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Biomarkers of Response to Immunotherapy

Alastair Greystoke

Senior Lecturer and Honorary Consultant in Medical Oncology

1

@AlastairGreyst2

Email; alastair.greystoke@newcastle.ac.uk

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

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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?