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NSCLC Immunotherapy
Post WCLC (& ECCO/ESMO) 2015
Solange Peters, MD-PhD Oncology Department & Ludwig Institue CHUV Lausanne Switzerland
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Hanahan & Weinberg. Cell 2011
Evading growth
suppressors Enabling
replicative immortality
Tumour- promoting
inflammation
Activating invasion & metastasis
Genome instability mutation
Resisting cell
death
Degrading cellular
energetics Sustaining
proliferative signalling
Inducing angiogenesis
PD-1
PDL-1
Avoiding immune
destruction
Therapeutic Intervention at Cancer Hallmarks
CTLA-4
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To make a long story short...
CTLA-4 Blockade (Ipilimumab) PD-1 Blockade (Nivolumab)
APC – T-cell Interaction
Activation (cytokine secretion, lysis,
proliferation, migration to tumor)
Tumor Microenvironment
Dendritic cell T cell Tumor cell
MHC
TCR TCR
PD-L1
PD-L2
MHC
PD-1
PD-1
B7
B7 CD28
CTLA-4
anti-CTLA-4
+++
---
+++ T cell +++
---
---
anti-PD-1
anti-PD-1
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Many checkpoints representing immune synapses have been identified as potential targets
Mellman , Nature 2011
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PD-1 axis immunotherapy for NSCLC
1) A new generation of expanded phase 1/2 trials for activity evaluation 2) Evidence-based data for checkpoint inhibitors monotherapy 3) Current evidence for biomarker-based selection of NSCLC patients
• Tumour mutation load • PD-L1 expression • Tumour infiltrating lymphocytes • Tumour molecular characteristics
4) Upfront perspectives for checkpoint inhibitors
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PD-1 axis immunotherapy for NSCLC
1) A new generation of expanded phase 1/2 trials for activity evaluation 2) Evidence-based data for checkpoint inhibitors monotherapy 3) Current evidence for biomarker-based selection of NSCLC patients
• Tumour mutation load • PD-L1 expression • Tumour infiltrating lymphocytes • Tumour molecular characteristics
4) Upfront perspectives for checkpoint inhibitors
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Clinical Development of Inhibitors of PD-1 Immune Checkpoint
PD-1 Nivolumab BMS-936558
Fully human IgG4 mAb Bristol-Myers Squibb Phase III
Pidilizumab CT-011
Humanized IgG1 mAb CureTech Phase II
Pembrolizumab MK-3475
Humanized IgG4 mAb Merck Phase III
AMP-224 Recombinant PD-L2-Fc fusion protein
GlaxoSmithKline Phase I
PD-L1 BMS-936559 Fully human IgG4 mAb Bristol-Myers Squibb Phase II
Durvalumab MedI-4736
Engineered human IgG1 mAb
MedImmune Phase III
Atezolizumab MPDL-3280A
Engineered human IgG1 mAb
Genentech Phase III
Avelumab MSB0010718C
Engineered human IgG1 mAb
EMD Serono Phase III
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Phase I design modifications
Soria, ECCO/ESMO 2015
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Pembrolizumab Phase I Study as an illustration
PN-001, Phase I study, began in 2011
Initially a 32 patient study
Actually enrolled over 1260 patients
Became basis for FDA Breakthrough designation in melanoma + lung cancer
NCT01295827
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OS in Nivolumab phase 1 (3yrs FU)
• Pts were heavily pretreated; 54% had 3–5 prior therapies Gettinger, JCO 2015
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Pembrolizumab phase 1 data
• Pretreated pts. Same efficacy 2mg or 10mg/kg • Lower ORR in patients with liver metastases: 13.6% vs 21.2%
Soria, ESMO 2015
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Pembrolizumab phase 1 data
Hellmann, WCLC 2015
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Pembrolizumab long-term phase 1 FU
Soria, ESMO 2015 FU 16 months
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Pembrolizumab and brain activity
•18 patients had sufficient follow-up time for response evaluation •Brain metastasis response rate and systemic response rate were both 33% •All patients with a systemic response also had a CNS response, except for 1
Goldberg, WCLC 2015
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Atezolizumab Phase 2 BIRCH trial
Besse, ESMO 2015
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Besse B, et al, atezolizumab in NSCLC (BIRCH)
BIRCH: Objective Response Rate TC3 or IC3 Subgroup vs TC2/3 or IC2/3 Subgroup by Cohort
0
10
20
30
1L 2L 3L+
26% 24%
27%
19% 17% 17%
8
Enriched clinical benefit was observed in TC3 or IC3 patients ORR data were similar using RECIST V1.1 or mRECIST criteria Responses were observed in patients with EGFR or KRAS mutations, although patient numbers were small
TC2/3 or IC2/3 TC3 or IC3
OR
R, %
N=115 N=253 N=267 N=139 N=65 N=122
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Besse B, et al, atezolizumab in NSCLC (BIRCH)
Progression-free Survival by IRF per RECIST v1.1
Line of Therapy PD-L1 Status
Median PFS (95% CI), mo
6-month PFS Rate
3L+ TC3 or IC3 4.2 (2.8, 5.6) 39%
3L+ TC2/3 or IC2/3 2.8 (2.7, 3.7) 31%
2L TC3 or IC3 4.1 (1.8, 5.5) 34%
2L TC2/3 or IC2/3 2.8 (1.5, 3.5) 29%
1L TC3 or IC3 5.5 (2.7, 8.3) 48%
1L TC2/3 or IC2/3 5.5 (3.0, 6.9) 46%
12 Data cut-off May 28, 2015.
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Besse B, et al, atezolizumab in NSCLC (BIRCH)
BIRCH: Overall Survival by Cohort TC2/3 or IC2/3 Subgroup
Data cut-off May 28, 2015.
Subgroup Median OS, mo (95% CI)
6-mo OS, %
Cohort 1 (1L) 14.0 (14.0, NE) 82%
Cohort 2 (2L) NE (11.2, NE) 76%
Cohort 3 (3L+) NE (8.4, NE) 71%
19
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Besse B, et al, atezolizumab in NSCLC (BIRCH)
BIRCH: Overall Survival by Cohort TC3 or IC3 Subgroup
20 Data cut-off May 28, 2015. 11
Subgroup Median OS, mo (95% CI)
6-mo OS, %
Cohort 1 (1L) NE (10.4, NE) 79%
Cohort 2 (2L) NE (10.6, NE) 80%
Cohort 3 (3L+) NE (NE, NE) 75%
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Activity in pretreated patients Nivolumab Pembrolizumab Atezolizumab Durvalumab Avelumab
N 129 475 175 228 184
RR Squamous
Non Sq.
17% 18%
23.5% 19%
27% 21%
21% 13%
14%
Drug rel AE
All grades Grade 3/4
41% 4.7%
71% 9.5%
66% 11%
50% 8%
77% 12%
RR PDL-1 + PDL-1 -
16% 13%
42% (>50%) 10% (<1%)
34% IC2/3 or TC 2/3 (half
if 3 used)
Gettinger S, J Clin Oncol 2015; 33: 2004-2012; Herbst R, Nature 2014; 515: 563-7; Soria JC, ESMO 2013; Garon E, NEJM 2015; 372: 2018-28; Rizvi N, ASCO 2015; Guley LJ, ASCO 2015
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Proportion of high expressors?
Agent Atezolizumab1 Pembrolizumab Nivolumab3,4
Highest PD-L1+ cut-off TC3 or IC3 TC ≥50% TC ≥10%
Trial/ Analysis
MDACC and UCCC tumor specimens1
POPLAR2 KEYNOTE-0013 CheckMate 0574
CheckMate 0175
Total samples 698 287 91 582 272
Positive based on cut-off
26% 16% 29.7% 12.4% 25.4%
MDACC=MD Anderson Cancer Center; UCCC=University of Colorado Cancer Center. 1. Gettinger SN, et al. Presented at: ASCO; May 29-June 2, 2015, Abstract 3015. 2. Spira A, et al. Presented at: ASCO; May 29-June 2, 2015, Abstract 8010. 3. Rizvi N et al. Presented at ASCO; May 29-June 2, 2015, Abstract 8026. 4. Paz-Ares L,, et al. Presented at: ASCO; May 30-June 3, 2014; Chicago, Illinois. Abstract LBA 109. 5. Brahmer J, et al. N Engl J Med. 2015 May 31. [Epub ahead of print].
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A consistant and significant tail of the curve across trials
Soria, ESMO 2015 FU 16 months
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Anti-PD1/PDL1 mAB: key-lessons for phase 1/2 trials
• Inability to identify a maximum tolerated dose (outside
CTLA4) – favorable toxicity profile in general • Lack of Dose –Response relationship • Huge variety of doses and schedules evaluated upfront (flat
doses) • Benefit possibly better translated in OS data than RR or PFS • Optimal duration of therapy not defined
• Like “vaccines”, a limited nb of boost sufficient to trigger a durable immune response?
• Selection based on PD-L1 expression as a enrichment for better outcome data. A matter of discussion
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PD-1 axis immunotherapy for NSCLC
1) A new generation of expanded phase 1/2 trials for activity evaluation
2) Evidence-based data for checkpoint inhibitors monotherapy 3) Current evidence for biomarker-based selection of NSCLC patients
• Tumour mutation load • PD-L1 expression • Tumour infiltrating lymphocytes • Tumour molecular characteristics
4) Upfront perspectives for checkpoint inhibitors
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Second line single agent chemotherapy improves survival
The database for a survival advantage of 2nd line chemotherapy is small and based on only one study of docetaxel vs BSC
Shepherd, J Clin Oncol 2000
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Poplar: atezolizumab vs docetaxel Randomized phase 2
Vansteenkiste, ESMO 2015
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Poplar: atezolizumab vs docetaxel Randomized phase 2
Vansteenkiste, ESMO 2015
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Poplar: atezolizumab vs docetaxel Randomized phase 2
Vansteenkiste, ESMO 2015
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Both PD-L1 expression on TC and IC are independent predictors of overall survival
Vansteenkiste & Schmid ESMO 2015
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Primary Objective • Overall survival (OS) Secondary Objectives • ORR • PFS • ORR and OS by PD-L1 status • Duration of OR • Time to OR • Proportion of patients exhibiting disease-
related symptom progression (Lung Cancer Symptom Scale)
Docetaxel
Nivolumab
Docetaxel
Nivolumab
CA209-017 NCT01642004
(Phase 3; N = 264)
Patients with stage IIIb/IV squamous
cell NSCLC
CA209-057 NCT01673867
(Phase 3; N = 574)
Patients with stage IIIb/IV
non-squamous cell NSCLC
Nivolumab phase III trial
Squamous & non-squamous 2nd line vs docetaxel
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16th World Conference on Lung Cancer, September 6-9, 2015 ̶ Denver, CO, USA
Overall Survival Nivolum
ab n=135
Docetaxel n=137
mOS mo (95% CI)
9.2 (7.33, 12.62)
6.0 (5.29, 7.39)
# events 103 122
HR=0.62 (0.48, 0.81); P=0.0004
Minimum follow-up for survival: 18 months • Survival was monitored until death or withdrawal of consent
Docetaxel 18-month OS rate=13%
OS
(%)
Time (months)
0 6 14 25 37 51 57 69 86 113 135 0 Nivolumab Number of Patients at Risk
0 4 7 11 17 22 33 46 69 104 137 Docetaxel 1
Nivolumab 18-month OS rate=28%
100
90
80
70
60
50
40
30
10
0
20
33 27 24 21 18 15 12 9 6 3 0 30
RR: 20% vs 9%
Reckhamp, WCLC 2015
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16th World Conference on Lung Cancer, September 6-9, 2015 ̶ Denver, CO, USA
Efficacy by PD-L1 Expression
Based on December 2014 DBL
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18th ECCO ̶ 40th ESMO European Cancer Congress, September 25-29, 2015, Vienna, Austria Note: this draft is currently undergoing editorial review and QC
DRAFT: Highly Confidential
12-mo OSa 18-mo OSb
Nivo (n = 292) Doc (n = 290) Nivo (n = 292) Doc (n= 290)
mOS, mos 12.2 9.4 12.2 9.4
1-year OS rate, % 51 39 51 39
18-mo OS rate, % – – 39 23
No. of events, n/N 190/292 223/290 206/292 236/290
HR (96% CI) = 0.73 (0.59, 0.89) P = 0.0015
HR (95% CI) = 0.72 (0.60, 0.88) Post-hoc P = 0.0009c
Overall Survival
• Minimum follow-up for 12-mo OS rate, 13.2 mos; for 18-mo OS rate, 17.1 mos
100
90
80
70
60
50
40
30
10
0
20
27 18 15 9 6 21 12 3 0 24 30
Nivolumab Docetaxel
Number of patients at risk (18-mo OS)b 292 233 195 171 148 128 107 55 4 27 290 244 194 150 111 89 61 23 4
0 0 6
Nivolumab Docetaxel
Nivolumab Docetaxel
Number of patients at risk (12-mo OS)a 292 232 194 169 146 123 62 32 0 9 290 244 194 150 111 88 34 10 0 5
18-mo OS rate = 23%
18-mo OS rate = 39%
1-yr OS rate = 39%
1-yr OS rate = 51%
Time (Months)
OS
(%)
RR: 12% vs 9%
Horn, ESMO 2015
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18th ECCO ̶ 40th ESMO European Cancer Congress, September 25-29, 2015, Vienna, Austria Note: this draft is currently undergoing editorial review and QC
DRAFT: Highly Confidential
OS by Baseline PD-L1 Expression PD-L1 expression level
Nivo n
Doc n
Unstratified HR (95% Cl)
Interaction P-valuea
OS ≥1% 123 123 0.59 (0.43, 0.82)
0.0646 <1% 108 101 0.90 (0.66, 1.24) ≥5% 95 86 0.43 (0.30, 0.63)
0.0004 <5% 136 138 1.01 (0.77, 1.34) ≥10% 86 79 0.40 (0.26, 0.59)
0.0002 <10% 145 145 1.00 (0.76, 1.31) Not quantifiable 61 66 0.91 (0.61, 1.35)
PFS ≥1% 123 123 0.70 (0.53, 0.94)
0.0227 <1% 108 101 1.19 (0.88, 1.61)
≥5% 95 86 0.54 (0.39, 0.76) <0.0001
<5% 136 138 1.31 (1.01, 1.71)
≥10% 86 79 0.52 (0.37, 0.75) 0.0002
<10% 145 145 1.24 (0.96, 1.61) Not quantifiable 61 66 1.06 (0.73, 1.56)
Based on a March 18, 2015 DBL aInteraction p-value from Cox proportional hazard model with treatment, PD-L1 expression and treatment by PD-L1 expression interaction
PD-L1 expressors PD-L1 non-expressors PD-L1 not quantifiable
1.0 0.5 2.0 0.25 Nivo Doc
Horn, ESMO 2015
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Lets discuss toxicty…
Toxicité Nivolumab squamous %
Docetaxel squamous %
Afatinib squamous %
Docetaxel / Ramucirumab %
All 59 87 93 98
Grade 3-4 8 58 57 79
Grade 5 0 2 2 5
Peters, WCLC 2015
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Toxicities are observed early in the course of treatment
Reckhamp, WCLC 2015
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Nivolumab is safe in PS 2 Community-based real-life trial
• PS 2 patients do not present with more AEs • Short FU (median 10.4 weeks), but most side effects
observed early
Hussein , WCLC 2015
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18th ECCO ̶ 40th ESMO European Cancer Congress, September 25-29, 2015, Vienna, Austria
Squamous : EQ-5D Utility Index Mean Scores Over Time While on Treatment
Lung Cancer Norm (UK-based): 0.67b
Mea
n EQ
-5D
Util
ity In
dex
Scor
e
97 50 32 32 21 18 13 13 8 Nivolumab (n = 97)
88 32 9 5 5 4 4 2 1 Docetaxel (n = 89)
0 12 24 30 36 42 48 54 60
1.0
0.9
0.8
0.7
0.6
0.5
0.4
Population Norma
Docetaxel Nivolumab
aBharmal M, Thomas J 3rd. Value Health. 2006;9:262–71. bPickard AS, et al. Health Qual Life Outcomes. 2007;5:70. 39
Higher scores indicate better health status. Only time points that had PRO data available for ≥5 patients in either treatment arm are plotted on the graph.
Week
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PD-1 axis immunotherapy for NSCLC
1) A new generation of expanded phase 1/2 trials for activity evaluation
2) Evidence-based data for checkpoint inhibitors monotherapy 3) Current evidence for biomarker-based selection of NSCLC patients
• Tumour mutation load • PD-L1 expression • Tumour infiltrating lymphocytes • Tumour molecular characteristics
4) Upfront for checkpoint inhibitors
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Mutation load counts, but is not realistic in our daily practice
Rizvi, Science 2015
Efficacy also correlates with the molecular smoking signature characteristic of squamous carcinoma
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Intricate role of PD-1 signalling with different cell types
Image from J. Allison
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PD-L1 positivity is a flexible concept
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Limitations in defining PD-L1 as the biomarker
•PD-L1 “biomarker” is to be defined (mAB, platform & technique, criteria & thresholds, tumour material & sampling)
•PD-L1 expression is dynamic
•PD-L1 is heterogeneous within tissue
•Cytoplasmic vs membranous?
•Quality of the biopsy
•Importance of co-localization with TILs
•We dont know how to handle a continuous variable as a biomarker and need a prospective validation!
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PD-L1 as a biomarker
0
2
4
6
8
10
12
0 10 20 30 40 50 60 70 80 90 100
PD-L1 IHC score
‘Negative’ ‘Positive’
Response?
Differential effects depend upon the Dose-response relationship
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What do we know about T-cells infiltration in NSCLC
Liu H et al. Cancer Immunol Immunother 2012
Presence of TILs associated with increased recurrence-free survival1
Recu
rren
ce-F
ree
Surv
ival
(%)
Survival Time (Months) 24 36 12 48 60 0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
FoxP3+ cell <3 FoxP3+ cell ≥3 Re
curr
ence
-Fre
e Su
rviv
al (%
) 1.0
0.8
0.6
0.4
0.2
0.0 0.0 10 20 30 40 50 60
Survival Time (Months)
TIL– TIL+
P=0.011
Higher NSCLC-Infiltrating Tregs associated with worse recurrence-free survival2
1. Shimizu K, et al. J Thorac Oncol. 2010 2. Horne ZD, et al. J Surg Res. 2011
TILs must be further characterized. Tissue is a limiting factor!
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High Tumor Teff gene signature Is associated with improved
OS benefit with atezolizumab
Teff: CD8A, GZMA, GZMB, IGN-γ, EOMES, CXCL9, CXCL10, TBX21 Schmid, ECCO 2015
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PD-L2/B7
• High expression of each component of the axis is associated with improved OS with atezolizumab.
• Blocking PD-1/PD-L1 signaling in highly immunologically dysfunctional tumors my be capable of reversing T-cell exhaustion and improving clinical benefit.
Schmid, ECCO 2015
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Response with durvalumab according to PD-L1 and IFNγ mRNA status
Higgs, et al. ECC 2015
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Are we ready to select patients ?
Schreiber, Science. 2011
Complexity of immune surveillance and escape might prevent us from identifying a simple & unique predictive biomarker.
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Checkpoint inhibitors in « oncogene-addicted » NSCLC ?
MK-3475 N ORRa % (95% CI)
EGRFR mutation 36 14 (5-30)
ALK rearrangement 6 17 (0-64)
Gettinger, ASCO 2014 Garon, ESMO 2014 Horn, WLCC 2013
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The real-life study…
ALK treated patients represent a very small subset today. However, ALK protein might represent an interesting neo-antigen. Hussein , WCLC 2015
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Need to induce T-cell response •Combinations with other immunotherapy strategies: checkpoints modulators/ TLR agonists / oncolytic viruses /cytokines / vaccines /targeted therapies • What about chemotherapy?
Do we expect a potential role for immunotherapy in
this patient population?
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Functional MHC class 1 presentation AND Probably (but not exclusively): -PD-L1 positivity AND/OR -Specific TILs tumour infiltration AND/OR -High mutation load (smoking, mismatch repair…) AND/OR -Expression of potent neo-antigens AND/OR -Others: interferon signature, …?
Are we confident in accurately identifying
these patients?
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PD-1 axis immunotherapy for NSCLC
1) A new generation of expanded phase 1 trials for activity evaluation
2) Evidence-based data for checkpoint inhibitors monotherapy 3) Current evidence for biomarker-based selection of NSCLC patients
• Tumour mutation load • PD-L1 expression • Tumour infiltrating lymphocytes • Tumour molecular characteristics
4) Upfront perspectives for checkpoint inhibitors
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Focus on pembrolizumab first line data (Keynote 001)
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Median PFS was 6.1 months in all treated patients and 12.5, 4.2 and 3.5 mos in >50%,1-49% and <1% resp. OS was not reached in all treated patients or in patients with ≥50% staining 16.2 months and 10.4 in patients with staining in 1%–49% and <1% of cells,
respectively
Rizvi, ASCO 2015
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CheckMate 012 Study Design: Nivolumab Plus Ipilimumab in First-line NSCLC
Primary endpoint: safety and tolerability Secondary endpoints: ORR (RECIST v 1.1) and PFS rate at 24 wks Exploratory endpoints: OS; efficacy by PD-L1 expression
Stage IIIB/IV NSCLC (any histology); no prior chemotherapy for advanced disease; ECOG PS 0 or 1
Nivo 3 mg/kg IV Q2W until disease progression or unacceptable toxicitya
Nivo 1 mg/kg IV Q3W x 4 +
Ipi 1 mg/kg IV Q3W x 4
Nivo 1 mg/kg IV Q2W +
Ipi 1 mg/kg IV Q6W
Nivo 3 mg/kg IV Q2W +
Ipi 1 mg/kg IV Q12W
Nivo 3 mg/kg IV Q2W +
Ipi 1 mg/kg IV Q6W
Until disease progression or unacceptable toxicitya
• Here, we report results from new cohorts explored to permit synergistic activity and acceptable safety profile of combination treatment with nivolumab and ipilimumab
aPatients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit 59
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• There were no treatment-related deaths. Toxicities mailnly GI, hepatic, endocrine, skin, lung
Nivo 1 + Ipi 1 Q3W
(n = 31)
Nivo 1 Q2W + Ipi 1 Q6W
(n = 40)
Nivo 3 Q2W + Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W + Ipi 1 Q6W
(n = 39)
Nivo 3 Q2Wa
(n = 52)
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Any Grade
Grade 3–4
Treatment-related AEs, % 77 29 73 35 74 29 69 28 71 19
Treatment-related AEs leading to discontinuation, % 13 10b 8 8c 5 3d 10 10e 10 10f
Nivolumab Median number of doses (range) Median duration of therapy, wks (range)
4
(1–42) 12.0
(3.0–92.0)
7
(1–26) 16.0
(2.0–59.0)
13
(1–26) 28.7
(2.0–52.0)
8
(1–25) 18.0
(2.0–53.0)
8
(1–62) 16.0
(2.0–129.6)
Ipilimumab Median number of doses (range) Median duration of therapy, wks (range)
NC
1–4g
11.6 (3.0–24.0)
3
(1–9) 17.6
(6.0–59.0)
3
(1–5) 35.7
(12.0–60.0)
2
(1–9) 15.0
(6.0–54.0)
NA
NA
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Nivo 1 + Ipi 1 Q3W
(n = 31)
Nivo 1 Q2W + Ipi 1 Q6W
(n = 40)
Nivo 3 Q2W + Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W + Ipi 1 Q6W
(n = 39) Nivo 3 Q2Wa
(n = 52)
Confirmed ORR, % (95% CI) 13 (4, 30)
25 (13, 41)
39 (24, 57)
31 (17, 48)
23 (13, 37)
Confirmed DCR, % (95% CI) 55 (36, 73) 58 (41, 73) 74 (57, 87) 51 (35, 68) 50 (36, 64)
Best overall response, %
Complete response Partial response
Unconfirmed partial response
0 13 3
0 25 3
0 39 5
0 31 8
8 15 0
Stable disease Progressive disease Unable to determine
42 35 6
33 30 10
34 13 8
21 26 15
27 38 12
PFS rate at 24 wks, % (95% CI) 55 (36, 71) NC 63 (44, 76) NC 41 (27, 54)
Median PFS, mos (95% CI) 10.6 (2.1, 16.3) 4.9 (2.8, ) 8.0 (4.2, ) 8.3 (2.6, ) 3.6 (2.3, 6.6)
Median OS, mos (95% CI) NR (11.5, ) NR (8.9, ) NR NR (8.7, ) 22.6 (14.9, )
Median length of follow-up, mos (range)
16.6 (1.8–24.5)
6.2 (0.4–13.1)
8.4 (0.9–12.3)
7.7 (1.1–12.2)
14.3 (0.2–30.1)
Summary of Efficacy
61 NR: the time point at which the percent of survivors drops below 50% has not been reached due to insufficient number of events and/or follow up. aResults for Nivo 3 Q2W are reported based on a March 2015 DBL
• Median DOR was not reached in any arm • Unconventional immune-related responses were observed in arms Nivo 3 Q2W + Ipi 1 Q12W (n = 2), Nivo 3 Q2W + Ipi 1 Q6W (n = 1) and
Nivo 3 Q2W (n = 3)
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Efficacy by Tumor PD-L1 Expression
62
≥1% PD-L1 expression <1% PD-L1 expression
Nivo 1 + Ipi 1 Q3W
(n = 12)
Nivo 1 Q2W
+ Ipi 1 Q6W
(n = 21)
Nivo 3 Q2W
+ Ipi 1 Q12W
(n = 21)
Nivo 3 Q2W
+ Ipi 1 Q6W
(n = 23)
Nivo 1 + Ipi 1 Q3W
(n = 13)
Nivo 1 Q2W
+ Ipi 1 Q6W
(n = 7)
Nivo 3 Q2W
+ Ipi 1 Q12W (n = 9)
Nivo 3 Q2W
+ Ipi 1 Q6W
(n = 7)
ORR, % 8 24 48 48 15 14 22 0
mPFS, wks (95% CI)
11.5 (7.1, )
21.1 (11.4, )
34.6 (15.9, 35.3)
NR (15.4, )
34.0 (8.9, )
NR (10.1, )
23.1 (4.0, )
10.3 (7.4, 12.7)
PFS rate at 24 wks, % (95% CI)
42 (15, 67)
40 (18, 61)
74 (48, 88)
65 (42, 81)
57 (25, 80)
NC
39 (9, 69)
0
NR: the time point at which the percent of survivors drops below 50% has not been reached due to insufficient number of events and/or follow up
• All patients had available pretreatment tumor samples; 76% (113/148) had samples evaluable for PD-L1 expression • Median DOR was not reached in any arm, regardless of PD-L1 expression
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Phase Ib GP28328 Atezolizumab and chemotherapy study design
• Primary endpoint: safety (including dose-limiting toxicities) • Secondary endpoints: pharmacokinetics; best overall response; objective response rate (ORR); duration of
response (DOR); progression-free survival (PFS) • Date of cut-off: 10 Feb 2015; median safety follow-up: 128.5 days (4.2 months)
Atezolizumab 15mg/kg i.v. q3w + carboplatin AUC=6 i.v. q3w + paclitaxel 200mg/m2 i.v. q3w (4–6 cycles)*
Atezolizumab 15mg/kg i.v. q3w + carboplatin AUC=6 i.v. q3w (4–6 cycles) + pemetrexed 500mg/m2 i.v. q3w
(maintenance pemetrexed permitted)*
Solid tumours ECOG PS 0–1 (n=58 NSCLC cohort at data cut-off; n=25
per arm planned)
Atezolizumab 15mg/kg i.v. q3w + carboplatin AUC=6 i.v. q3w + nab-paclitaxel 100mg/m2 i.v. q1w (4–6 cycles)*
Arm C: NSCLC
Arm D: NSCLC
Arm E: NSCLC
Camidge, WCLC 2015
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Summary of response by RECIST v1.1 (response-evaluable patients*)
• Data are preliminary; ~25 patients will be included in each arm for final analysis
Arm C – cb/pac (n=8)
Arm D – cb/pem (n=17)
Arm E – cb/nab (n=16)
All NSCLC patients (n=41)
Overall response, n (ORR %) 4 (50.0) 13 (76.5) 9 (56.3) 26 (63.4)
[95% CI for ORR] [15.7–84.3] [50.1–93.2] [29.9–80.3] [46.9–77.9]
Complete response, n (%) 0 (0) 0 (0) 4 (25.0) 4 (9.8)
Partial response, n (%) 4 (50.0) 13 (76.5) 5 (31.3) 22 (53.7)
Stable disease, n (%) 4 (50.0) 1 (5.9) 4 (25.0) 9 (22.0)
Progressive disease, n (%) 0 (0) 2 (11.8) 2 (12.5) 4 (9.8)
Missing or not evaluable, n (%) – 1 (5.9) 1 (6.3) 2 (4.9)
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Depth of response and changes in tumor burden by treatment arm
Arm C – cb/pac (n=8) Arm D – cb/pem (n=17) Arm E – cb/nab (n=16)
No unexpected toxicity!
Max
imum
SLD
redu
ctio
n fr
om b
asel
ine
(%)
100
50
0
–50
–100
9 –7
Complete response Partial response Progressive disease Stable disease
–12
–31 –31 –38 –41 –42 –47 –50 –53 –57 –57 –57 –58
–69 Max
imum
SLD
redu
ctio
n fr
om b
asel
ine
(%)
100
50
0
–50
–100
–16 –22 –23 –25
–43 –45
–64
–84
Complete response Partial response Progressive disease Stable disease
0 42 84 126 168
Time on study (days)
210 252 294 336 378 420 450
–100
–80
–60
–40
–20
0
20
40
60
80
100 PD (n=2) PR/CR (n=13) SD (n=1) Progression* Discontinued New lesion
Max
imum
SLD
redu
ctio
n fr
om b
asel
ine
(%)
100
50
0
–50
–100
11 9
Complete response Partial response Progressive disease Stable disease
–17
–21 –21 –22 –43
–67 –72 –72 –76
–86 –87
–100 –100
0 42 84 126 168
Time on study (days)
210 252 294 336 378 420 450
–100
–80
–60
–40
–20
0
20
40
60
80
100 PD (n=2) PR/CR (n=9) SD (n=4) Progression* Discontinued New lesion
Cha
nge
in S
LD fr
om b
asel
ine
(%)
0 42 84 126 168
Time on study (days)
210 252 294 336 378 420 450
–100
–80
–60
–40
–20
0
20
40
60
80
100 PR/CR (n=4) SD (n=4) Progression* Discontinued New lesion
Cha
nge
in S
LD fr
om b
asel
ine
(%)
Cha
nge
in S
LD fr
om b
asel
ine
(%)
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Chemotherapy combination trials GP28328
PhIb solid tumours (incl. 1L NSCLC) atezo + chemo
(n=58)
KEYNOTE-021 PhI/II 1L NSCLC
pembro + chemo (n=49)
CheckMate 012 PhI 1L NSCLC
nivo (N) + chemo (n=56)
CheckMate 012 PhI 1L NSCLC
nivo (N) + ipi (I) (n=49)
Atezo + carbo/
pac
Atezo + carbo/ pem
Atezo + carbo/ abrax
Pembro + carbo/
pac
Pembro + carbo/ pem
N10 + gem/ cis
N10 + pem/ cis
N10 + carbo/
pac
N5 + carbo/
pac
N1 q3w +
I1 q3w
N1 q2w +
I1 q6w
N3 q2w +
I1 q12w
N3 q2w +
I1 q6w
n 8* 17* 16* 25 24 12 15 15 15 31 40 38 39
ORR, %
Grade 3–4 treatment-
related AEs
69% 35% 45%
71% 54% 85% 32% 38% 25% 47% 73% 29%
29%
35%
29%
28%
0
25
50
75
100
50
77
56
28
58
33 47 47 43
13 25
39 31
Refs.
Camidge, et al. WCLC 2015
Giaccone, et al. ECC 2015
Papadimitrakopoulos, et al. ASCO 2015
Gettinger, et al. ESMO 2014
Rizvi, et al. WCLC 2015
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Phase III trials in 1st-line advanced NSCLC (selected)
Nivolumab
Pembrolizumab
MEDI4736
SOC=standard of care. ClinicalTrials.gov. http://www.clinicaltrials.gov/. Accessed August 2015.
KEYNOTE-042 Pembrolizumab
SOC chemotherapy Primary endpoint: OS PD-L1+ NSCLC
N = 1240
Primary endpoints: OS, PFS
Treatment-naïve or recurrent NSCLC N = 1980 CheckMate 227
Nivolumab
Nivolumab + ipilimumab
Platinum-based chemotherapy
Primary endpoint: PFS Treatment-naïve or recurrent PD-L1+ NSCLC N = 535 CheckMate 026
Nivolumab
Investigator’s choice chemotherapy
KEYNOTE-024 Pembrolizumab
Platinum-based chemotherapy Primary endpoint: PFS PD-L1 strong NSCLC
N = 300
Atezolizumab
IMpower 111 Atezolizumab
Gemcitabine + cisplatin or carboplatin Primary endpoint: PFS Stage IV squamous PD-L1+ NSCLC
N = 400
IMpower 150
Atezolizumab + carboplatin + paclitaxel
Bevacizumab + paclitaxel + carboplatin
Primary endpoint: PFS Stage IV non-squamous NSCLC N = 1200
Atezolizumab + bev. + paclitaxel + carboplatin
IMpower 130 Atezolizumab + carboplatin + nab-paclitaxel
Carboplatin + nab-paclitaxel Primary endpoint: PFS Stage IV non-squamous NSCLC
N = 550
IMpower 110 Atezolizumab
Carboplatin or carboplatin + pemetrexed Primary endpoint: PFS Stage IV non-squamous PD-L1+
NSCLC N = 400
IMpower 131
Atezolizumab + carboplatin + nab-paclitaxel
Carboplatin + nab-paclitaxel
Primary endpoint: PFS Stage IV squamous NSCLC N = 1200
Atezolizumab + carboplatin + paclitaxel
Primary endpoint: PFS Advanced NSCLC N = 675
MYSTIC
MEDI4736
MEDI4736 + tremelimumab
SOC chemotherapy
IPI + Paclitaxel/Carboplatin IPI
Pbo + Paclitaxel/Carboplatin Pbo Primary endpoint: OS Squamous NSCLC
N = 920 CA184-104
IPI + Paclitaxel/Carboplatin IPI
Pbo+ Paclitaxel/Carboplatin Pbo Primary endpoint: OS Squamous NSCLC
N = 867 CA184-153
Ipilimumab
Anti-
PD-1
/PD
-L1
Anti-
C
TLA-
4
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Thanks for your attention