1st line Immune-checkpoint blockadefor NSCLC

Luis Paz-Ares

Hospital Universitario 12 de Octubre

Madrid, Spain

DOI (5 years)

Honoraria (self/spouse)– Scientific advice, speaker: Lilly, MSD, BMS, Roche,

Pharmamar, Merck, Astra-Zeneca, Novartis, Boehringer, Celgene, Servier, Sysmex,

Celgene, Amgen, Incyte, Pfizer, Ipsen, Adacap

Board – Genómica

Research grants to Institution – MSD, BMS, Astra-Zeneca, Pfizer

• IO Monotherapy

• First Line Combos

• QT-IO

• IO-IO

• Sequence

Agenda

• IO Monotherapy

• First Line Combos

• QT-IO

• IO-IO

• Sequence

Agenda

The immune system has memoryLong term benefit from IO?

Hirsch et al. Lancet 2016

IO Phase III Trials in pre-treated patients

*850 in primary populationNR = not reached 1. Borghaei, et al. ASCO 2016

2. Herbst, et al. Lancet 2015; 3. Barlesi, et al. ESMO 2016

CheckMate 0171

Nivolumab

vs docetaxel

CheckMate 0571

Nivolumab

vs docetaxel

KEYNOTE-0102

Pembrolizumab (2mg/kg or

10mg/kg) vs docetaxel

OAK3

Atezolizumab

vs docetaxel

Phase of study III III II/III III

PD-L1 selected No No Yes (TPS* ≥1%) No

Study size, n272

(135 vs 137)

582

(292 vs 290)

1,033

(344 vs 346 vs 343)

1,225

(425 vs 425)*

Histology Squamous Non-squamous All-comers All-comers

Line of therapy, %

2L

3L

>3L

Other/unknown

100

0

0

0

88

11

<1

0

69

20

9

<1

75

25

0

0

Subsequent CIT

(immunotherapy arm vs

chemo arm), %

<1 vs 2 1 vs 2 0.6 vs 1.7 vs 13.1 4.5 vs 17.2

Crossover from chemo arm to

study immunotherapy, %4 6 Not permitted Not permitted

Median OS, months

HR vs docetaxel (p value)

9.2 vs 6.0

0.62 (p=0.0004)

12.2 vs 9.5

0.75 (p<0.001)

10.4 vs 12.7 vs 8.5

2mg/kg: 0.71 (p=0.0008)

10mg/kg: 0.61 (p<0.0001)

13.8 vs 9.6

0.73 (p=0.0003)

OS by PD-L1 expression CheckMate 057 - Nivolumab

7

Nivo

Doc

100

90

80

70

60

50

40

30

10

0

20

Time (months)

24211815129630 27

Median OS(mo)

Nivo 10.4

Doc 10.1

Median OS (mo)

Nivo 17.2

Doc 9.0

≥1% PD-L1 expression level

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

<1% PD-L1 expression level

OS (

%)

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

OS (

%)

24211815129630 27

100

90

80

70

60

50

40

30

10

0

20

Nivo

Doc

aPD-L1 expression was measured in pretreatment tumor biopsies (DAKO automated IHC assay).2

CI=confidence interval; Doc=docetaxel; IHC=immunohistochemistry; Nivo=nivolumab;

1. Paz-Ares L, et al. Presented at ASCO 2015, Abstract LBA109. 2. Rizvi NA, et al. Lancet Oncol 2015;16:257–265.

PD-L1 expression level

Median OS (mo)HR

Nivolumab Docetaxel

≥5%

<5%

18.2

9.7

8.1

10.1

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

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

≥10%

<10%

19.4

9.9

8.0

10.3

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

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

Brahmer et al. WLCC 2017

EMA approval December 2016

30% of 1ºL patients

KEYNOTE-024 Trial: Pembro v QTFirst Line treatment in PD-L1 > 50% NSCLC

Overall Survival: TPS ≥1%

Presented By Gilberto Lopes at 2018 ASCO Annual Meeting

KEYNOTE-042 Trial: Pembro v QTFirst Line treatment in PD-L1 > 1% NSCLC

• IO Monotherapy

• First Line Combos

• QT-IO

• IO-IO

• Sequence

Agenda

Leisha A. Emens, and Gary Middleton Cancer Immunol Res 2015;3:436-443

Lorenzo Galluzzi et al. Cancer Immunol Res 2016

Immunotherapy can modify tumor micro-environment increasing sensitivity to chemotherapy

• Reduced support to cancer cells (effect on MDSC and macrophages)

• Reprogrammed tumor vasculature

Chemotherapy can boost the immune response• Immunogenic cell death

• Depletion of myeloid cells & Tregs, influx of TILs, inflammation

Combining Inmunotherapy plus Chemotherapy

Immunomodulatory Effects of Pemetrexed:

Key Preclinical Findings

A. Pemetrexed induces intratumor gene expression indicative of T-

cell inflamed phenotype known to correlate with PD(L)1 mAb

efficacy; paclitaxel and carboplatin do not have the same effect.

B. Among the chemotherapeutic agents tested, pemetrexed

induces robust immunogenic tumor cell death in vitro as

demonstrated by marked extracellular release of HMGB1.

C. Pemetrexed exerts T-cell intrinsic effects exemplified by

increased expression of CD137, a marker associated with T-cell

activation

Novosiadly R et al. Presented at AACR 2018. Abstract 4549

Front-line therapy: anti-PDL1/PD1 agents in combination with chemotherapy

1. Giaccone, et al. ECC 2015; 2. Gadgeel, et al. ASCO 2016; 3. Rizvi, et al. J Clin Oncol 2016

GP283281

phase Ib solid tumours (incl. first-line NSCLC)

Atezolizumab + chemotherapy

KEYNOTE-0212

phase I/II first-line NSCLC

Pembrolizumab + chemotherapy

CheckMate 0123

phase I first-line NSCLC

Nivolumab (N) + chemotherapy

Atezo +

carbo +

pac

Atezo +

carbo +

pem

Atezo +

carbo +

nab-pac

Pembro

+ carbo

+ pac

Pembro +

carbo +

pac + bev

Pembro

+ carbo

+ pem

N10 +

cis +

gem

N10 +

cis +

pem

N10 +

carbo

+ pac

N5 +

carbo +

pac

N 8* 17* 16* 25 25 24 12 15 15 14

ORR, %

50

77

5652

48

33

47 47 43

71

KEYNOTE-021, cohort G - Efficacy

Langer C et al., Lancet Oncol 2016Borghaei et al., ESMO 2017

Platin/Pem + Pembrolizumab in Non-SCC NSCLCKeyNote 189 Trial

Ghandi et al., NEJM 2018

Gandhi et al., NEJM 2018

Platin/Pem + Pembrolizumab in Non-SCC NSCLCKeyNote 189 Trial

Benefit according to PD-L1 expression

Final Investigator-Assessed PFS, ORR and DOR

17

5.2 mo(95% CI: 4.3, 5.6)

7.6 mo(95% CI: 6.6, 8.5)

HR 0.60 (95% CI: 0.49, 0.72)P < 0.0001

Minimum follow-up, 11.7 moMedian follow-up, 14.8 mo

Platin/Pem + Atezo in Non-SCC NSCLCImpower 132 Trial

13.6 mo(95% CI:

11.4, 15.5)

18.1 mo(95% CI:

13.0, NE)

HR: 0.81 (95% CI: 0.64, 1.03)

P = 0.0797Minimum follow-up: 11.7 mo

Median follow-up: 14.8 mo

VA Papadimitrakopoulou et al. WLCC 2018

Chemo+ Beva + Atezolizumab in Non-SCC NSCLCIMPower 150 Trial

Socinski et al, NEJM, 2018

Chemo+ Beva + Atezolizumab in Non-SCC NSCLCIMPower 150 Trial

Socinski et al, NEJM, 2018

Chemo+ Beva + Atezolizumab in Non-SCC NSCLCIMPower 150 Trial

Socinski et al, NEJM, 2018

OS rate, % 1-year 2-year

Atezolizumab

+ CnP63.1 39.6

CnP 55.5 30.0

Cappuzzo F, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA53

PFS rate, % 6-month 12-month

Atezolizumab

+ CnP56.1 29.1

CnP 42.5 14.1

Investigator-assessed PFS (ITT-WT)

PF

S,

%

Months after randomisation

1.0

0.8

0.6

0.4

0.2

0.0

0

451228

1

432214

2

383174

3

351150

4

329136

5

281110

30

No. at riskAtezo + CnP

Chemo

6

24290

7

21375

8

18361

9

15748

10

13840

11

13235

12

11929

13

10823

14

8318

15

7815

16

627

17

606

18

415

19

365

20

293

21

233

22

132

23

122

24

71

25

41

26

1

27 28 29

Median follow-up: ~19 months

HR 0.64

(95%CI 0.54, 0.77)

p<0.0001

OS (ITT-WT)

OS

, %

Months after randomisation

1.0

0.8

0.6

0.4

0.2

0.0

0

451

228

1

435

218

2

422

206

3

400

190

4

384

176

5

365

167

30

4

No. at riskAtezo + CnP

Chemo

6

351

161

7

333

154

8

315

147

9

305

136

10

294

132

11

284

124

12

268

119

13

253

109

14

217

96

15

194

90

16

167

75

17

147

65

18

129

58

19

103

49

20

88

39

21

75

31

31

2

22

59

24

32

1

23

49

17

3324

40

13

3425

29

9

26

19

8

27

12

3

28

10

1

29

6

HR 0.79

(95%CI 0.64, 0.98)

p=0.033

Median: 5.5 mo(95%CI 4.4, 5.9)

Median: 7.0 mo(95%CI 6.2, 7.3)

Median: 13.9 mo(95%CI 12.0, 18.7)

Median: 18.6 mo(95%CI 16.0, 21.2)

Nab-Paclitaxel/Carbo+ Atezo in Non-SCC NSCLCImpower 130 Trial

Chemo + Pembrolizumab in SCC NSCLCKeyNote 407 Trial

Paz-Ares et al., NEJM 2018

Chemo + Atezolizumab in SCC NSCLCIMPower 131 Trial – Overall Survival

Minimum follow-up: 9.8 mo

Median follow-up: 17.1 mo

Time (months)

12.0%

24.7%

12-month PFS

Presented By Robert Jotte at 2018 ASCO Annual Meeting

Chemo + Pembrolizumab in SCC NSCLCKeyNote 407 Trial – Benefit by PD-L1 expression

Paz-Ares et al., NEJM 2018

Hellmann MD et al, (Paz-Ares L) New Eng J Med 2018;Borghaei H etal. ASCO 2018

CM 227- PD-L1 Negative TumorsChemo + Trial

Nivolumab + Chemotherapy

Chemotherapy

• TMB ≥10 mut/Mb: ORR was 60.5% with nivo + chemo and 20.8% with chemo

• TMB <10 mut/Mb: ORR was 27.8% with nivo + chemo and 22.0% with chemo

43 36 21 14 9 5 2 0No. at risk

48 30 16 4 1 1 1 0Chemo

Nivo + chemo(n = 43)

Chemo(n = 48)

Median PFS,a mo 6.2 5.3

HR(95% CI)

0.56(0.35, 0.91)

Nivolumab + chemotherapy

Months

Chemotherapy0

20

40

60

80

100

0 6 12 183 9 15 21

TMB ≥10 mut/Mb and <1% Tumor PD-L1 Expression

1-y PFS = 27%

1-y PFS = 8%

Months

TMB <10 mut/Mb and <1% Tumor PD-L1 Expression

Nivo + chemo(n = 54)

Chemo(n = 59)

Median PFS,b mo 4.7 4.7

HR(95% CI)

0.87 (0.57, 1.33)

0

20

40

60

80

100

0 6 12 183 9 15 21

1-y PFS = 18%

1-y PFS = 16%

54 38 19 13 6 3 0 059 39 16 6 6 3 1 0

Nivo + chemo

No. at risk

Chemo

PF

S (

%)

Nivo + chemo

Nivo + Chemo in 1L NSCLC PD-L1 Negative & High TMB (>10 mut/MB)

H Borghaei et al.,. ASCO 2018

CheckMate 227 Part 1 Study Designa

Database lock: January 24, 2018; minimum follow-up: 11.2 months

N = 1189

<1% PD-L1expression

N = 550

Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W

n = 396

Histology-based chemotherapyb

n = 397

Nivolumab 240 mg Q2Wn = 396

Nivolumab 3 mg/kg Q2W Ipilimumab 1 mg/kg Q6W

n = 187

Histology-based chemotherapyb

n = 186

Nivolumab 360 mg Q3W + histology-based chemotherapyb

n = 177

R1:1:1

Key Eligibility Criteria•Stage IV or recurrent NSCLC•No prior systemic therapy•No known sensitizing EGFR/ALK alterations •ECOG PS 0–1

Stratified by SQ vs NSQ

R1:1:1

7

aNCT02477826 bNSQ: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivolumab + pemetrexed maintenance following nivolumab + chemotherapy; SQ: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles; cThe TMB co-primary analysis was conducted in the subset of patients randomized to nivolumab + ipilimumab or chemotherapy who had evaluable TMB ≥10 mut/Mb

≥1% PD-L1expression

Nivolumab + ipilimumab n = 396

Chemotherapyb

n = 397

Patients for PD-L1 co-primary analysis

Co-primary endpoints: Nivolumab + ipilimumab vs chemotherapy

• OS in PD-L1–selected populations

• PFS in TMB-selected populations

Nivolumab + ipilimumab n = 139

Chemotherapyb

n = 160

Patients for TMB co-primary analysisc

Hellmann et al., NEJM 2018

TMB and Tumor PD-L1 Expression Identify Distinct and Independent Populations of NSCLC

Tumor PD-L1 expression

11aSymbols (dots) in the scatterplot may represent multiple data points, especially for patients with <1% tumor PD-L1 expression. The black line shows the relationship between TMB and PD-L1

expression as described by a linear regression model; bAmong patients in the nivolumab +ipilimumab and chemotherapy arms; TMB ≥10 mut/Mb, n = 299; TMB <10 mut/Mb, n = 380

TMB and tumor PD-L1 expressiona

PD-L1 expression (%)

TM

B (

nu

mb

er

of

mu

tati

on

s/M

b)

0

20

40

60

80

100

160

120

140

0 20 40 60 80 100

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

Hellmann MD,…Paz-Ares L. New Eng J Med 2018

Checkmate 227: TMB as predictor of response with nivo+ipi

N Rizvi et al., ESMO-IO 2018; :Abstr LBA

MYSTIC Trial

Progression-free Survival

Overall Survival

bTMB ≥16 mut/Mb populationbTMB <16 mut/Mb population

Durvalumab

(n=175)

Durvalumab +

tremelimuma

b

(n=162)

Chemotherapy

(n=153)

mOS,

months

(95% CI)

12.2

(9.0–15.5)

8.5

(6.6–9.7)

11.6

(9.1–13.1)

HR vs CT*

(95% CI)

0.92

(0.715–

1.174)

1.23

(0.964–1.575) –

Durvalumab

(n=111)

Durvalumab +

tremelimuma

b

(n=106)

Chemotherapy

(n=102)

mOS,

months

(95% CI)

11.0

(7.8–16.1)

16.5

(10.3–22.9)

10.5

(8.8–12.4)

HR vs CT*

(95% CI)

0.80

(0.588–

1.077)

0.62

(0.451–0.855) –

Pro

ba

bil

ity o

f O

S

Time from randomisation (months)

Pro

ba

bil

ity o

f O

S

Time from randomisation (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 36302421 3327

0.0

0.2

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 36302421 3327

No. at risk

D 175 138 112 97 85 74 62 55 48 42 17 6 0D+T 162 128 101 78 57 49 41 34 29 26 12 3 0

CT 153 132 111 90 73 55 46 40 36 29 15 1 0

111 93 75 61 52 47 40 33 32 30 14 3 0

106 83 75 63 58 53 49 43 39 38 20 3 0

102 95 75 61 43 38 28 21 17 16 8 0 0

19%

29%

24%

30%

18%

39%

No role for D+T in TMB low’s

Both D and D+T superior to Cx

Analysis by PD-L1?

MYSTIC TrialbTMB Analysis

N Rizvi et al., ESMO-IO 2018; :Abstr LBA

Kim ES, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA55

ORR per RECIST v1.1

bTMB subgroups

14.5% 16.3%

28.6%

36.8%

10.1%

5.7% 4.4% 5%

0

5

10

15

20

25

30

35

40

Ove

rall

resp

on

se

ra

te, %

ITT

(N=152)

BEP

(n=119)

High

(n=49)

Low

(n=70)

High

(n=28)

Low

(n=91)

High

(n=19)

Low

(n=100)

PR CR

≥10 cut-off ≥16 cut-off ≥20 cut-off

p<0.0001

p=0.0002

p=0.0595

B-TMB as a Predictive BMK in NSCLCB-F1RST Trial – Atezolizumab First Line

Key results (cont.)

Conclusion• In patients with NSCLC treated with atezolizumab monotherapy a numerical

improvement in outcomes was seen in those with a bTMB cut-off of ≥16

Kim ES, et al. Ann Oncol 2018;29(suppl 5):Abstr LBA55

bTMB high

(n=28)

bTMB low

(n=91)

Median PFS,

months (90%CI)4.6 (1.6, 11.0) 3.7 (2.6, 4.3)

HR (90%CI) 0.66 (0.42, 1.02)

p-value 0.12

PFS in bTMB high (≥16) vs. low (<16) subgroups

Pro

gre

ssio

n-f

ree

su

rviv

al, %

Time, months

100

80

60

40

20

0

0

2891

1

2786

2

1756

3

1443

No. at riskHigh (≥16)

Low (<16)

High, ≥16 (n=28)

Low, <16 (n=91)

6-month PFS

41.6% vs. 32.8%

9-month PFS

37.4% vs. 9.7%

4

1439

5

1328

6

1121

7

811

8

85

9

84

10

53

11

43

12

31

13

2

14

1

B-TMB as a Predictive BMK in NSCLCB-F1RST Trial – Atezolizumab First Line

Underlying Genomic Aberrations

Skoulidis et al., Cancer Discovery 2018

Slide 12

Relevance of a Genomic Aberration on Relevance of a Genomic Aberration on Relevance of a Genomic Aberration on Relevance of a Genomic Aberration on

Immune landscapeImmune landscapeImmune landscapeImmune landscape

• IO Monotherapy

• First Line Combos

• QT-IO

• IO-IO

• Sequence

Agenda

1º Line TMB Low & high Other Charact.

PDL1 Neg Chemo-IO ?

PDL1 ≥1% IO Chemo-IO

Unfit for Chemo

PDL1 ≥ 50%IO

Chemo-IO AgressiveDisease ?

What do I do?

1º Line TMB high TMB low Other Charact.

PDL1 NegChemo

Chemo-IOChemo

Chemo-IO?

PDL1 ≥1% IO Chemo-IO

IOChemo-IO

Unfit for Chemo

PDL1 ≥ 50%IO

Chemo-IO IO

Chemo-IOAgressiveDisease ?

What I may do in the future?

Gracias

lpazaresr@seom.org

1º Line TMB high TMB lowOther

Charact.

PDL1 NegChemo

Chemo-IO

Chemo

Chemo-IO?

PDL1 ≥1% IO Chemo-IO

IOChemo-IO

Unfit forChemo

PDL1 ≥ 50%IO

Chemo-IO

IO

Chemo-IO

AgressiveDisease ?

What will I do?