pd-l1 expression as a potential predictive biomarker -...

Paolo A. Ascierto, MDUOC Melanoma, Immunoterapia Oncologica e Terapie InnovativeIstituto Nazionale Tumori – Fondazione “G. Pascale”, Napoli, Italy

PD-L1 expression as a potential predictive biomarker


Disclosures• Employment or Leadership Position: None • Consultant/Advisory Role: Bristol-Myers Squibb,

Roche-Genentech, Merck Sharp & Dohme, Ventana, Novartis, Amgen, Array

• Stock Ownership: None • Honoraria: None• Research Funding: Bristol-Myers Squibb, Roche-

Genentech, Ventana, Array • Expert Testimony: None• Other Remuneration: None


The ideal predicitve biomarkers should be able to predict the patients who can havea benefit from a treatment, from thosewho cannot have such a benefit.

In other words can be useful for patientselection.

PD-L1 expression as a potential predictive biomarker: considerations

a) Immunological (not molecular) marker


a) Immunological (not molecular) markerb) Dynamic and inducible markers (IFN,

RT, etc.)



RT, etc.) c) Topographical distributions in the

tumor

Topographical localization

Lyford-Pike S, et al. CCR 2012




tumord) Different antibodies used in IHC




tumord) Different antibodies used in IHCe) Different cut-off and scoring system

used

BMS Merck Roche AZ

mAb clone 28-8 22C3 SP142 SP263

Automated Yes Yes Yes Yes

Diagnostic partner Dako Dako Ventana Ventana

Scoring Tumor cells(membrane)

Tumor cells (membrane)

Tumor and/orimmune cells (membrane)

Tumor cells (membrane)

Positive cutoff

≥ 5%(also studied ≥ 1% and ≥ 10%

thresholds)

≥ 1% for trial enrollment

other analysis at > 50%

• TC3 (>50%) or IC3 (>10%)

• TC2/3 or IC2/3 (>5%)

• TC 1/2/3 or IC 1/2/3 (>1%)

• TC0 and IC0 (0%)

>25%

PD-L1 IHC methods

PD-L1 IHC staining

Garon E, et al. NEJM 2015

PS <1% PS 1-49% PS > 50%

NSCLC

Melanoma

RCC

**2 pts still under evaluation

42 pts include 18 MEL, 10 NSCLC, 7 CRC, 5 RCC, and 2 CRPC.

Correlation of PD-L1 expression in pretreatment tumor biopsies with clinical outcomes

Association Between Pretreatment Tumor PD-L1 Expression and Clinical Response

Response Status

PD-L1 Positive no. (%)

PD-L1 Negativeno. (%)

Totalno. (%)

CR/PR 9 (36) 0 9 (21)

Non responder 16* (64) 17 (100) 33 (79)

All Patients 25 17 42

Topalian S, et al. NEJM 2012;366:2443-2454.

Prop

ortio

n of patients

p=0.006

0

0,2

0,4

0,6

0,8

1

PD‐L1(+) PD‐L1(‐)

PD‐L1(+)PD‐L1(‐)9/25

16*/25

17/17

0/17† analysis not pre-planned and based on subset of subjects'.

†

PD-L1 as a potential biomarker: response accordingto PD-L1 expression in NSCLC and melanoma

1. Antonia SJ, et al. Poster presentation at WCLC 2013. J Thorac Oncol 2013;8(Suppl 2):abstract: P2.11-035; 2. Garon EB, et al. Oral presentation at WCLC 2013. J Thorac Oncol 2013;8(Suppl 2):abstract: MO18.02; 3. Horn L, et al. Mini-Oral presentation at WCLC 2013. J Thorac Oncol. 2013;8(Suppl 2):abstract: MO18.01. Bottom table Presented by: Walter J. Urba, MD, PhD

TumourPDL1+

PositiveORR n/N (%)

PDL1-Negative

ORR n/N (%)

MPDL3280A (Hamid #9010) Melanoma 4/15 (27) 3/15 (20)

Nivolumab (Weber #9011) Melanoma 8/12 (67) 6/32 (19)

Nivolumab (Grosso #3016) Melanoma 7/16 (44) 3/18 (17)

Nivolumab (Topalian, N Engl J Med, 2012) NSCLC 9/25 (36) 0/17 (0)

Nivolumab (Antonia, WCLC 2013) NSCLC 5/31 (16) 4/32 (13)Pembrolizumab (Garon, WCLC 2013) NSCLC 4/7 (57) 2/22 (9)MPDL3280A3 (Horn, WCLC 2013) NSCLC 8/26 (31) 4/20 (20)Nivolumab/ Ipilimumab (Callahan #3003) NSCLC 4/10 (40) 8/17 (47)

Key questions• Variability in tissue collection timing, cell sampling, types of assay, IHC criteria

CA209-037: Tumor Burden Change by PD-L1 Status

Max

imum

Cha

nge

from

B

asel

ine

in T

arge

t Les

ion

(%)

PD-L1+

PD-L1-

Nivolumab ICCORR* 44%

ORR* 20%

ORR* 9%

ORR* 13%

*ORR among treated patients in the ORR population

100

75

50

25

0

-25

-50

-75

-100

Patients

100

75

50

25

0

-25

-50

-75

-100Confirmed respondersTruncated to 100%

CA209-066: ORR by PD-L1 Status*

*PD-L1 positive: ≥ 5% tumor cell surface staining. PD-L1 negative: < 5% tumor cell surface staining.Based on 5 August 2014 database lock.

0 10 20 30 40 50 60 70

PD-L1+

PD-L1-

ORR (%) (95% CI)

Nivolumab(N=210)

Dacarbazine(N=208)

53% (41–64%)

11% (5–20%)

33% (25–42%)

16% (10–23%)

CA209-066: OS by PD-L1 Status*

Improved OS irrespective of PD-L1 status100

90

80

70

60

0

50

40

30

20

10

0 3 6 9 12 15 18Months

Nivolumab PD-L1+

Dacarbazine PD-L1+

Nivolumab PD-L1-

Dacarbazine PD-L1-

Patients at RiskDacarbazine PD-L1-Nivolumab PD-L1-Dacarbazine PD-L1+Nivolumab PD-L1+

7412874126

6910864107

56884478

39633052

18261111

1712

0000

Patie

nts

Surv

ivin

g (%

)

1-Yr OS% (95% CI)

82.1 (69.6–89.8)67.8 (58.3–75.7)52.7 (37.7–65.7)37.4 (26.4–48.3)

Patients who died,

n/NMedian OS mo (95% CI)

Nivolumab PD-L1+ 11/74 NRNivolumab PD-L1- 37/128 NRDacarbazine PD-L1+ 29/74 12.4 (9.2–NR)

Dacarbazine PD-L1- 64/126 10.2 (7.6–

11.8)

*PD-L1 positive: ≥ 5% tumor cell surface staining. PD-L1 negative: < 5% tumor cell surface staining. NR = not reached.Based on 5 August 2014 database lock.

Is PD-L1 status useful for selecting patients for treatment in melanoma?

Nivolumab ORR by PD-L1 Status*


0 10 20 30 40 50 60 70

PD-L1+

PD-L1-

ORR (%) (95% CI)

Nivolumab (N=210)

Nivolumab (N=210)

53% (41–64%)

33% (25–42%)


0 10 20 30 40 50 60 70

PD-L1+

PD-L1-

ORR (%) (95% CI)

Nivolumab (N=210)

Nivolumab (N=210)

53% (41–64%)

33% (25–42%)

47% NR



0 10 20 30 40 50 60 70

PD-L1+

PD-L1-

ORR (%) (95% CI)

Nivolumab (N=210)

PD-L1+PD-L1-

53% (41–64%)

33% (25–42%)

47% NR


21

OS by PD-L1 expression level (5%)

aHazard ratios expressed as PD-L1 ≥5% over PD-L1 <5%CI = confidence interval; HR = hazard ratio; mo = month; NR = not reached

Median OS, mo(95% CI)

HR (95% CI)a

NIVO ≥5%(N = 59)

NIVO <5%(N = 127)

NR(NR, NR)

NR(16.6, NR)

0.56 (0.32, 0.98); P = 0.0399

Months300 272421181512963

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prob

abili

ty o

f Sur

viva

l

NIVO PD-L1 ≥5%NIVO PD-L1 <5%

80.9%

68.3%66.8%

54.2%

Median OS, mo(95% CI)

HR (95% CI)a

DTIC ≥5%(N = 61)

DTIC <5%(N = 116)

9.7(6.7, 13.5)

11.6(9.3, 13.0)

1.16 (0.79, 1.68); P = 0.451

DTIC PD-L1 ≥5%DTIC PD-L1 <5%

Months300 272421181512963

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Prob

abili

ty o

f Sur

viva

l

42.4%

44.7%

27.1%

28.9%

2222

Larkin J et al. N Engl J Med 2015;373:23-34

Ipilimumab plus nivolumab - results from the three arms randomized phase 3 study in untreated advanced melanoma patients with ipilimumab/nivolumab or nivolumab alone vs

ipilimumab alone (CA209-067): NIVO + IPI resulted in a longer PFS

Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

Is PD-L1 status useful for selecting treatment for patients in melanoma?

Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

PD-L1 as a potential biomarker: % of Pts PD-L1 positive in the different clinical trials

Study

Pts PDL1+

Positive(%)

CA209-037 (Weber J et al. LO 2015) 49

CA209-066 (Robert C et al. NEJM 2014) 35

Ca209-067 (Larkin J et al. NEJM 2015) ipi/nivo arm 21,7

Ca209-067 (Larkin J et al. NEJM 2015) nivo arm 25,3

Keynote 006 (Robert C et al. NEJM 2015) pembro every 2 wks 80,6Keynote 006 (Robert C et al. NEJM 2015) pembro every 3 wks 79,8Keynote 002 (Puzanov I et al. ASCO 2015) 69Keynote 001 (Daud A et al SMR 2014)) 77

Ascierto PA et al. J Trans Med 2015

Changes in Target Lesions: Comparing Nivolumab Alone and in Combination

Wolchok JD, et al. J Clin Oncol 2013;31(suppl): abstract 9012^; Sznol M, et al. J Clin Oncol 2013;31(suppl): abstract CRA9006^

Horizontal line at −30% = threshold for defining objective response (partial tumour regression) in absence of new lesions or non-target disease according to RECIST

Nivolumab monotherapy

1st occurrence of new lesion3 mg/kg

Weeks since treatment initiation

Cha

nge

in ta

rget

lesi

ons

from

bas

elin

e (%

)

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150–100

–80

–60

–40

–20

0

20

40

60

80

100

1 mg/kg nivolumab + 3 mg/kg ipilimumab

First occurrence of new lesion

Weeks since treatment initiation

Cha

nge

in ta

rget

lesi

ons

from

bas

elin

e (%

)–100

–80

–60

–40

–20

0

20

40

60

80

300

100

200

0 10 20 30 40 50 60 70 80 90 100 110

Nivolumab + ipilimumab

Chapman P et al. NEJM; 2015

MISIPI STUDY: MELANOMA IMMUNOSCORE EVALUATION IN

PATIENTS TREATED WITHIPILIMUMAB

• 200 FPFE samples from metastatic melanoma patients treated with Ipilimumab

• Assess density of different immune populations, using a digital image analysis application to characterize immune infiltrate expression of:– CD3, CD8, CD20, FoxP3 and CD163– PD-L1

• Correlate marker expression profile with clinical outcome; study ongoing.

MISIPI Study

Bifulco C. et al. Journal of Translational Medicine 2014, 12(Suppl 1):P11.

Correlation of PD-L1 Expression and Survival

PD-L1 status using a 5% tumor cell expression cut-off

PD-L1 status using a 1% tumor cell expression cut-off

0

0.2

0.4

0.6

0.8

1.0

0.0

6 12 18 24 30 36 42 48Time (months)

Ove

rall

Surv

ival

0

0.2

0.4

0.6

0.8

1.0

0.0

6 12 18 24 30 36 42 48Time (months)

Ove

rall

Surv

ival

Negative (score <5): 88 pts

Positive (score > 5): 21 pts

Negative (score <1): 74 pts

Positive (score > 1): 35 pts

Is PD-L1 status useful for selecting patients for treatment in lung cancer?

SQ NSCLC - Checkmate 017: OS by PD-L1 Expression

mOS (mo)

Nivolumab Docetaxel

PD-L1 ≥1% 9.3 7.2

PD-L1 <1% 8.7 5.9

mOS (mo)

Nivolumab Docetaxel

PD-L1 ≥5% 10 6.4

PD-L1 <5% 8.5 6.1

mOS (mo)

Nivolumab Docetaxel

PD-L1 ≥10% 11 7.1

PD-L1 <10% 8.2 6.1

1% PD-L1 Expression level 5% PD-L1 Expression level 10% PD-L1 Expression level

Nivolumab PD-L1+Nivolumab PD-L1–

Time (months)

24211815129630

Time (months)

24211815129630

Time (months)

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100

90

80

70

60

50

40

30

10

0

20

OS

(%)

24211815129630

100

90

80

70

60

50

40

30

10

0

20

Docetaxel PD-L1+ Docetaxel PD-L1–

Spigel DR et al. ASCO 2015

SQ NSCLC – Keynote 010: OS by PD-L1 Expression

Herbst RS et al. Lancet Oncology 2015

PD-L1 + > 50 %

All patients

NSCLC - POPLAR Study: PD-L1 Scoring Criteria

Fehrenbacher L et al. Lancet Oncology 2016

NSCLC - POPLAR Study: Overall Survival (ITT)


Vansteenkiste J et al. ECC 2015

NSCLC - POPLAR Study: OS by PD-L1 Expression


NSQ NSCLC (Checkmate 057) - OS by PD-L1 Expression

NivoDoc

mOS (mo)

Nivo 17.2

Doc 9.0

mOS (mo)

Nivo 19.4

Doc 8.0

Time (months)

≥5% PD-L1 expression level

mOS (mo)Nivo 18.2Doc 8.1


HR (95% CI) = 0.59 (0.43, 0.82)

Time (months)

HR (95% CI) = 0.43 (0.30, 0.63)

OS

(%)

Time (months)


HR (95% CI) = 0.40 (0.26, 0.59)

24211815129630 27

100

90

80

70

60

50

40

30

10

0

20

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100

90

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0

20

24211815129630 27

100

90

80

70

60

50

40

30

10

0

20

Symbols represent censored observations.DOC = docetaxel; Nivo = nivolumab

Horn et al, ESMO 2015

Symbols represent censored observations.DOC = docetaxel; Nivo = nivolumab

NivoDoc

100

90

80

70

60

50

40

30

10

0

20

Time (months)

100

90

80

70

60

50

40

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0

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24211815129630 27Time (months)

24211815129630 27

mOS (mo)

Nivo 10.4

Doc 10.1

mOS (mo)

Nivo 17.2

Doc 9.0

mOS (mo)

Nivo 9.9

Doc 10.3

mOS (mo)

Nivo 19.4

Doc 8.0

Time (months)


<5% PD-L1 expression level




HR (95% CI) = 0.59 (0.43, 0.82)

Time (months)


OS

(%)

HR (95% CI) = 0.90 (0.66, 1.24)

HR (95% CI) = 0.43 (0.30, 0.63)

HR (95% CI) = 1.01 (0.77, 1.34)

OS

(%)

Time (months)

Time (months)



HR (95% CI) = 0.40 (0.26, 0.59)

HR (95% CI) = 1.00 (0.76, 1.31)

24211815129630 27

100

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NivoDoc

NSQ NSCLC (Checkmate 057) - OS by PD-L1 Expression


10090807060504030

100

20

27181596 211230 24 30

NivolumabDocetaxel

18-mo OS rate = 23%

18-mo OS rate = 39%1-yr OS rate = 39%

1-yr OS rate = 51%

Time (mos)

OS

(%)

NivolumabDocetaxel

No. of patients at risk (18-mo OS)b

292 233 195 171 148 128 107 55 427290 244 194 150 111 89 61 23 4

006

NivolumabDocetaxel

No. of patients at risk (12-mo OS)a

292 232 194 169 146 123 62 32 09290 244 194 150 111 88 34 10 05

00

12-mo OSa

(13.2 mo minimum follow-up)18-mo OSb

(17.1 mo minimum follow-up)Nivo (n = 292) Doc (n = 290) Nivo (n = 292) Doc (n= 290)

mOS, mos 12.2 9.4 12.2 9.41-yr OS rate, % 51 39 51 3918-mo OS rate, % – – 39 23No. of events/Total no. of patients, 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 = 0.0009

a 12-month OS based on a March 18, 2015, DBL. b 18-month O based on a July 2, 2015, DBL. Symbols represent censored observations.

NSQ NSCLC - CheckMate 057: Overall Survival


Is PD-L1 status useful for selecting patients for treatment in other

cancers?

RCC – Checkmate 025 - Overall survivalMedian OS, months (95% CI)

Nivolumab 25.0 (21.8–NE)Everolimus 19.6 (17.6–23.1)

HR (98.5% CI): 0.73 (0.57–0.93)P = 0.0018

0 3 6 129 15Months

18 21 24 27 30 33

No. of patients at riskNivolumab 410 389 359 337 305 275 213 139 73 29 3 0

411 366 324 287 265 241 187 115 61 20 2 0Everolimus

0.0

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0O

vera

ll Su

rviv

al (P

roba

bilit

y)

Nivolumab

Everolimus

Minimum follow-up was 14 months.NE, not estimable. Sharma P et al, ECC 2015

RCC Checkmate 025 - Overall survival by PD-L1 expression

PD-L1 <1% (n = 76%)Median OS, months (95% CI)

Nivolumab 21.8 (16.5–28.1)Everolimus 18.8 (11.9–19.9)

No. of patients at riskNivolumab 94 86 79 73 66 58 45 31 18 4 1 0Everolimus 87 77 68 59 52 47 40 19 9 4 1 0

0.00 3 6 129 15

Months18 21 24 27 30 33

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ove

rall

Surv

ival

(Pro

babi

lity)

Nivolumab

Everolimus

PD-L1 ≥1% (n = 24%)Median OS, months (95% CI)

Nivolumab 27.4 (21.4–NE)Everolimus 21.2 (17.7–26.2)

276 265 245 233 210 189 145 94 48 22 2 0299 267 238 214 200 182 137 92 51 16 1 0

Nivolumab

0 3 6 129 15Months

18 21 24 27 30 33

0.3

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

Everolimus

HR (95% CI): 0.79 (0.53–1.17)HR (95% CI): 0.77 (0.60–0.97)

Sharma P et al, ECC 2015

Phase II study Atezolizumab in locally advanced andmetastatic urothelial carcinoma: Overall Survival

Rosenberg JE et al. Lancet Oncology 2016

…the use of PD-L1 as a biomarker is problematic and otherbiomarkers are emerging as potentially more importantpredictive factors of response. Until then, decisions abouttreatment options need to be made on an individual patient basis, withclinicians accepting that full understanding of PD-L1 is far fromcomplete and erring on the side of caution so as to ensure thatotherwise eligible patients are not denied the chance of an effectivetreatment.

Fusi A et al. Lancet Oncology 2015

Presented By Dung Le at 2015 ASCO Annual Meeting

ChairPaolo A. AsciertoMedical OncologistsEster SimeoneAntonio M. GrimaldiLucia FestinoDermatologistsFabrizio AyalaRossella Di TrolioMarco PallaLuigi ScarpatoResearch GroupRosalba CamerlingoMariaelena CaponeRosaria FalconeFederica FratangeloGabriele MadonnaDomenico Mallardo Chiara Botti

Study Coordinators/Data ManagerSusy EspositoMiriam PaoneMarcello CurviettoGianni RinaldiResearch NursesFederica HuberRaffaella Furia

Secretary’s OfficeMariarosaria CeccoAnna Riccio

Via Mariano Semmola, 80131, Napoli, ItalyTel. +39 081 5903 431; Fax +39 081 5903 841Email: [email protected]

Melanoma, Cancer Immunotherapyand Innovative Therapies UnitIstituto Nazionale Tumori – Fondazione “G. Pascale”

pd-l1 expression as a potential predictive biomarker -...

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