Tratamiento en primera línea, ¿Cuando indicar y retirar la ... · Keynote 024. PDL1 > 50%. QT vs pembrolizumab. Beneficio SG para pembrolizumab. Nivolumab Chemotherap y Months %)

Tratamiento en primera línea, ¿Cuando indicar y retirar la inmunoterapia?

Papel del re-tratamiento

Ángel Artal

Servicio de Oncología Médica

Hospital Universitario Miguel Servet

Pre-inmunoterapia

Chansky, JTO 2017Ekman, WCLC 17, MA18.14

5-yr OS

Advanced

Checkpoint inhibitors in NSCLC<br />Key milestones

Anti Pd1/ PDL1 en segunda líneaNivolumab Pembrolizumab Atezolizumab

Ensayo CheckMate 017 CheckMate 057 Keynote 010 POPLAR OAK

Fase III III II/ III II III

N 272 (135/ 137) 582 (292/ 290) 1.033 144 425

Dosis 3 mg/ Kg 3 mg/ Kg 2 mg/ Kg y 10 mg/ Kg 1.200 mg 1.200 mg

Brazo control Docetaxel Docetaxel Docetaxel Docetaxel Docetaxel

Histología Escamoso No escamoso Escamoso y no

escamoso

Escamoso y no

escamoso

Escamoso y no

escamoso

Respuesta objetiva (%) 20 19 18 18 14 15

Duración respuesta (meses) No alcanzada 17,2 No

alcanzada

No

alcanzada

17,2 16,3

Tiempo hasta progresión

(mediana, HR)

3,5

0,62

2,3

0,92 NS

5,0

0,88 NS

5,2

0,79 NS

2,8

0,94 NS

2,7

0,94 NS

Supervivencia global

(mediana, HR frente a

Docetaxel)

9,2

0,62

12,2

0,75

10,4

0,71

12,7

0,61

12,6

0,94

13,8

0,73

Supervivencia 1 año (%) 42 51 43,2 52,3 52 55

2 años (%) 23 29 - - 32 31

3 años (%) 17* - - - 19 -

*: combinado 017 y 057. NS: No significativa

Monoterapia

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

OS

, %

P e m b r o 1 5 4 1 3 6 1 2 1 1 1 2 1 0 6 9 6 8 9 8 3 5 2 2 2 5 0

C h e m o 1 5 1 1 2 3 1 0 7 8 8 8 0 7 0 6 1 5 5 3 1 1 6 5 0

N o . a t r is k

Median (95% CI)30.0 mo (18.3 mo–NR)14.2 mo (9.8 mo–19.0 mo)

70.3%

54.8%

aEffective crossover rate from chemotherapy to anti-PD-L1 therapy, 62.3% (82 patients crossed over to pembrolizumab during the study and 12 received anti-PD-L1 therapy outside of crossover). bNominal P value. NR, not reached.Data cutoff: July 10, 2017.

51.5%

34.5%

Events, n HR (95% CI)

Pembrolizumaba 73 0.63

(0.47–0.86)

P = 0.002bChemotherapy 96

Bhramer JR. IASLC Tokio 2017

Keynote 024. PDL1 > 50%. QT vs pembrolizumab. Beneficio SG para pembrolizumab

Nivolumab

Chemotherap

y

Months

PFS

(%

)

2421181512963 27

100

80

60

40

0

20

0

All randomized patients (≥1% PD-L1+)

HR = 1.17 (95% CI: 0.95, 1.43)

HR = 1.15 (95% CI: 0.91, 1.45), P = 0.2511

MonthsO

S (%

)

2421181512963 30

100

80

60

40

0

20

0 27

Nivolumab

Chemotherapy

HR = 1.02 (95% CI: 0.80, 1.30)

All randomized patients (≥1% PD-L1+)

HR = 1.07 (95% CI: 0.86, 1.33)

CI=confidence interval; HR=hazard ratio; mos=months; OS=overall survival; PFS=progression-free survival; PD-L1=programmed death ligand 1..

Nivolumabn = 211

Chemon = 212

Median PFS, mos(95% CI)

4.2(3.0, 5.6)

5.9(5.4, 6.9)

1-year PFS rate, % 23.6 23.2

Nivolumab

n = 211

Chemo

n = 212

Median OS, mos

(95% CI)

14.4

(11.7, 17.4)

13.2

(10.7, 17.1)

1-year OS rate,

%56.3 53.6

No. of patients at risk:

Nivo 211 104 71 49 35 24 6 3 1 0

Chem

o

212 144 74 47 28 21 8 1 0 0

No. of patients at risk:

Nivo 211 186 156 133 118 98 49 14 4 0 0

Chemo 212 186 153 137 112 91 50 15 3 1 0

Socinski M et al. Oral presentation at ESMO 2016

Checkmate 026. PDL1 > 5%. Quimioterapia vs Nivolumab.

fármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación

Keynote 042. PDL1 > 1%. Fase III Quimioterapia vs pembrolizumab. Pembrolizumab. Beneficio en SG para pembrolizumab

G Lopes. ASCO 2018. Plenary sesion. Abstract LBA4

Beneficio a expensas de casi el 49% de pacientes PDL1 >50%

G Lopes. ASCO 2018. Plenary sesion. Abstract LBA4

Inmuno-Inmunoterapia

CheckMate 227: Nivo + Ipi in 1L NSCLC With High TMB (≥10 mut/Mb)

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

R

1:1:1

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

R

1:1:1

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


• Whole exome sequencing in tumor tissue samples from patients with NSCLC and SCLC treated with nivolumab + ipilimumab demonstrates the potential of TMB as an independent biomarker of efficacy, distinct from PD-L11,2

12

1. Hellmann MD, et al. Cancer Cell 2018. doi: https://doi.org/10.1016/j.ccell.2018.03.018. Epub; 2. Hellmann MD, et al. Cancer Cell (in press) 2018.

Preliminary Analyses of TMB in Lung Cancers Treated With Nivolumab + Ipilimumab

SCLC (CheckMate 032; n = 78)

High TMB tertile

Medium TMB tertile

Low TMB

tertile

100

75

50

25

0

0 6 12 18 24 30

PF

S (

%)

Months

PF

S (

%)

NSCLC (CheckMate 012; n = 75)

60 12 18 24 30 36 42 48

0

50

100

Months

TMB > median

TMB ≤ median25

75


CheckMate 026. Nivo vs Quimioterapia 1º línea PDL1>5%. No diferencias SG. Pero en

pacientes con alta carga mutacional, nivolumab tiene PFS significativamente menor.


TMB Analysis Using FoundationOne CDx™

• 58% of all randomized patients had TMB-evaluable samplesa

TMB-evaluable patients

(n = 1004)

≥10 mut/Mb<10 mut/Mb

44%56%

All randomized patients

(N = 1739)a

TMB-evaluable patients

(n = 1004)

Age, median (range), y 64 (26-89) 64 (29-89)

Female, % 32 33

ECOG PS, %

0

1

≥2

Not reported

34

65

<1

<1

33

67

<1

<1

Smoking status, %

Current/former smoker

Never smoker

Unknown

85

13

1

87

12

1

Histology, %

Squamous

Non-squamous

28

72

29

71

Tumor PD-L1 expression, %

<1%

≥1%

32

68

29

71


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%


Co-primary Endpoint: PFS With Nivolumab + Ipilimumab vs Chemotherapy in Patients With High TMB (≥10 mut/Mb)a

16

Nivo + ipi 139 85 66 55 36 24 11 3 0

Chemo 160 103 51 17 7 6 4 0 0

Nivo + ipi

(n = 139)

Chemo

(n = 160)

Median PFS,b mo 7.2 5.4

HRc

97.5% CI

0.58

0.41, 0.81

P = 0.0002

Months

0

20

40

60

80

100

0 6 12 183 9 15 21 24

PF

S (

%)

Chemotherapy

Nivolumab +ipilimumab

1-y PFS = 43%

1-y PFS = 13%

aPer blinded independent central review (BICR); median (range) of follow-up in the co-primary analysis population was 13.6 mo (0.4, 25.1) for nivo + ipi and 13.2 mo (0.2, 26.0) for chemo;b95% CI: nivo + ipi (5.5, 13.2 mo), chemo (4.4, 5.8 mo); c95% CI: 0.43, 0.77 mo; dThe P-value for the treatment interaction was 0.0018

No. at risk

• In patients with TMB <10 mut/Mb treated with nivo + ipi vs chemo, the HR was 1.07 (95% CI: 0.84, 1.35)d


ORR and DOR in Patients With High TMB (≥10 mut/Mb)a

17

0

10

20

30

40

50

Nivo + Ipi Chemo

ORR (TMB ≥10 mut/Mb)b

OR

R (

%)

DOR (TMB ≥10 mut/Mb)

63/139n/N:

Months

100

Chemotherapy


Pa

tie

nts

in

re

sp

on

se

(%

)

• Median time to response was 2.7 months with nivolumab + ipilimumab and 1.5 months with chemotherapy

43/160

a Per BICR; bORR in patients with TMB <10 mut/Mb was 24.6% in nivo + ipi arm and 25.9% in chemo arm

45.3

26.9

CR

PR

Nivo + ipi Chemo

≥1-y DOR = 68%

≥1-y DOR = 25%

Nivo + ipi

(n = 63)

Chemo

(n = 43)

Median DOR, mo

(95% CI)

NR

(12.2, NR)

5.4

(4.2, 6.9)

Nivo + ipi 63 56 46 32 22 10 5 0

Chemo 43 32 15 5 2 2 1 0

No. at risk

0

20

40

60

80

0 6 12 183 9 15 21

3.6

41.70.6

26.3


Nivo + ipi

(n = 95)

Chemo

(n = 104)

Median PFS, moa 9.5 5.6

HR

95% CI

0.55

0.38, 0.80

PFS in Patients With High TMB (≥10 mut/Mb) by Tumor Histology

18

Non-squamous

1-y PFS = 46%

1-y PFS = 17%

Nivo + ipi 95 59 49 41 27 18 8 1 0

104 70 38 15 6 6 4 0 0

Chemotherapy


Months

PF

S (

%)

0

20

40

60

80

100

0 6 12 183 9 15 2421

Squamous

44 26 17 14 9 6 3 2 0

56 33 13 2 1 0 0 0 0

Months

1-y PFS = 36%

1-y PFS = 7%

Nivo + ipi

(n = 44)

Chemo

(n = 56)

Median PFS, mob 4.9 4.3

HR

95% CI

0.63

0.39, 1.04

Chemotherapy


0

20

40

60

80

100

0 6 12 183 9 15 2421

No. at risk

Chemo

a95% CI: nivo + ipi (5.6 mo, NR), chemo (4.5, 7.0 mo); b95% CI: nivo + ipi (2.7, 13.7 mo), chemo (3.2, 5.6 mo)


Preliminary Overall Survival With Nivolumab + Ipilimumab vs Chemotherapy in Patients With High TMB (≥10 mut/Mb)

19

Nivo + ipi

(n = 139)

Chemo

(n = 160)

Median OS,b mo 23.0 16.4

HR

95% CI

0.79

0.56, 1.10

Months

OS

(%

)a

aIn the first 1.5 months, 8 deaths occurred in the nivo + ipi arm (4 due to disease progression; 1 patient never treated [respiratory sepsis]; 2 due to AEs unrelated to study drug per investigator [thromboembolism, septic shock]; 1 due to myocarditis related to study drug), and 2 deaths occurred in the chemo arm (1 due to disease progression; 1 due to multiple brain infarctions related to carboplatin); b95% CI: nivo + ipi (16.5 mo, NR), chemo (12.6 mo, NR); cPer investigator

No. at risk

Nivo + ipi 139 120 112 98 90 71 44 16 5

Chemo 160 148 129 104 90 75 45 23 9

0

1

0

0

Chemotherapy

Nivolumab + ipilimumab

1-y OS = 67%

1-y OS = 58%

0

20

40

60

80

100

0 6 12 183 9 15 21 24 27 30

• Database lock: March 15, 2018; minimum follow-up: 14.2 months; 53% of patients were censored

• In the chemotherapy arm, 31.3% received subsequent immunotherapy (38.3% among those with disease progressionc)

Combinaciones con QT

21

Brahmer J

22


Luis Paz-Ares. ASCO 2018. ORAL


Atezolizumab 1200 mg IV q3w; carboplatin AUC 6 IV q3w; nab-paclitaxel 100 mg/m2 IV qw; paclitaxel 200 mg/m2 IV q3w. a Patients with a sensitising EGFR mutation or ALK translocation must have disease progression or intolerance to treatment with ≥ 1 approved targeted therapies. Testing for EGFR mutation or ALK translocation was not mandatory.

Arm A

Atezolizumab + Carboplatin + Paclitaxel

4 or 6 cycles

Atezolizumab

Arm C (control)

Carboplatin + Nab-Paclitaxel

4 or 6 cycles

Best Supportive Care

Surv

ival

fo

llow

-up

Stage IV squamous NSCLC• Chemotherapy naivea

• ECOG PS 0 or 1 • Any PD-L1 IHC status

Stratification factors:• Sex• PD-L1 IHC expression• Liver metastases

N = 1021

R1:1:1

Arm B

Atezolizumab + Carboplatin + Nab-Paclitaxel

4 or 6 cycles

Atezolizumab

Maintenance therapy

(no crossover permitted)

Until PD per RECIST v1.1 or loss of clinical

benefit

Until PD per RECIST v1.1

Co-primary endpoints

• Investigator-assessed PFS per RECIST v1.1 (ITT)• OS (ITT)

Secondary endpoints

• PFS and OS in PD-L1 subgroups• ORR, DOR; safety

IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in

advanced non- squamous NSCLC.


Robert Jotte, et al. ASCO 2018


INV-Assessed PFS in the ITT Population (Arm B vs Arm C)

Data cutoff: January 22, 2018. INV, investigator. a Stratified HR.

Minimum follow-up, 9.8 mo

Median follow-up, 17.1 mo

Time (months)

12.0%

24.7%

12-month PFS

Arm B:

Atezo +

CnP

Arm C:

CnP

Median

PFS

(95% CI),

mo

6.3

(5.7, 7.1)

5.6

(5.5, 5.7)

HRa (95%

CI)

P value

0.71 (0.60, 0.85)

0.0001

Pro

gre

ssio

n-F

ree

Su

rviv

al (

%)

No. at risk

IPW 131, INV-Assessed PFS




Data cutoff: January 22, 2018. a Stratified HR.

56.9

%55.6

%

12-month OS

24.1

%

31.9

%

24-month OS

Arm B:

Atezo +

CnP

Arm C:

CnP

Median OS

(95% CI),

mo

14.0

(12.0, 17.0)

13.9

(12.3, 16.4)

HRa (95%

CI)

P value

0.96 (0.78, 1.18)

0.6931

Ove

rall

Surv

ival

(%

)

Time (months)No. at risk

IPW 131, INV-Assessed OS . Datos inmaduros



Inmuno + QT + Antiangiogénico


IMpower150 Study Design

Presented By Mark Socinski at 2018 ASCO Annual Meetingfármaco /combinaciones aún no aprobadas por Agencias Regulatorias en esta indicación

Mark A Socinski, et al. ASCO 2018


Updated PFS Analysis in the ITT-WT (Arm B vs Arm C)



OS in the ITT (Arm B vs Arm C)




Safety




OS in Key Subgroups (Arm B vs Arm C)



Duración del tratamiento

➢ Dos años vs Hasta pérdida de beneficio clínico

➢ En segunda línea parece que 1 años es inferior a 2 años

Robert C, Ribas A, Hamid O, et al: Durable complete response following

discontinuation of pembrolizumab in patients with metastatic melanoma.

J Clin Oncol 36:1668-1674, 2018

Resumen➢ Inmunoterapia en primera línea

Actual: MonoterapiaPróximamente: Combinaciones

➢ Integrar marcadores (TMB)

➢ Duración: Basada en ensayos clínicos

➢ Papel del re-tratamiento: EspeculativoTipo de respuesta previa, tiempo hasta la progresión, tipo de progresión, motivo de la interrupción

Documents

Tratamiento en primera línea, ¿Cuando indicar y retirar la ... · Keynote 024. PDL1 > 50%. QT vs pembrolizumab. Beneficio SG para pembrolizumab. Nivolumab Chemotherap y Months %)