Inmunoterapia 2018: Mejora de la Supervivencia en Título ... · Esquema de la charla IO en CPNM • Aumento de Supervivencia en 1ª línea • Aumento de Supervivencia en 2ª línea

Título ponencia

Inmunoterapia 2018:

Mejora de la Supervivencia en

Cáncer de Pulmón No Microcítico

Antonio Calles

Servicio de Oncología Médica

Hospital General Universitario Gregorio Marañón

Instituto de Investigación Sanitaria HGUGM

Esquema de la charla

IO en CPNM

• Aumento de Supervivencia en 1ª línea


• Biomarcadores de eficacia

– PD-L1, TMB

• Eficacia en poblaciones especiales

– EGFR, ALK

• Toxicidad y QoL

• Mensajes para llevar a casa

Cáncer de Pulmón:

Cada avance impacta en supervivencia

0

5

10

15

20

25

30

35

1980s 1990s 2000s 2006 2013 2016 2017

1. Ganz, et al. Cancer 1989; 2. Bunn, et al. Clin Cancer Res 1998; 3. Schiller, et al. N Engl J Med 2002; 4. Scagliotti, et al. J Clin

Oncol 2008; 5. Sandler, et al. N Engl J Med 2006; 6. Paz-Ares, et al. J Clin Oncol 2013; 7. Paz-Ares, et al. Lancet 2017; 8. Reck,

et al N Eng J Med 2016.

BSC:

2–5

months1

Platinum-doublets:

8–10 months3,4

Single-agent platinum:

6–8

months2

Ove

rall

Surv

ival

(m

on

ths)

1-year

Platinum-based era

Cáncer de Pulmón:


0

5

10

15

20

25

30

35

1980s 1990s 2000s 2006 2013 2016 2017

Pemetrexed-maintenance

14 months6




BSC:

2–5

months1

Platinum-doublets:

8–10 months3,4


6–8

months2

Bevacizumab+chemo

>12.3 months5

Ove

rall

Surv

ival

(m

on

ths)

1-year

Platinum-based era Histology era

Cáncer de Pulmón:


0

5

10

15

20

25

30

35

1980s 1990s 2000s 2006 2013 2016 2017

Targeted therapies:

>24 months7

Pemetrexed-maintenance

14 months6

Pembrolizumab TPS≥50%

30 months8




BSC:

2–5

months1

Platinum-doublets:

8–10 months3,4


6–8

months2

Bevacizumab+chemo

>12.3 months5

Ove

rall

Surv

ival

(m

on

ths)

1-year

Platinum-based era Histology era Biomarkers era

Divide and Conquer to Treat Lung Cancer

Jordan et al., Cancer Discov. 2017 Johnson, NEJM. 2016

Lung adenocarcinoma Non-Small Cell Lung Cancer

≥50%%

<50%

PD-L1 TPS ≥50% in NSCLC

Patient Characteristics • Female • Never-smoker • Adenocarcinoma

Patient Characteristics • Male • 90% Smokers • 20% Squamous

30%

Larger population than EGFR + ALK + ROS1 combined

Ongoing phase III studies of anti-PDL1/PD1 therapy in first-line NSCLC

Study name Study description Monotherapy Chemotherapy combination

Anti-CTLA4 combination

Atezolizumab

IMpower110 Atezolizumab monotherapy (squamous and non-squamous) TC1/2/3 or IC1/2/3 (TC or IC ≥1%)

IMpower130 Atezolizumab + platinum doublet chemotherapy (non-squamous)

IMpower131 Atezolizumab + platinum doublet chemotherapy (squamous)

IMpower132 Atezolizumab + platinum doublet chemotherapy (non-squamous)

IMpower150 Atezolizumab + platinum doublet chemotherapy ± bevacizumab (non-squamous)

Pembrolizumab

KEYNOTE-024 Pembrolizumab monotherapy (squamous and non-squamous) TPS ≥50%

KEYNOTE-042 Pembrolizumab monotherapy (squamous and non-squamous) TPS ≥1%

KEYNOTE-407 Pembrolizumab + platinum doublet chemotherapy (squamous)

KEYNOTE-189 Pembrolizumab + platinum doublet chemotherapy (non-squamous)

Nivolumab

CheckMate 026 Nivolumab monotherapy (squamous and non-squamous) TC ≥1% (TC ≥5% as co-primary endpoint)

CheckMate 227 Nivolumab monotherapy or + ipilimumab or + platinum doublet chemotherapy (squamous and non-squamous) PD-L1+ only for monotherapy arm

Durvalumab

MYSTIC Durvalumab monotherapy or + tremelimumab (squamous and non-squamous)

NEPTUNE Durvalumab + tremelimumab (squamous and non-squamous)

Avelumab

JAVELIN Lung 100 Avelumab monotherapy (squamous and non-squamous)

62% crossover

KEYNOTE-024

KEYNOTE-024

ORR

QOL

AE

Novello, et al. Ann Oncol 2016 27(Suppl.5): v1–27

eUpdate Published: 28 June 2017. Authors: ESMO Guidelines Committee

ESMO & Magnitude of Clinical Benefit Scale

NCCN Guidelines

Phase III studies of first-line monotherapy

(KEYNOTE-024 and CheckMate 026)

• Stage IV NSCLC (EGFR WT, ALK-)

• Squamous or non-squamous

• PD-L1 ≥50% by IHC

• No prior chemotherapy

• ECOG PS 0–1

(n=305)

Paclitaxel or pemetrexed or gemcitabine + carboplatin or

cisplatin (4–6 cycles)

1 2 PFS OS, ORR, PFS in patients with any PD-L1 status Endpoints

Pembrolizumab 200mg i.v. q3w

Optional pemetrexed maintenance

PD-L1 TPS ≥50% by IHC Until PD

Crossover to pembrolizumab permitted

R

1 2 OS, ORR, PFS Endpoints PFS in patients with

PFS in ITT population (PD-L1 TC ≥1% by IHC) [co-primary]

•PD-L1 TC ≥5% by IHC [co-primary]

• Stage IV or recurrent NSCLC

• No prior systemic therapy

• PD-L1 TC ≥1% by IHC

• ECOG PS 0–1

(n=541)

Investigator’s choice chemotherapy (Gemcitabine + cisplatin or carboplatin, paclitaxel +

carboplatin, or pemetrexed + cisplatin or carboplatin)

Nivolumab 3mg/kg i.v. q2w

Until PD

Crossover to nivolumab permitted

KEYNOTE-024

CheckMate 026

PD-L1 TC ≥1% by IHC

Reck, et al. N Engl J Med 2016 [Epub ahead of print]

Reck, et al. ESMO 2016 (Abs. LBA8); Socinski, et al. ESMO 2016 (Abs. LBA7)

R

KEYNOTE-024 and CheckMate 026: PFS

Reck, et al. N Engl J Med 2016 [Epub ahead of print]

Reck, et al. ESMO 2016 (Abs. LBA8); Socinski, et al. ESMO 2016 (Abs. LBA7)

KEYNOTE-024 PFS

PD-L1 TPS ≥50%

CheckMate 026 PFS

TC PD-L1 ≥5%

1.0

0.8

0.6

0.4

0.2

0

0

Time (months)

6 3 9 18 15 12

Nivolumab (n=211)

Chemotherapy (n=212)

HR=1.15 (95% Cl 0.91–1.45)

p=0.2511

4.2 5.9

21 24 27

Time (months)

PF

S e

sti

ma

te

1.0

0.8

0.6

0.4

0.2

0

0 27

Pembrolizumab (n=154)

Chemotherapy (n=151)

HR=0.50 (95% Cl 0.37–0.68)

p<0.001

Median follow-up of 11.2 months Median follow-up not reported

6 3 9 18 15 12

6.0 10.3

21 24

Analysis of the Association Between TMB and PD-L1 Expressiona CheckMate 026 TMB Analysis: Nivolumab in First-Line NSCLC

• There was no association between TMB and PD-L1 expression in patients with ≥1% PD-L1 tumor expression

PD-L1 (% Tumor Expression)a

High TMB

75 50

1000

316

100

32

10

0 25 100

TM

B (N

o. o

f M

isse

ns

e M

uta

tio

ns

)

Low/medium TMB

243

aAll patients had ≥1% PD-L1 tumor expression

PFS by Tumor Mutation Burden Subgroup CheckMate 026 TMB Analysis: Nivolumab in First-Line NSCLC

Nivolumab

Chemotherapy 47 30 26 21 16 12 4 1

60 42 22 15 9 7 4 1

111 54 30 15 9 7 2 1 1

94 65 37 23 15 12 5 0 0

Nivolumab n = 47 n = 60

9.7 (5.1, NR)

5.8 (4.2, 8.5)

Chemotherapy

Median PFS, months (95% CI)

High TMB

PF

S (

%)

3 6 9 12 15 18 21

No. at Risk Months

100

90

80

70

60

50

40

30

20

10

0

0

Nivolumab

Chemotherapy

0 3 6 9 12

Months

15 18 21 24

Nivolumab

Chemotherapy

100

90

80

70

60

50

40

30

20

10

0

n = 111 n = 94

4.1 (2.8, 5.4)

6.9 (5.5, 8.6)

HR = 1.82 (95% CI: 1.30, 2.55)

Nivolumab Chemotherapy

(95% CI) Median PFS, months

Low/medium TMB

HR = 0.62 (95% CI: 0.38, 1.00)

Can we enhance cancer immunotherapy with

combinations?

Adapted from Sharma and Allison. Cell 2015 161(2): 205–14

Targeted therapy

Immune checkpoint therapy

Combinations with

immunotherapy

Chemotherapy

Hypothetical KM curve

Time

Pe

rce

nt

su

rviv

al

Chemo + IO combos

IO + IO combos

Combinations with anti-PD1 and anti-PDL1

therapies in first line advanced NSCLC

Chemotherapy Checkpoint

inhibitor

Nivolumab Durvalumab

20mg/kg

IV q4w

3mg/kg

IV q2w

Pembrolizumab

2mg/kg

IV q3w

Atezolizumab

1200mg

IV q3w

Anti-PD1 Anti-PDL1 Anti-PD1 Anti-PDL1

Chemotherapy

Checkpoint inhibitor Ph1-Ph2

ORR 40-90% Giaccone, et al. ECC 2015 (Abs. 513)

Gadgeel, et al. ASCO 2016 (Abs. 9016)

Rizvi, et al. J Clin Oncol 2016 34(25): 2969–79

First-line immunotherapy plus chemo combination:

pembrolizumab plus chemo (KEYNOTE-021, cohort G)

56.7% 31.7%

KEYNOTE-021 Cohort G


FDA accelerated

approval KN-189 KEYNOTE-021 Cohort G


Reck M, et al. IMpower150 PFS analysis. 22

a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance of treatment

with one or more approved targeted therapies. b Atezolizumab: 1200 mg IV q3w. c Carboplatin: AUC 6 IV q3w. d Paclitaxel: 200 mg/m2 IV q3w. e Bevacizumab: 15 mg/kg IV q3w.

IMpower150 study design

Arm A

Atezolizumabb +

Carboplatinc + Paclitaxeld

4 or 6 cycles

Atezolizumabb

Arm C (control)


+ Bevacizumabe

4 or 6 cycles

Bevacizumabe

Su

rviv

al fo

llo

w-u

p

Stage IV or

recurrent metastatic

non-squamous NSCLC

Chemotherapy-naivea

Tumour tissue available

for biomarker testing

Any PD-L1 IHC status

Stratification factors:

• Sex

• PD-L1 IHC expression

• Liver metastases

N = 1202

R

1:1:1

Arm B

Atezolizumabb +


+ Bevacizumabe

4 or 6 cycles

Atezolizumabb

+

Bevacizumabe

Maintenance therapy

(no crossover permitted)

Treated with

atezolizumab

until PD by

RECIST v1.1

or loss of

clinical benefit

AND/OR

Treated with

bevacizumab

until PD by

RECIST v1.1

The principal question is to assess whether the addition of atezolizumab to Arm C provides clinical benefit

Reck M, et al. IMpower150 PFS analysis.

INV-assessed PFS in ITT-WT (Arm B vs Arm C)

23

INV, investigator.

Data cutoff: September 15, 2017

6.8 mo (95% CI: 6.0, 7.1)

8.3 mo (95% CI: 7.7, 9.8)

HR, 0.617 (95% CI: 0.517, 0.737)

P < 0.0001 Minimum follow-up: 9.5 mo

Median follow-up: ~15 mo

Arm B: atezo + bev + CP

Arm C: bev + CP

• Teff gene signature is a surrogate for PD-L1 expression and pre-existing immunity

Teff signature was defined by mRNA expression of 3 genes (PDL1, CXCL9, IFNG) and derived from

a broader 9-gene signature from POPLAR1

In the OAK study, the Teff signature was associated with PD-L1 expression assessed by IHC (P = 7.3 x 10-45)

• Teff signature partially overlaps with patients identified as PD-L1 positive by IHC and also identifies

a unique subset of patients within the PD-L1–negative population

Teff Gene Signature and Overlap With PD-L1 IHC in tumor

specimens from study OAK

IC, tumor-infiltrating immune cell; IHC, immunohistochemistry; mRNA, messenger RNA; TC, tumor cell. a Percentages of the overall NSCLC population (N = 753). b TC1/2/3 or IC1/2/3 = TC or IC ≥ 1% PD-L1–expressing cells.

1. Fehrenbacher L, et al. Lancet. 2016.

Kowanetz et al. OAK Teff biomarker. WCLC 2017. 24

Teff Gene

Signature

PDL1

IFNG

CXCL9

Pre-existing

immunity

PD-L1 expression

on TC and IC

Teff Gene Signature vs PD-L1 IHC (SP142)a

36% 14% 20%

Teff

≥ median

TC1/2/3

or IC1/2/3b

N = 753


a ITT, EGFR/ALK mutants, and ITT-WT % prevalence out of ITT (n = 800);

Teff % prevalence out those tested in ITT-WT (n = 658); PD-L1 IHC % prevalence out of ITT-WT (n = 692). b Patients with a sensitising EGFR mutation or ALK translocation must have disease progression

or intolerance of treatment with one or more approved targeted therapies. c Stratified HRs for ITT, ITT-WT and Teff-high WT populations; unstratified HRs for all other subgroups.


PFS in key biomarker populations

0,25

Population n (%)a

ITT (including EGFR/ALK mutant +) 800 (100%)

EGFR/ALK mutant + onlyb 108 (14%)

ITT-WT 692 (87%)

Teff-high (WT) 284 (43%)

Teff-low (WT) 374 (57%)

PD-L1 IHC TC2/3 or IC2/3 (WT) 244 (35%)

PD-L1 IHC TC1/2/3 or IC1/2/3 (WT) 354 (51%)

PD-L1 IHC TC0 and IC0 (WT) 338 (49%)

PD-L1 IHC TC3 or IC3 (WT) 135 (20%)

PD-L1 IHC TC0/1/2 or IC0/1/2 (WT) 557 (80%)

Median PFS, mo

1.0

In favour of Arm C:

bev + CP

Hazard Ratioc

In favour of Arm B:

atezo + bev + CP

0.61

0.59

0.76

0.48

0.50

0.77

0.51

0.62

1.25

0.39

0.68

Arm B Arm C

8.3 6.8

9.7 6.1

8.3 6.8

11.3 6.8

7.3 7.0

11.1 6.8

11.0 6.8

7.1 6.9

12.6 6.8

8.0 6.8


a Including fatal haemorrhagic AEs: Arm C: haemoptysis n = 1, pulmonary haemorrhage n = 2; Arm B haemoptysis n = 3,

pulmonary haemorrhage n = 2, haemorrhage intracranial n = 1; Arm A: haemoptysis n = 1, haemorrhage intracranial n = 1. b Investigator text for AEs encoded using MedDRA v20.1.


Safety summary

Arm A: atezo + CP (n = 400)

Arm B: atezo + bev + CP

(n = 393)

Arm C (control): bev + CP (n = 394)

Median doses received (range), n Atezolizumab Bevacizumab

10 (1-37)

NA

12 (1-38) 10 (1-38)

NA

8 (1-33)

All cause AE, n (%) Grade 3-4 Grade 5

389 (97%) 226 (57%)

10 (3%)

385 (98%) 242 (62%)

23 (6%)

390 (99%) 230 (58%)

21 (5%)

Treatment-related AE, n (%) Grade 3-4 Grade 5a

372 (93%) 170 (43%)

3 (1%)

371 (94%) 219 (56%)

11 (3%)

376 (95%) 188 (48%)

9 (2%)

Serious AE, n (%) Treatment-related serious AE

155 (39%) 77 (19%)

165 (42%) 100 (25%)

134 (34%) 76 (19%)

AEs of special interest, n (%)b

Grade 3-4 Grade 5

184 (46%) 37 (9%) 2 (1%)

199 (51%) 45 (11%)

0

108 (27%) 13 (3%)

0

AE leading to withdrawal from any treatment 56 (14%) 128 (33%) 98 (25%)

AE leading to dose interruption or modification 203 (51%) 235 (60%) 189 (48%)

Future first-line combinations for NSCLC:

immune doublets

Hellmann, et al. ASCO 2016 (Abs. 3001)

43

18

57 54

64

78

92

23

14

28 31

40 44

50

0

20

40

60

80

100 Nivo 3 q2w + ipi 1 q6/12w (pooled)

Nivo 3 q2w

OR

R (

%)

72 52 17 14 44 32 35 26 28 20 18 18 13 12

Overall <1% ≥1% ≥5% ≥10% ≥25% ≥50%

PD-L1 expression

Combinations of anti-PDL1 or anti-PD1 with other

immunotherapies may offer synergistic benefits

Nivolumab plus ipilimumab (CheckMate 012 phase I study)

OS by Tumor PD-L1 Expression CheckMate 012: First-Line Nivolumab ± Ipilimumab in NSCLC

Based on a September 2016 database lock

All treated patients (n = 77) ≥1% PD-L1 (n = 46) ≥50% PD-L1 (n = 13)

1-year OS rate: 76%

100

80

60

40

20

0

OS

(%

)

0 6 12 18 24 30 36 42 48

100

80

60

40

20

0

0 6 12 18 24 30 36 42 48

1-year OS rate: 87%

100

80

60

40

20

0

0 6 12 18 24 30 36 42 48

1-year OS rate: 100%

Nivo 3 Q2W +

ipi 1 Q6/12W

1-year OS rate: 73%

100

80

60

40

20

0

Months

OS

(%

)

0 6 12 18 24 30 36 42 48

100

80

60

40

20

0

Months

0 6 12 18 24 30 36 42 48

1-year OS rate: 69%

100

80

60

40

20

0

Months

0 6 12 18 24 30 36 42 48

1-year OS rate: 83%

All treated patients (n = 52) ≥1% PD-L1 (n = 32) ≥50% PD-L1 (n = 12)

Nivo 3 Q2W

• Data are based on median follow-up durations of 16 months (combination cohorts) and 22 months (monotherapy)

CM-227

TMB high

Nivo 3 Q2W (n = 52)

Nivo 3 Q2W + Ipi 1 Q12W

(n = 38)

Nivo 3 Q2W + Ipi 1 Q6W

(n = 39)

Any grade

Grade 3–4

Any grade

Grade 3–4

Any grade

Grade 3–4

Treatment-related AEs, % 73 19 84 42 74 31

Treatment-related AEs leading to discontinuation, %

12 12 18 8 18 8

Safety Summary CheckMate 012: First-Line Nivolumab ± Ipilimumab in NSCLC

• There were no treatment-related deaths

• After an additional 6 months of follow-up in the Q12W and Q6W combination cohorts, rates of treatment-

related AEs with nivolumab + ipilimumab remained similar to those previously reported1

Based on a September 2016 database lock; includes events reported between first dose and 100 days after the final dose of nivolumab or ipilimumab, whichever was given last 1. Hellmann MD, et al. Lancet Oncol 2016 Dec 5. [Epub ahead of print].

Conclusiones 1ª línea Mejora de la Supervivencia en Cáncer de Pulmón con Inmunoterapia

30 months median OS is a landmark in 1st line NSCLC Sets a new Standard to compare

Monotherapy (no chemo) Better toxicity profile QoL improvement 20% of patients (TPS PD-L1 >50%)

Combination of anti-PD1/PD-L1 with either anti-CTLA4 or chemo

Potential to increase the proportion of pts who benefit from IO Expect more toxicity Financial toxicity

Pending to define which patients need to combine IO with chemo, IO with IO, and who will do well with IO alone anyway (avoid overtreatment)

PD-L1, TMB, others


IO en CPNM




– PD-L1, TMB


– EGFR, ALK

• Toxicidad y QoL


Anti-PD1 and anti-PDL1 therapies in previously

treated advanced NSCLC: trial design

Brahmer, et al. N Engl J Med 2015 373(2): 123–35; Borghaei, et al. N Engl J Med 2015 373(17): 1627–39

Herbst, et al. Lancet 2016 387(10027): 1540–50; Barlesi, et al. ESMO 2016 (Abs.LBA44)

NSCLC Stage IV (2L/3L)

1. Nivolumab SqCC N=272

2. Nivolumab NSq N=582

3. Pembrolizumab >1% N=1024

4. Atezolizumab Any N=1225

5. Avelumab >1% N=792

Docetaxel

Checkpoint inhibitor

R

1:1 13%

17%

26%

Cro

sso

ver

rate

Nivolumab Durvalumab Avelumab

20mg/kg

IV q4w

3mg/kg

IV q2w

10mg/kg

IV q2w

Pembrolizumab

2mg/kg

IV q3w

Atezolizumab

1200mg

IV q3w

Anti-PD1 Anti-PDL1 Anti-PDL1 Anti-PD1 Anti-PDL1

Efficacy summary for anti-PDL1 and anti-PD1

therapies in previously treated NSCLC

*Phase III dose: 2mg/kg q3w and 10mg/kg q3w; §Tumour

proportion score (TPS) is the proportion of viable tumour cells

showing partial or complete membrane PD-L1 expression

Barlesi, et al. ESMO 2016 (Abs. 1215PD)

Herbst, et al. ESMO 2016 (Abs. LBA48)

Barlesi, et al. ESMO 2016 (Abs. LBA44)

CheckMate 0171

ITT population

(n=272)

CheckMate 0571

ITT population

(n=582)

KEYNOTE-0102

ITT population

(n=1033)

OAK3

ITT population

(n=850)

Histology Squamous Non-squamous All comers All comers

PD-L1

selected No No Yes (TPS§ ≥1%) No

ORR, % Nivo 20%

vs doc 9%

Nivo 19%

vs doc 12%

Pembro 2mg/kg

19%

vs doc 10%

Atezo 14%

vs doc 13%

Follow-up Minimum follow-up

24.2 months

Minimum follow-up

24.2 months

Median follow-up

19.2 months

Minimum follow-up

19 months

HR 0.62 HR 0.75 HR 0.73

Nivo Doc Nivo Doc Atezo Doc 0

4

8

12

16

Me

dia

n O

S

(mo

nth

s)

HR 0.72

Pembro

2mg/kg

Doc

13.8

9.6 9.2 6.0

9.5 12.2

10.5 8.6

CheckMate 017 and CheckMate 057:

phase III nivolumab vs docetaxel

*Included pemetrexed, bevacizumab or erlotinib Borghaei, et al. ASCO 2016; Barlesi, et al. ESMO 2016

PD or

toxicity


(n=135)

PD or

toxicity

Docetaxel 75mg/m2 i.v. q3w

(n=137)

CheckMate 017

• Stage IIIB/IV squamous NSCLC

• Known PD-L1 status

• One prior platinum-based therapy

• ECOG PS 0–1

(n=272)

R

PD or

toxicity


(n=292)

PD or

toxicity

Docetaxel 75mg/m2 i.v. q3w

(n=290)

CheckMate 057

• Stage IIIB/IV non-squamous NSCLC

• Known PD-L1 status

• One prior platinum-based therapy

• Prior maintenance therapy allowed*

• Prior TKI allowed

• ECOG PS 0–1

(n=582)

R

1 OS

2 ORR, PFS, efficacy by

tumour PD-L1

expression, safety, QoL

Endpoints

1 OS

2 ORR, PFS, efficacy by

tumour PD-L1

expression, safety, QoL

Endpoints

PD-L1 expression measured on TCs using Dako 28-8 IHC assay

Crossover permitted

Crossover permitted

CheckMate 017 and CheckMate 057: OS

Barlesi, et al. ESMO 2016 (Abs.1215PD)

CheckMate 057 (non-squamous NSCLC) CheckMate 017 (squamous NSCLC)

Nivolumab

(n=135)

Docetaxel

(n=137)

12-month OS rate,

% 42 24

24-month OS rate,

% 23 8

Nivolumab

(n=292)

Docetaxel

(n=290)

12-month OS rate,

% 51 39

24-month OS rate,

% 29 16

1.0

0.8

0.6

0.4

0.2

0

0 6 12 24 18 Time (months)

OS

es

tim

ate

36 30 42

9.2 6.0

Nivolumab (n=135)

Docetaxel (n=137)

HR=0.62 (95% CI 0.47–0.80)

1.0

0.8

0.6

0.4

0.2

0

0 6 12 24 18 Time (months)

OS

es

tim

ate

36 30 42

12.2 9.5

Nivolumab (n=292)

Docetaxel (n=290)

HR=0.75 (95% CI 0.63–0.91)

Minimum follow-up 24.2 months Minimum follow-up 24.2 months

OS by PD-L1 Expression

1. 1. Paz-Ares L et al.; J Clin Oncol 33, 2015 (suppl; abstr LBA109)

Checkmate 057 – Biomarker-Analysis: OS benefit in the ITT

population in PD-L1 expressing tumors

36

KEYNOTE-010: phase II/III pembrolizumab vs docetaxel

(PDL1-selected)

Herbst, et al. Lancet Oncol 2015

• Advanced NSCLC with progression per

RECIST v1.1

• ECOG PS 0–1

• TPS >1%

• At least 1 prior regimen for advanced NSCLC

• No prior treatment with PD-1 checkpoint

inhibitors or docetaxel

(n=1,033) Docetaxel

75mg/m2 i.v. q3w

(n=343)

Pembrolizumab

2mg/kg i.v. q3w

(n=344)

Pembrolizumab

10mg/kg i.v. q3w

(n=346)

R

1 2 OS and PFS ORR, DoR, safety

Endpoints

PD-L1 expression measured on TCs using Dako 22C3 IHC assay

OAK: phase III atezolizumab vs docetaxel

Barlesi, et al. ESMO 2016

• Locally advanced/metastatic NSCLC

• Tumour specimen available (FFPE)

• 1–2 prior lines of chemotherapy including 1 line of platinum chemotherapy

• Any PD-L1 expression status is permitted

• ECOG PS 0–1

(n=1,225)

R

Until PD or loss of clinical benefit

Until PD Docetaxel

75mg/m2 q3w

Atezolizumab 1,200mg q3w

1 2 • OS ITT in Primary Population (PP,

i.e. the first 850 patients enrolled)

• OS TC1/2/3 or IC1/2/3 in PP

ORR, PFS and DoR, (RECIST v1.1),

safety, tolerability

Endpoints

PD-L1 expression was centrally evaluated on TCs and ICs with the VENTANA SP142 IHC assay

Crossover not permitted

OAK: OS in the ITT population


9.6 13.8

HR=0.73 (95% CI 0.62–0.87)

p=0.0003

Atezolizumab (n=425)

Docetaxel (n=425) 1.0

0.8

0.6

0.4

0.2

0 0

OS

esti

mate

27 6 3 9 18 24 21 15 12 Time (months)

Minimum follow-up 19 months

OAK: OS in the TC1/2/3 or IC1/2/3 population


1.0

0.8

0.6

0.4

0.2

0

OS

esti

mate

10.3 15.7


Docetaxel (n=222)

HR=0.74 (95% CI 0.58–0.93)

p=0.0102

0 27 6 3 9 18 24 21 15 12 Time (months)


OAK: OS in the TC0 and IC0 population


1.0

0.8

0.6

0.4

0.2

0 0

Time (months)

OS

esti

mate

27 6 3 9 18 24 21 15 12


Docetaxel (n=199)

HR=0.75 (95% CI 0.59–0.96)

p=0.0205

8.9 12.6


OAK: OS by histology

Histology information from eCRF

*Unstratified HRs; §P values for descriptive purpose only Barlesi, et al. ESMO 2016 (Abs. LBA44)

OS in squamous OS in non-squamous

0

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

0 6 27 12 24 18 3 9 15 21 Time (months) Time (months)

OS

es

tim

ate

6 27 12 24 18 3 9 15 21

7.7 8.9 11.2 15.6

HR=0.73*

(95% CI 0.54–0.98)

p=0.0383§


Docetaxel (n=110) HR=0.73*

(95% CI 0.60–0.89)

p=0.0015§


Docetaxel (n=315)


OAK: OS by PD-L1 subgroup

*Stratified HR for ITT and TC1/2/3 or IC1/2/3, unstratified for all other subgroups Barlesi, et al. ESMO 2016

0.73

0.75

0.74

0.67

0.41 TC3 or IC3 (16%)

TC2/3 or IC2/3 (31%)

TC1/2/3 or IC1/2/3* (54%)

TC0 and IC0 (45%)

ITT* (n=850)

0.2 2 1

PD-L1 Subgroups

Atezolizumab Docetaxel

Median OS, months

20.5 8.9

16.3 10.8

15.7 10.3

12.6 8.9

13.8 9.6

In favour of docetaxel In favour of atezolizumab

HR


IO en CPNM




– PD-L1, TMB


– EGFR, ALK

• Toxicidad y QoL


• Biomarkers indicative of

hypermutation & neoantigens may

predict response to IO treatment

Examples:

‒ TMB, MSI-high, neoantigens

Tumor Antigens

• Biomarkers that identify tumor

immune system evasion beyond

PD-1/CTLA-4 to inform new IO

targets and rational combinations

Examples:

‒ Tregs, MDSCs, IDO, LAG-3

Tumor Immune

Suppression

• Biomarkers (intra- or peri-tumoral) indicative of an inflamed phenotype may predict response to IO treatment

Examples:

‒ PD-L1, inflammatory signatures

Inflamed Tumor

Microenvironment

• Biomarkers which characterize the

host environment, beyond tumor

microenvironment, may predict

response to IO treatment

Examples:

‒ Microbiome, germline genetics

Host Environment

Tumor

Antigens

Tumor Immune

Suppression

Inflamed

Tumor

IDO = indoleamine-2,3 dioxygenase; LAG-3 = lymphocyte activation gene-3; MDSCs = myeloid-derived suppressor cells; MSI-high = microsatellite instability high; TMB = tumor mutational burden. Adapted from Blank C.U. et al. Science 2016;352:658–660.

Tumor and Immune Biomarkers Being Evaluated to

Predict Better Outcomes to Immuno-Oncology Therapy

Immunotherapy in previously treated patients:

efficacy by PD-L1 status

*TC3 or IC3: ≥50% of TCs or ≥10% of ICs; TC2/3 or IC2/3: ≥5% of TCs or ICs;

TC1/2/3 or IC1/2/3: ≥1% of TCs or ICs; TC0 and IC0: <1% of TCs and ICs

1. Brahmer, et al. N Engl J Med 2015; 2. Borghaei, et al. N Engl J Med 2015

3. Herbst, et al. Lancet 2015; 4. Barlesi, et al. ESMO 2016

CheckMate 017

(phase III)1

2L nivo vs doc (n=272)

CheckMate 057 (phase III)2

2/3L nivo vs doc

(n=582)

KEYNOTE-010 (phase II/III)3

≥2L pembro¶ vs doc

(n=1,033)

OAK (phase III)4

≥2L atezo vs doc (n=850)

Histology Squamous Non-squamous All comers All comers

PD-L1

selected No No Yes (TPS ≥1%) No

Efficacy by

PD-L1

status

PD-L1

assay 28-8 (Dako) on TCs 22C3 (Dako) on TCs

SP142 (Ventana) on ICs and

TCs

0.53

0.76

HR

1–49% (n=591)

≥50% (n=442)

Subgroup

(pooled doses)

doc

HR

pembro

0.1 1 2 0.5 0.2

0.67 ITT (n=1,033)

≥5% (n=81)

<5% (n=144)

≥10% (n=69)

<10% (n=156)

≥1% (n=119)

<1% (n=106)

ITT (n=272)

0.69

0.58

0.53

0.70

0.50

0.70

0.39

0.59

HR Subgroup

doc

HR

nivo

0.1 1 2 0.5 0.2

NQ (n=47)

≥5% (n=181)

<5% (n=274)

≥10% (n=165)

<10% (n=290)

≥1% (n=246)

<1% (n=209)

ITT (n=582)

0.58

0.87

0.43

0.96

0.40

0.96

0.72

HR Subgroup

doc

HR

nivo

0.1 1 2 0.5 0.2

doc atezo

HR

TC1/2/3 or IC1/2/3 (n=463)

TC0 and IC0 (n=379)

TC3 or IC3 (n=137)

TC2/3 or IC2/3 (n=265)

ITT (n=850) 0.73

0.41

0.67

0.74

0.75

HR Subgroup*

<1% not available

study design

2 1 0.1 0.2 0.5

Nivolumab Pembrolizumab Atezolizumab Durvalumab

Detection

antibody 28-81 22C31 SP1423 SP2634

IHC platform Dako1 Dako1 Ventana1 Ventana4

Cell types scored

for NSCLC TC1 TC1 IC and TC1,3 TC1

Cut-offs in

NSCLC

PDL1-selected as

≥5% of TCs

exhibiting

positive

membrane

PD-L1 staining at

any intensity

PDL1-selected as

≥50% (treatment-

naïve) or ≥1%

(previously treated)

of viable TCs

showing partial or

complete

membrane PD-L1

expression*

TC3 or IC3: ≥50% of TCs or

≥10% of ICs

TC2/3 or IC2/3: ≥5% of TCs or

ICs

TC1/2/3 or IC1/2/3: ≥1% of TCs

or ICs

TC0 and IC0: <1% of TCs and

ICs

(proportion of cells stained at

any intensity)

PDL1-selected as

≥25% of TCs with

membrane PD-L1

staining

Estimated PD-L1

prevalence in

NSCLC

Do we have the right assay?

*For the 22C3 assay, the proportion of viable tumour cells showing partial or complete membrane PD-L1 staining is termed the tumour proportion score (TPS)

1. Kerr, et al. J Thorac Oncol 2015; 2. Aggarwal, et al. ESMO 2016 3. Vansteenkiste, et al. ECC 2015; 4. Rebelatto, et al. ASCO 2015; 5. Rizvi, et al. ASCO 2015

37%

68%

16%

TC <5%

TC ≥5%

≥2L1

54%

46%

TC <25%

TC ≥25%

≥2L5

54%

46%

TPS <1%

TPS 1–49%

TPS ≥50%

1L2 ≥2L2

31% 35%

40% 38%

30% 27%

Harmonization Iniciatives:

Blueprint Trial

Adapted from Hirsch, et al. AACR 2016.

• The vast majority (77%, 115 out of 150 patients) of SP142 PD-L1 negative patients were also

PD-L1 negative by the 22C3 assay

50

Overlap of 22C3 and SP142 PD-L1 Negative Populations in OAK BEP

Gadgeel S, et al. 22C3 vs SP142 in OAK

SP142 Assay

Dx–, n Dx+, n

22C3

Assay

Dx–, n 115 103

Dx+, n 35 145

Dx–, no or low PD-L1 expression; Dx+, positive for PD-L1 expression.

N = 103 N = 115 N = 35 22C3

TPS < 1%

SP142 TC0 and IC0

N = 218

N = 150

115 patients

PD-L1–negative by 22C3 and SP142

Double negative

Negative

By 22C3

Negative

By SP142

• OS benefit observed in PD-L1 negative populations as defined by either assay

SP142 assay: TC0 and IC0, PD-L1 expression on <1% TC and IC.

22C3 assay: TPS <1%, PD-L1 expression on <1% TC.

Dx-, no or low PD-L1 expression.

Overall Survival in PD-L1 Negative Subgroups in OAK BEP

Gadgeel S, et al. 22C3 vs SP142 in OAK

OS HR

(95% CI)

SP142 Dx-

(N = 150)

0.55

(0.37, 0.80)

22C3 Dx-

(N = 218)

0.61

(0.45, 0.84)

+ Censored

Atezolizumab

Docetaxel

SP142 TC0 and IC0

Months

+ Censored

Atezolizumab

Docetaxel

22C3 TPS < 1%

Ove

rall

Su

rviv

al (%

)

Months

Ove

rall

Su

rviv

al (%

)

Gandara DR, et al. bTMB in POPLAR & OAK

Increasing Atezolizumab benefit with higher bTMB cut-points

in OAK

BEP, biomarker-evaluable population; ITT, intention-to-treat.

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. bTMB in POPLAR & OAK

LIMITED Overlap between bTMB ≥16 and PD-L1 expressiona

(OAK BEP)

a PD-L1 expression was evaluated by immunohistochemistry (IHC) using the VENTANA SP142 assay;

TC3 or IC3, ≥50% of TC or ≥10% of IC express PD-L1.

BEP, biomarker-evaluable population; IC, tumor-infiltrating immune cell; TC, tumor cell.

• Non-significant overlap between the

bTMB ≥16 and TC3 or IC3 subgroups

(Fisher exact test, P = 0.62)

– 19.2% of tumors with bTMB ≥16

were also TC3 or IC3

– 29.1% of tumors with TC3 or IC3

also had bTMB ≥16

PFS HR (95% CI) OS HR (95% CI)

bTMB ≥16 0.64 (0.46, 0.91) 0.64 (0.44, 0.93)

TC3 or IC3 0.62 (0.41, 0.93) 0.44 (0.27, 0.71)

bTMB ≥16 and

TC3 or IC3 0.38 (0.17, 0.85) 0.23 (0.09, 0.58)

Gut microbes shape response to

cancer immunotherapy

Blank CU et al. Science 2016; 352:658


IO en CPNM




– PD-L1, TMB


– EGFR, ALK

• Toxicidad y QoL


JAMA Oncol. 2018;4(2):210-216.

Anti-PD1/PD-L1 efficacy in EGFR mutant NSCLC

Garassino et al. Lancet Oncol 2018

Cohort 1: EGFR+/ALK+ NSCLC with at least

25%, or less than 25%, of tumour cells with

PD-L1 expression

Anti-PD1/PD-L1 efficacy in EGFR mutant NSCLC

Reck M, et al. IMpower150 PFS analysis.

a ITT, EGFR/ALK mutants, and ITT-WT % prevalence out of ITT (n = 800);

Teff % prevalence out those tested in ITT-WT (n = 658); PD-L1 IHC % prevalence out of ITT-WT (n = 692). b Patients with a sensitising EGFR mutation or ALK translocation must have disease progression

or intolerance of treatment with one or more approved targeted therapies. c Stratified HRs for ITT, ITT-WT and Teff-high WT populations; unstratified HRs for all other subgroups.


IMpower150: PFS in key biomarker populations

0,25

Population n (%)a

ITT (including EGFR/ALK mutant +) 800 (100%)

EGFR/ALK mutant + onlyb 108 (14%)

ITT-WT 692 (87%)

Teff-high (WT) 284 (43%)

Teff-low (WT) 374 (57%)

PD-L1 IHC TC2/3 or IC2/3 (WT) 244 (35%)

PD-L1 IHC TC1/2/3 or IC1/2/3 (WT) 354 (51%)

PD-L1 IHC TC0 and IC0 (WT) 338 (49%)

PD-L1 IHC TC3 or IC3 (WT) 135 (20%)

PD-L1 IHC TC0/1/2 or IC0/1/2 (WT) 557 (80%)

Median PFS, mo

1.0

In favour of Arm C:

bev + CP

Hazard Ratioc

In favour of Arm B:

atezo + bev + CP

0.61

0.59

0.76

0.48

0.50

0.77

0.51

0.62

1.25

0.39

0.68

Arm B Arm C

8.3 6.8

9.7 6.1

8.3 6.8

11.3 6.8

7.3 7.0

11.1 6.8

11.0 6.8

7.1 6.9

12.6 6.8

8.0 6.8

JAMA Oncol. 2018;4(2):210-216.

Anti-PD1/PD-L1 efficacy in KRAS mutant NSCLC

Best overall response to immunotherapy

(RECIST1.1) in co-mutation defined KRAS-

mutant LUAC subsets

P=0.0028, Fisher’s exact test

WCLC 2017 Presentation Number: 6343

Similar results in independent MSKCC cohort

Hellmann MD, Rizvi H, Rudin CM (unpublished)

ORR: 59% (KP) vs 0% (KL)

Impact of major co-mutations on the immune contexture and

response of KRAS-mutant lung adenocarcinoma to

immunotherapy

K

C

KL KP

KRAS

KRAS

TP53

STK11

ATM

KEAP1

Anti-PD1/PD-L1 efficacy in KRAS mutant NSCLC


IO en CPNM




– PD-L1, TMB


– EGFR, ALK

• Toxicidad y QoL


Toxicidad inmunomediada de la inmunoterapia

Postow; N Engl J Med 2018

KN-024

KN-010 OAK

Safety of anti-PDL1 and anti-PD1

compare to chemotherapy

0

20

40

60

80

100

Pa

tie

nts

, %

Safety summary for anti-PDL1 and anti-PD1

therapies in previously treated NSCLC

NR, not reported Brahmer, et al. N Engl J Med 2015 373(2): 123–35; Borghaei, et al. N Engl J Med 2015 373(17): 1627–39

Herbst, et al. Lancet 2016 387(10027): 1540–50; Herbst, et al. ESMO 2016 (Abs. LBA48); Barlesi, et al. ESMO 2016 (Abs. LBA44)

Nivolumab

Docetaxel

CheckMate 017 CheckMate 057 KEYNOTE-010 OAK

Nivolumab

Docetaxel

Pembrolizumab

Docetaxel

Atezolizumab

Docetaxel

Selected immune-

mediated AEs

(immunotherapy arm)

CheckMate 017

n = 131

CheckMate 057

n = 287

KEYNOTE-010

(2mg/kg arm)

n = 339

OAK

n = 609

All

Grade

Grade

3–4

All

Grade

Grade

3–4

All

Grade

Grade

3–4

All

Grade

Grade

3–4

Pneumonitis 5% 1% 3% 1% 4% 2% 1% 1%

Hypothyroidism 4% 0% 7% 0% 9% 0% NR NR

Hyperthyroidism NR NR 1% 0% 7% 2% NR NR

Hepatitis NR NR NR NR 1% 0% <1% <1%

Colitis 1% 1% 1% <1% 1% <1% <1% 0%

Treatment-related AEs Grade 1–2 Grade 3–4 Immunotherapy

Docetaxel

CHEST 2017 152, 271-281DOI: (10.1016/j.chest.2017.04.177)

Higher incidence of pneumonitis with PD-1 inhibitors compared with PD-L1 inhibitors in NSCLC

Anti-PD-1 Anti-PD-L1 P

Incidence 3.6% 1.3% 0.001

Grade 3-4 1.1% 0.4% 0.02

Anti-PD-1

Anti-PD-L1

La Inmunoterapia con ICI antiPD1-PDL1 aumenta la Supervivencia Global en enfermedad metastásica, independientemente de la línea de

tratamiento.

• Muchos estudios pendientes (redundancia), muchos con resultados a lo largo del 2018, que definirán el mejor esquema (monoterapia, combinación), orden de tratamiento y selección de pacientes óptimo.

• Se pueden identificar pacientes con beneficios extraordinarios a la inmunoterapia:

• TPS PD-L1 >50% (1ª línea > beneficio que en 2L y sucesivas)

• IC3 or TC 3 PD-L1

• High-TMB

• Y subgrupos que no se benefician de monoterapia con anti-PD1/PDL1:

• Low-TMB

• EGFR mutados (diferente biología) - ¿combinaciones con IO?

• Objetivo: Aumentar el número de pacientes que se beneficien de la inmunoterapia (transformar “cold tumors” en “hot tumors”)

• A la espera del impacto de la Inmunoterapia en SG en enfermedad localmente avanzada y en etapa adyuvante. Estudios en marcha.

Take Home Messages Mejora de la Supervivencia en Cáncer de Pulmón con Inmunoterapia

The next pillar of lung cancer therapy

Cancer therapy

Su

rgery

Ch

em

oth

era

py

Rad

ioth

era

py

Ta

rgete

d

thera

py

Imm

un

oth

era

py

[email protected]

Gracias por vuestra atención!

Documents

Inmunoterapia 2018: Mejora de la Supervivencia en Título ... · Esquema de la charla IO en CPNM • Aumento de Supervivencia en 1ª línea • Aumento de Supervivencia en 2ª línea