n/N
HR (95%
CI)
Pembro + PC 26/60 0.54
(0.33–0.88)
P = 0.0067a PC alone 40/63
Δ24.8%
(95% CI, 7.2%‒40.9%)
P = 0.0029a
Progression-Free Survival
0 3 6 9 12 15 18 21 24 270
10
20
30
40
50
60
70
80
90
100
Time, months
Ove
rall S
urv
ival, %
60 57 55 51 46 44 36 22 7 1 63 58 57 51 43 39 29 18 9 0
No. at risk
Overall Survival Data Cut-Off: May 31, 2017
•a24 additional deaths since primary analysis (pembro + PC, n = 7; PC alone, n = 17). bP value is descriptive (one-sided P < 0.025).
Median Follow-Up: 18.7 mo
Events,
n/N
HR (95%
CI)
Pembro + PC 20/60a 0.59
(0.34–1.05)
P = 0.03b PC alone 31/63a
77%
69%
Median (95% CI)
NR (22.8–NR)
20.9 (14.9–NR)
70%
56%
Hossein Borghaei, et al. WCLC 2017
Crossover ~ 75%
IO-IO Combinations (Phase I) (Nivolumab/Ipilimumab – Durvalumab/Tremelimumab)
• Response: 23-43%
• Substantial Toxicity
• Conflicting Impact of PD-L1 expression:
23% 22%
29%
40%
0%
10%
20%
30%
40%
50%
60%
70%
All PDL-L1+ (>25%) PD-L1- (<25%) PD-L1- (0%)
Objective Response Rate (D10-20 q4/2w T1)
Durva + Treme
Goldmann J, ASCO 2017, abstract 9093 Goldmann J, ASCO 2017, abstract 9093
Goldmann J, ASCO 2017, abstract 9093; Antonia et al. Lancet Oncol. 2016;17(3):299-308
43
21
57
92
2313
28
50
0
20
40
60
80
100
… … … …
Nivo 3 + ipi 1 Q6/12W Nivo 3
Overall <1% ≥1% ≥50%
PD-L1
expression
• Response: 33 – 68%
• PFS: 5.5 – 8.4 m
• OS / 1 year OS: 11.6 – 19.2 m / 50 – 86%
• Grade 3/4 AEs: 25 – 72%
• No Impact of PD-L1 Expression
Rizvi N et al, J Clin Oncol 2016; Liu S et al, ASCO 2017; abstract
9092
Phase I Nivolumab + CT,
Atezolizumab + CT
CheckMate 012: First-Line Nivolumab + Chemotherapy in NSCLC
3-Year KM Estimates of OS Rates
• 3-year KM estimates of OS rates by chemotherapy regimen: nivolumab + pemetrexed–cisplatin (non-SQ only), 27%; nivolumab + paclitaxel–carboplatin (any histology), 32%; nivolumab + gemcitabine–cisplatin (SQ only), 8%
33
No. of patients at risk
56 54 40 30 20 16 13 9 4 1 0
1-year OS: 71%
2-year OS: 37%
3-year OS: 25%a
100
80
60
40
20
0
0 6 12 18 24 30 36 42 48 54 57
OS
(%
)
Time since first dose (months)
aBetween 2 and 3 years, there were 6 deaths due to disease and 1 patient was censored due to loss to follow-up; KM = Kaplan–Meier
Selected phase 3 combination studies with immune checkpoint inhibitors in 1st-line advanced NSCLC
Pembrolizumab
Durvalumab
SOC=standard of care. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed September 2017.
Atezolizumab
An
ti-P
D-1
/PD
-L1
KEYNOTE-407 Pembrolizumab+Carbo+Paclitaxel (or nab)
Placebo+Carbo+Paclitaxel (or nab) Primary endpoint: OS, PFS
Stage IV Squamous NSCLC
N=560
Nivolumab Primary endpoints:
OS, PFS
CheckMate 227
Part 1
Nivolumab + ipilimumab
Nivolumab
Platinum-based chemotherapy Stage IV o recurrent NSCLC
N=2220
KEYNOTE-189 Pembrolizumab+Platinum+ Pemetrexed
Placebo+Platinum+ Pemetrexed Primary endpoint: PFS
Stage IV Non squamous NSCLC
N=570
IMpower 150
Atezolizumab + carboplatin + paclitaxel
Bevacizumab + paclitaxel + carboplatin
Primary endpoint: PFS, OS Atezolizumab + bevacizumab + paclitaxel + carboplatin Stage IV non-squamous NSCLC
N=1202
IMpower 130 Atezolizumab + carboplatin + nab-paclitaxel
Carboplatin + nab-paclitaxel Primary endpoint: PFS, OS
Stage IV non-squamous NSCLC
N=724
IMpower 131
Atezolizumab + carboplatin + nab-paclitaxel
Carboplatin + nab-paclitaxel
Primary endpoint: PFS, OS Atezolizumab + carboplatin + paclitaxel Stage IV squamous NSCLC
N=1021
Primary endpoint: PFS, OS MYSTIC
Durvalumab
Durvalumab + tremelimumab
SOC chemotherapy
Stage IV NSCLC
N=1118
Nivolumab + ipilimumab
Nivolumab + chemotherapy
Platinum-based chemotherapy
IMpower 132 Atezolizumab + platinum+ pemetrexed
Platinum + pemetrexed Primary endpoint: PFS, OS
Stage IV non-squamous NSCLC
N=568
NEPTUNE Durvalumab + tremelimumabl
SOC chemotherapy Primary endpoint: OS
Stage IV NSCLC
N=960
Primary endpoint: PFS POSEIDON
Durvalumab + SOC chemotherapy
Durvalumab + tremelimumab + SOC chemotherapy
SOC chemotherapy
Stage IV NSCLC
N=801
CheckMate 227
Part 2
Nivolumab + chemotherapy
Chemotherapy Primary endpoint: PFS, OS
Stage IV or recurrent NSCLC
N=480
PD-L1≥1%
PD-L1<1%
MYSTIC Study Design
• Phase 3, randomized, open-label, multicenter, global study (>175 sites across Asia, Australia, Europe, and North America)1-3
FPCD: 3Q2015 LPCD: 2Q2016
Data anticipated: mid-2017
Primary endpoint 1. PFS in all patients and in PD-L1(+) patients 2. OS in all patients
Secondary endpoints • ORR, DoR, PFS,e OSf
• Safety/tolerability, QoL • PK, immunogenicity
Follow-up for OS
Subsequent treatments Arm 1
Durvalumab iv 20 mg/kg q4w for 4 doses +
Tremelimumab iv 1 mg/kg q4w for 4 doses
Durvalumab iv 20 mg/kg q4w starting on Week 16, for 9 doses (n=364)
Arm 2 Durvalumab iv 20 mg/kg q4w for 13 doses,
for up to 12 months (n=364)
Arm 3 SoCb (n=364)
PD R
1:1:1
n=1118 Patients with locally
advanced or metastatic NSCLC (EGFR and
ALKwt,a Stage IV), 1L (N=1850)
Stratification
1. PD-L1 status (positive vs negative)
2. Histology (squamous vs nonsquamous)
IMpower150 (GO29436) All-Comer NSQ Phase III Trial
NSQ = non-squamous
A: Atezolizumab +
Carboplatin + Paclitaxel
C: Carboplatin + Paclitaxel +
Bevacizumab
B: Atezolizumab +
Carboplatin + Paclitaxel +
Bevacizumab
R
1:1
Su
rviv
al F
/U
PD or loss of clinical benefit
PD
Atezolizumab
Maintenance (No crossover permitted)
Atezolizumab +
Bevacizumab
Bevacizumab
PD or loss of clinical benefit
Stage IV Non-Squamous
NSCLC
Chemo naive
Stratification factors:
• Sex
• PD-L1 IHC expression
• Liver mets
N=1200
Secondary endpoints
• Investigator-assessed ORR, DOR, TTD, TIR
• IRF-assessed PFS; safety
Co-Primary endpoints
• Investigator-assessed PFS
• OS
PD-L1 stratification = TC3 and any IC vs T0/1/2 and IC2/3 vs TC0/1/2 and IC0/1
Borghaei et al. WCLC 2017, Reck et al. NEJM 2016, Leighl et al JCO 2017, Sandler et al. NEJM 2006, Schiller et al. NEJM 2002
PD1 2nd line
Chemotherapy
Anti-VEGFAnti-VEGF
How much improve in NSCLC?
Pro
po
rtio
n S
urv
ivin
g
PD1 1st line 51.5% at 2ys
IO-CT1st line 70% at 18 months
Some take home messages
• Monotherapy is the standard today in PD-L1>50%.
• Combinations must be better than monotherapy but not for all.
• Multiple remaining questions—?
• We need betters biomarkers.
• Different toxicities and more toxic in combo!!.
• Several phase 3 IO-CT and IO-IO now ongoing but close.
Thanks!!
Dr. Delvys Rodríguez Abreu
Servicio Oncología Médica
Hospital Universitario Insular de Gran Canaria