The evolving landscape of biomarkers for immune checkpoint inhibitors in thoracic oncology

(1)

The evolving landscape of biomarkers for immune checkpoint inhibitors

in thoracic oncology

Paul Hofman

Laboratory of Clinical and Experimental Pathology FHU OncoAge, Inserm U1081/CNRS 7284

Côte d’Azur University, Nice, France

(2)

Biomarkers

Response Resistance Toxicity

Hyperprogression

(3)

Biomarkers

Response

(4)

I-IPD-L1 TMB

TCR

GEP

Other

(5)

Two independent predictive biomarkers

IHC PD-L1 Tumor mutational burden

+ EGFR, ALK, ROS1 & BRAF

Validated

Daily practice

Not Validated

Clinical trials

(6)

PD-L1 has limitations

– Patient with 0% of PD-L1 IHC positivity can be good responder – Patient with > 50% of PD-L1 IHC positivity can be non responder

– Heterogeneity of PD-L1 IHC staining limits the assessment in small biopsies – Inter & intra oberver variability

– PD-L1 IHC is not well-validated to date

– Many PD-L1 clones, many devices, different performances – Many cut off (>1%, > 25%, > 50%)

– Clinical value of positive immune cells for PD-L1 is controversial

(7)

PD-L1 IHC

<1%

>50%

Prembrolizumab first line

Chemotherapy first line

…..or…..!

(8)

Matched specimens in NSCLC patients

Ilie et al, Ann Oncol 2016

(9)

> 50% TC ?

First line I-O according to the PD-L1 expression on TC (May 2018)

> 25% TC ? > 1% TC ? …All comers ?

(10)

Controversies about EMA decision

EMA excluded patients with PD-L1 <1%

from access to durvalumab

Expands pembrolizumab indication for first- line treatment of NSCLC (TPS ≥1%).

Accessed April 11, 2019.

https://www.fda.gov/Drugs/InformationOnD rugs/ ApprovedDrugs/ucm635857.htm.FDA

(11)

Summary of interobserver concordance studies for PD-L1 IHC assessment in NSCLC

Low concordance

at TPS 1% !

(12)

Tumor mutational burden

What’s next ?

(13)

(14)

CheckMate 026: Nivolumab in first-line in stage IV NSCLC PFS by TMB subgroup

Nivolumab Chemotherapy

(15)

CheckMate 227: PFS in Patients With High TMB (≥10 mut/Mb) by Tumor PD-L1 Expression

≥1% PD-L1 expression <1% PD-L1 expression

Nivo + ipi (n = 38)

Chemo (n = 48) Median PFS, mo^b 7.7 5.3 HR

95% CI

0.48 0.27, 0.85

Chemotherapy Nivolumab + ipilimumab

Months 0

20 40 60 80 100

0 3 6 9 12 15 18 21 24

1-y PFS = 45%

1-y PFS = 8%

1-y PFS = 42%

1-y PFS = 16%

PFS (%)

Months 0

20 40 60 80 100

0 3 6 9 12 15 18 21 24

Nivo + ipi (n = 101)

Chemo (n = 112) Median PFS, mo^a 7.1 5.5 HR

95% CI

0.62 0.44, 0.88

2018

(16)

CheckMate 227: PFS in Patients With High TMB (≥10 mut/Mb) by Tumor PD-L1 Expression

≥1% PD-L1 expression <1% PD-L1 expression

Nivo + ipi (n = 38)

Chemo (n = 48) Median PFS, mo^b 7.7 5.3 HR

95% CI

0.48 0.27, 0.85

Months 0

20 40 60 80 100

0 3 6 9 12 15 18 21 24

1-y PFS = 45%

1-y PFS = 8%

1-y PFS = 42%

1-y PFS = 16%

PFS (%)

Months 0

20 40 60 80 100

0 3 6 9 12 15 18 21 24

Nivo + ipi (n = 101)

Chemo (n = 112) Median PFS, mo^a 7.1 5.5 HR

95% CI

0.62 0.44, 0.88

(17)

(18)

The pros The cons

1. Alternative / complementary biomarker to PD-L1 2. Compatible with targeted panel NGS tests

3. Less heterogeneity than PD-L1 (?)

1. Turnaround times for getting the results 2. Sensitivity links to DNA quantity/quality

3. Proposed cutpoints for TMB High

4. Reproducibility across sequencing platforms 5. Cost effectivness

6. Accreditation is mandatory

TMB

(19)

Lung Cancer with a High Tumor Mutational Burden

VanderLaan PA, et al. N Engl J Med 2018

VanderLaan PA. N Engl J Med 2018; 379: 11.

In-House Testing versus

External to Referral Center?

(20)

TMB

Main challenge

TMB

in thoracic oncology

(21)

Samstein et al, Nat Genet. 2019 Feb;51(2):202-206.

Which cutoff?

(22)

Estimated number of patients over 100 cases who will benefit to ICIs according to a high TMB

Without

Without TAT consideration

(>10 mut/Mb)

(<10 mut/Mb)

(23)

The tumor neoantigen hypothesis

(24)

TCR repertoire variability may serve as a predictive biomarker for immunotherapy in solid tumors,

including those where TMB is not predictive of response

(25)

Biomarkers

Resistance

(26)

Skoulidis et al, Cancer Discovery May 2018

Patients treated by PD1/PD-L1 inhibitors

STK11 mutation

(27)

Biomarkers

Toxicity

TCR repertoire ?

(28)

Biomarkers

Hyperprogression

MDM2 amplification?

EGFR amplification?

(29)

More and more biomarkers in I-O pipeline

PD-L1 TMB

TCR

GEP

?

(30)

Tumor mutational burden &

genomic alterations PD1/PD-L1 and other ICIs

Adaptative immunity TCR repertoire SNPs (germline DNA)

Microbiome

Innate immunity

(31)

Combination of

therapies Combination of

biomarkers

(32)

J Clin Oncol. 2019 Feb 1;37(4):318-327

(33)

Which targets?

Which methods?

How many fields to assess per tumor?

Primary and/or metastatic site (s)?

How to quantify the different signals?

How to assess the different cut off?

&

How to integrate genomic associated data ?

(34)

Comment optimiser? How to optimize?