Biomarkers of Response to Immunotherapy
Alastair Greystoke
Senior Lecturer and Honorary Consultant in Medical Oncology
1
@AlastairGreyst2
Email; [email protected]
Disclosures
Consultancy and speakers fee for Roche, MSD, BMS, AstraZeneca, Boehringer-Ingelheim, Takeda, Pfizer and Novartis
NSCLC Biased
Not comprehensive
1549
Pubmed search “cancer immunotherapy biomarker”; 13370 papers
What is a biomarker?
“A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”
Biomarkers Definitions Working Group National Institute of Health 2001
A Perfect Biomarker?
There’s no such thing as a…Perfect Biomarker for Immunotherapy
Why do we need a biomarker?
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8
129 49 27 20 17 16 3 1 0
YearsNo. at Risk
OS
(%)
1 y OS, 42%
2 y OS, 24%
3 y OS, 18% 5 y OS, 16%
Brahmer et al AACR 2017
Nivolumab in NSCLC in Checkmate -003
8
Updated 3 year overall survival Wolchok et al NEJM 2017 and ESMO 2017
Why do we need a biomarker?
9
More than one organ involved in many patients in CheckMate 067
Larkin et al (2015). Efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naïve patients with advanced melanoma (MEL) (CheckMate 067). Presented at the annual meeting of the European Society of Medical Oncology, Vienna. Abstract Number: 3303
10
Checkmate 038 – one year of either ipi (10 mg/kg) or nivo – with matched placebos
ESMO 2017 and Weber et al NEJM 2017
Why do we need a biomarker?
Champiat et al CCR 2016
Why do we need a biomarker?
Dec 2016 Feb 2017
Why do we need a biomarker?
Fig. 1
Eur J Cancer 2017 74, 55-72
KEYNOTE-010: Overall survival in PD-L1 subgroups
Adapted from Herbst RS et al. 2016.
Analysis cut-off date: 31 March 2016. CI, confidence interval; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand 1; TPS, tumour proportion score.
1. Herbst RS et al. Abstract LBA48. Presented at ESMO 2016, 7-11 October 2016, Copenhagen, Denmark.
PD-L1 TPS ≥1% PD-L1 TPS ≥50%
Pembrolizumab
2 mg/kg Docetaxel
HR [95%
CI]P value
Median OS
(months)10.5 8.6
0.72
[0.60–0.87]0.0003
Pembrolizumab
2 mg/kg Docetaxel
HR [95%
CI]P value
Median OS
(months)15.8 8.2
0.54
[0.39–0.73]0.00004
CheckMate 057: OS by PD-L1 expression
Adapted from Borghaei H et al. 2015.
CI, confidence interval; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand
1. Borghaei H et al. N Engl J Med 2015;373:1627-1639. Appendix.
≥5% PD-L1 expression level <5% PD-L1 expression level
CheckMate 057: OS by PD-L1 expression
Adapted from Borghaei H et al. 2015.
CI, confidence interval; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand
1. Borghaei H et al. N Engl J Med 2015;373:1627-1639. Appendix.
Nivolumab
Docetaxel
HR (95% CI)
Median OS
(months)19.9 8.0
0.40 (0.27–0.58)
Nivolumab
Docetaxel
HR (95% CI)
Median OS
(months)9.9 10.3
0.96 (0.74–1.25)
≥10% PD-L1 expression level <10% PD-L1 expression level
100
90
80
70
60
50
40
30
10
0
20
3024211815129630 27
Time (months)
Overa
ll s
urv
ival
(%)
100
90
80
70
60
50
40
30
10
0
20
3024211815129630 27
Time (months)O
vera
ll s
urv
ival
(%)
No. at risk
86 77 67 61 58 53 44 19 11 3 0
79 63 50 35 23 21 13 3 1 1 0
No. at risk
145 104 90 78 65 56 48 28 15 1 0
145 126 99 79 59 46 35 16 4 3 0
0
0.2
0.4
0.6
0.8
1
1.2
1% 5% 10% 1% 5% 10%
Above BiomarkerThreshold
Below BiomarkerThreshold
Haz
ard
Rat
io
Squamous Cancer (Checkmate 017)
Non-Squamous Cancer (Checkmate 057)
Benefit of PDL1 as a Biomarker May Depend on Context?
The confusion of PDL1 testing (in lung)
Agent Antibody Clone
Platform Cell Preferred Cut-off (s)
Enforced Cut-off
Nivolumab 28-8 Dako Tumour 1% 10%
Pembrolizumab 22C3 Dako Tumour 1, 50%
Atezolizumab SP142 Ventana Tumour/ Infiltrating
lymphocytes
TC/IC 0-3
Durvalumab SP263 Ventana Tumour 25% 1%
The confusion of PDL1 testing
Agent Lung Cell Lung Preferred Cut-off (s)
Bladder Cell Bladder Preferred Cut-off
(s)
Nivolumab Tumour 1% Tumour 1%
Pembrolizumab Tumour 1, 50% Tumour/ Infiltrating
lymphocytes
10%
Atezolizumab Tumour/ Infiltrating
lymphocytes
TC/IC 0-3 Infiltrating lymphocytes
5%
Durvalumab Tumour 25% Tumour/ Infiltrating
lymphocytes
25%
Figure 2
Journal of Thoracic Oncology 2017 12, 208-222DOI: (10.1016/j.jtho.2016.11.2228)
Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions
Sorting Out the Mess; the Blue-print Project?
Date of download: 11/30/2018Copyright © 2016 American Medical
Association. All rights reserved.
From: Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non–Small-Cell Lung Cancer
JAMA Oncol. 2016;2(1):46-54. doi:10.1001/jamaoncol.2015.3638
PD-L1 Protein Heterogeneity Using DiaminobenzidinePD-L1 indicates programmed cell death 1 ligand 1.
Figure Legend:
89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer
N=22 across 3 tumour types
Bensch et al Nature Medicine 2018
PDL1
• Some benefit in some contexts
• Relatively easy to integrate into routine practice
• Not perfect
• Confused by different anti-bodies, different cut-offs, different cells (sometimes even within the same drug programme).
Alexandrov et al Nature. 2013 500(7463): 415–421.
Tumour Mutational Burden
Rosemberg et al., Lancet 2016
Yarchoan et al., NEJM 2017
Not the same thing-TMB and PD-L1?
Tumor PD-L1 expression
TMB ≥10 mut/Mbb
TMB <10 mut/Mbb
<1%
29%≥1%
71%
<1%
29%≥1%
71%
<1%
29%≥1%
71%
<1%
29%≥1%
71%
Hellmann et al., NEJM 2018
27
PFS by Tumor Mutation Burden TertileCheckMate 026 TMB Analysis: Nivolumab in First-line NSCLC
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12
Months
15 18 21 24
PF
S (
%)
High
Low
Medium
Medium
n = 49 n = 47
3.6
(2.7, 6.9)
Low
n = 62
4.2
(1.5, 5.6)
9.7
(5.1, NR)
Median PFS, months
(95% CI)
High
Nivolumab Arm Chemotherapy Arm
Medium
n = 53 n = 60
6.5
(4.3, 8.6)
Low
n = 41
6.9
(5.4, NR)
5.8
(4.2, 8.5)
Median PFS, months
(95% CI)
High100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 12
Months
15 18
High
Low
Medium
21
Ann Oncol. 2018;29(Supplement_4):iv192-iv237. doi:10.1093/annonc/mdy275
Not all Mutations are equal
McGranaham et al., Science 2016
Are individual Mutations as Important
Skoulidis et al., Cancer Discovery 2018
What about cfDNA
D’Arcangelo and Greystoke Biomarkers in Medicine 2015 ;9(10):1011-23.
Gandara DR, et al. bTMB in POPLAR & OAK
Increasing Atezolizumab benefit with higher
bTMB cut-points in OAK Trial
Progression-Free Survival – OAK Overall Survival – OAK
• Enrichment of PFS benefit was observed in the bTMB ≥16 subgroup,
while OS was consistent between the bTMB ≥16 subgroup and the BEP
Gandara DR et al.., Nat Med 2018
Change in cfDNA predicts outcome
Raja et al Clin Can Res 2018 doi 10.1158/1078-0432.CCR-18-0386
TMB
• Added information over PDL1
• Difficult to integrate into routine practice
– ?cfDNA easier
• Not all mutations equal
• Confused by different assays different cut-offs.
Inflammed
Checkpoint Inhibitor
Immune Contexture
Immune Excluded
Inflammed
Immune Desert Immune Excluded
Inflammed
By ESO/S. Brunier -http://www.eso.org/public/images/armazonesparanal/, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=26458337
Immune Desert Immune Excluded
Inflammed
RadiotherapyVirusesAnti-CTLA4(Chemotherapy)
CD8
CD4
Cancer Nest Stroma
Meng et al Clin Lung Cancer. 2018 Sep 24.
Kaplan–Meier analysis of OS and PFS in NSCLC patients by IFNγ mRNA signature (A and C)
and PD-L1 status (B and D) and in urothelial cancer patients by IFNγ mRNA signature (E and
G) and PD-L1 status (F and H).
Brandon W. Higgs et al. Clin Cancer Res 2018;24:3857-
3866
©2018 by American Association for Cancer Research
Brandon W. Higgs et al. Clin Cancer Res 2018;24:3857-3866
Chen and Mellman Nature 541, 321–330
Chen and Mellman Nature 541, 321–330
Blank CU et al. Science 2016; 352:658
Sayano et al J Immunother Cancer. 2018; 6: 129.
Should we just go simple Neutrophil/Lymphocyte ration in NSCLC treated with anti-PD1
There’s no such thing as a…Perfect Biomarker for Immunotherapy
Questions?