inmunoterapia en primera línea de cancer de pulmón no ......ph3 rct. un oncólogo ante el cáncer...

Antonio CallesServicio de Oncología Médica

Unidad de Tumores Torácicos y Unidad de Fases 1

Hospital General Universitario Gregorio Marañón

Instituto Investigación Sanitaria HGUGM

Universidad Complutense de Madrid

Madrid, España

Inmunoterapia en primera línea de cancer de pulmón

no microcítico: ¿sola o en combinación?

Conflicts of interest

Honorary/consulting fees:

AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli

Lilly and Company, Novartis, Merck Sharp & Dohme, Bristol-Myers

Squibb, AbbVie.

Año 2018: La inmunoterapia conquista la 1ª línea a la

quimioterapia en cáncer de pulmón

11

Ph3 RCT

Un oncólogo ante el cáncer de pulmón en el año 2018

Inmunoterapia en 1L de CPNM Avanzado

Y tras AACR18, ASCO18, WCLC18 y ESMO18 ¿qué?

• Cambio de paradigma: La quimioterapia ya no es el el componentefundamental…

• ….la inmunoterapia es el componente fundamental del tratamiento de primera línea del CPNM Avanzado

• Se van a beneficiar más pacientes de recibir tratamiento con IO en 1L (30%-50% no reciben tratamiento tras progresión a 1L)

• Beneficio de la IO parece superior cuanto antes se utilice (1L > 2L)

• Monoterapias: Menos tóxicas que la quimioterapia

• Combos: Similares en toxicidad a la quimioterapia, >irAEs

Inmunoterapia en 1L de CPNM Avanzado

Agenda

Inmunoterapia sola

Inmunoterapia + quimioterapia

Inmunoterapia + Inmunoterapia

Inmunoterapia sola

1L NSCLC: Phase 3 Trials With I-O Monotherapy

KEYNOTE-0241 /

KEYNOTE-0422 Checkmate 0263 MYSTIC4,5

Study ArmsPembrolizumab 200 mg q3w Nivolumab 3 mg/kg q2w

Durvalumab 20 mg/kg q4w

Durvalumab 20 mg/kg q4w

+ tremelimumab 1 mg/kg q4w

Pt-based chemo Pt-based chemo Pt-based chemo

N 305 / 1274 541 675

PD-L1 Cutoff ≥50% / ≥1% ≥5%* ≥25%

PD-L1 Assay Dako 22C3 Dako 28-8 Ventana SP263

Primary

Endpoint(s)PFS / OS PFS PFS, OS

Key Findings

• PFS benefit demonstrated with

pembrolizumab in patients with

PD-L1 ≥50%

• OS benefit demonstrated with

pembrolizumab in patients with

PD-L1 ≥1%

PFS benefit not demonstrated with

nivolumab in patients with PD-L1

≥5%

PFS and OS benefit not

demonstrated with durvalumab

monotherapy† in patients with PD-L1

≥25%

Cross-study comparisons are not intended. *For primary analysis. Patients with ≥1% PD-L1 expression were eligible. †Not yet formally tested.1. Reck M et al. N Engl J Med. 2016;375(19):1823-1833. 2. Lopes G et al. Oral presentation at ASCO 2018. 105. 3. Carbone DP et al. N Engl J Med. 2017;376(25):2415-2426. 4. Peters S et al. Poster presentation at ELCC 2016. 191TiP. 5. AstraZeneca [press release]. July 27, 2017.

MSD AZAZBMS

62% crossover

KEYNOTE-024

KEYNOTE-024: More frequent TRAEs with chemotherapy

Phase III CheckMate 026 Study Design: Nivolumab vs Chemotherapy in First-lineNSCLC

Carbone et al: NEJM 2017

PrimaryEndpoint:PFSin patients with>5%PD-L1

60% crossover

PFS by Tumor Mutation Burden SubgroupCheckMate 026 TMB Analysis (WES): Nivolumab vs Chemotherapy in

First-Line NSCLC

Nivolumab

Chemotherapy47 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

Nivolumabn = 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 RiskMonths

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)

Carbone DP et al. N Engl J Med. 2017

OS by Tumor Mutation Burden SubgroupCheckMate 026 TMB Analysis: Nivolumab in First-Line NSCLC

n = 111 n = 94

12.7(9.9, 16.1)

13.2(9.5, 15.2)

HR = 0.99 (95% CI: 0.71, 1.40)


(95% CI)Median OS, months

Low/medium TMB

55% received nivolumab as crossover and/or post-study treatment

1-y OS rate = 54% vs 53%

0 3 6 9 12

Months

15 18 21 24

100

90

80

70

60

50

40

30

20

10

0

111 99 82 69 59 47 28 11 3

94 87 71 60 50 38 21 6 2

27

Nivolumab

Chemotherapy

0

1

n = 47 n = 60

18.3(11.4, NR)

18.8(11.3, NR)

HR = 1.10 (95% CI: 0.64, 1.88)


(95% CI)Median OS, months

68% received nivolumab as crossover and/or post-study treatment

High TMB

0 3 6 9 12

Months

15 18 21 24

No. at Risk

Nivolumab

Chemotherapy

OS

(%

)

100

90

80

70

60

50

40

30

20

10

0Nivolumab

Chemotherapy

47 41 35 33 30 24 13 4 0

60 56 48 45 36 34 19 9 1

1-y OS rate = 64% vs 60%

KN-024, KN-042 y CM 026: Datos dispares en OS de la monoterapia

KEYNOTE-042 OSPD-L1 TPS ≥1%

No crossover

PLENARY SESSION

Checkmate 026 and KEYNOTE-042: Differences in Study Design and Patient Characteristics

• Checkmate 0261,2

• 60.4% in the chemotherapy arm had subsequent nivolumab therapy—crossover allowed

• 43.6% in the nivolumab arm had subsequent systemic therapy

• 32% of patients in the nivolumab arm and 47% of patients in the chemotherapy arm had ≥50% PD-L1 expression

• Primary analysis population included patients with PD-L1 ≥5%

• Lower response rate in nivolumab arm (26%) compared to chemotherapy arm (33%)

• KEYNOTE-0421,3

• 19.8% in the chemotherapyarm had subsequent immunotherapy (3% in pembrolizumab arm)

• 37% in the pembrolizumabarm had subsequent chemotherapy (31.6% in chemotherapy arm)

• 47% of patients in both arms had ≥50% PD-L1 expression

• Primary analysis population included patients with PD-L1 ≥1%

• Response rate similar overall to chemotherapy (27%)

1. Gandhi L. Discussant section at ASCO 2018. LBA4. 2. Carbone DP et al. N Engl J Med. 2017;376(25):2415-2426 [supplemental appendix]. 3. Lopes G et al. Oral presentation at ASCO 2018. LBA4.

KEYNOTE-042 OS by PD-L1

1. Se puede llegar a deducir que el beneficio en OS es derivado fundamentalmente del

subgrupo PD-L1 TPS >50%

2. Amplio sobrecruzamiento en las curvas de supervivencia en el subgrupo de PD-L1

TPS 1-49%, indica probablemente la existencia de 2 poblaciones (¿TMBhigh?)

47% 53%

Combinaciones con Inmunoterapia

• Histología no-escamosa

• Histología escamosa

• Combinaciones con anti-CTLA4

Phase 3 Trials of I-O + Chemotherapy in 1L NSCLC

KEYNOTE-189

Pembro + CT1

IMpower150

(Arms B & C)

Atezo + CT2

IMpower132

Atezo + CT3

IMpower130

Atezo + CT6

KEYNOTE-407

Pembro + CT4

IMpower131

(Arms B & C)

Atezo + CT5

Histology Nonsquamous Nonsquamous Nonsquamous Nonsquamous Squamous Squamous

N 616 800 578 679 559 683

PD-L1

StatusAll comers All comers All comers All comers All comers All comers

Primary

Endpoint(s)PFS, OS PFS, OS PFS, OS PFS, OS PFS, OS PFS, OS

Study Arms Pembro

pem

cis/carb

Pem

cis/carb

Atezo

bev

carb

pac

(Arm B)

Bev

carb

pac

(Arm C)

Atezo

carb/cis

pem

Carb/cis

pem

Atezo

carb

nab-pac

Carb

nab-pac

Pembro

carb

pac/

nab-pac

Carb

pac/

nab-pac

Atezo

carb

nab-pac

(Arm B)

Carb

nab-pac

(Arm C)

Cross-trial comparisons are not intended. *Nonsquamous: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivo lumab + pemetrexed maintenance following nivolumab + chemotherapy; squamous: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles.1. Gandhi L et al. N Engl J Med. 2018;378(22):2078-2092. 2. Socinski MA et al. N Engl J Med 2018;378(24):2288-2301. 3. Papadimitrakopoulou VA et al. Oral presentation at WCLC 2018. OA05.07. 4. Paz-ares L, et al. N Engl J Med. 2018; doi: 10.1056/NEJMoa1810865. 5. Jotte et al. Oral presentation at ASCO 2018. LBA9000. 6. Capuzzo et al. ESMO 2018.

MSD MSDRoche Roche RocheRoche

50%

crossover

Gandhi et al., NEJM 2018

Beneficio independiente de la expresión de PD-L1

KN189

¿Necesitan quimioterapia los pacientes con PD-L1 >50%?

KN189

KN024

¿Necesitan quimioterapia los pacientes con PD-L1 >50%?

Adverse Events

5.2% vs 0.5% acute renal injury

Reck IM150 ESMO-IO 2017Socinski IM150 ASCO 2018

Atezolizumab + Taxane-based 1L Chemo in NSCLC

IMpower130

PFS OS

Cross over to immunotherapy 135 (59.2%)

HR: 0.64

(95% CI: 0.54, 0.77)

P < 0.0001

HR: 0.79

(95% CI: 0.64, 0.98)

P = 0.033

Clear improvement of ORR, PFS and OS adding atezolizumab

Control arm: 20% Pemetrexed switch maintenance

Cappuzzo ESMO 2018


PFS (ITT-WT)

*Arm B vs. C

Pro

gres

sio

n-F

ree

Surv

ival

(%)

HRa, 0.59(95% CI: 0.50, 0.70)

P < 0.0001b

Median follow-up: ~20 mo

Cappuzzo, ESMO 2018; Socinski ASCO 2018

P(

)

%

F

S

HR: 0.64(95% CI: 0.54, 0.77)

P < 0.0001

Median follow-up: ~19 mo

Median: 7.0 mo

(95% CI: 6.2, 7.3)

Median: 5.5 mo

(95% CI: 4.4, 5.9)

Median, 8.3 mo(95% CI: 7.7, 9.8)

Median, 6.8 mo(95% CI: 6.0, 7.1)

IMpower 130Nab-Pacli.Carbo +/- atezo

IMpower 150Pacli.Carbo.Bev. +/- atezo*


Ove

rall

Surv

ival

(%)

OS (ITT-WT)

HRa, 0.78(95% CI: 0.64, 0.96)

P = 0.0164

OS

(%)

HR 0.79(95% CI 0.64–0.98)

P=0.033

Median, 18.6 mo(95% CI 16.0–21.2)

Median, 13.9 mo(95% CI 12.0–18.7)

Median, 19.2 mo(95% CI: 17.0, 23.8)

Median, 14.7 mo(95% CI: 13.3, 16.9)

IMpower 130Nab-Pacli.Carbo +/- atezo

IMpower 150Pacli.Carbo.Bev. +/- atezo*

Cappuzzo, ESMO 2018; Socinski ASCO 2018*Arm B vs C

What is the role of bevacizumab?


Impower 132 study design

•

a Atezolizumab: 1200 mg IV q3w; Carboplatin: AUC 6 mg/mL/min IV q3w; Cisplatin: 75 mg/m2 IV q3w;

Pemetrexed: 500 mg/m2 IV q3w. NCT02657434. Data cutoff: May 22, 2018

Maintenance therapy

Arm PPa

Carboplatin or cisplatin

+ pemetrexed

4 or 6 cycles

Pemetrexeda

Su

rviv

alfo

llo

w-u

p

Chemotherapy-naive

patients with Stage IV

non-squamous NSCLC

without EGFR or ALK

genetic alteration

Stratification factors:

• Sex

• Smoking status

• ECOG PS

• Chemotherapy regimen

N = 578

R

1:1

Atezolizumaba

+

pemetrexeda Maintenance

Treatment

until PD by

RECIST v1.1

or loss of

clinical benefit

Induction therapy

Arm APPa

Atezolizumab

+ carboplatin or cisplatin

+ pemetrexed

4 or 6 cycles

Barlesi, ESMO 2018

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 mo

Median follow-up: 14.8 mo

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 = 0.0797

Minimum follow-up: 11.7 mo

Median follow-up: 14.8 mo

Clear improvement of PFS and OS adding atezolizumab

PFS OS

IMpower 132 - OSPemetrexed Platin +/- Atezo

Barlesi, ESMO 2018

Capuzzo, ESMO 2018

IMpower 130 - OSNab-Pac Platin +/- Atezo

* VEGFRexpression

Sandler NEJM 2006, Tagliamonte Curr Opin Immun 2016, Koinis JTO 2016

* ** *

Liver = immunesuppressive microenvironment

Whithout Bevacizumabno benefit in the liver mets

subgroup

Phase 3 Trials of I-O + Chemotherapy in 1L NSCLC

KEYNOTE-189

Pembro + CT1

IMpower150

(Arms B & C)

Atezo + CT2

IMpower132

Atezo + CT3

IMpower130

Atezo + CT6

KEYNOTE-407

Pembro + CT4

IMpower131

(Arms B & C)

Atezo + CT5

Histology Nonsquamous Nonsquamous Nonsquamous Nonsquamous Squamous Squamous

N 616 800 578 679 559 683

PD-L1

StatusAll comers All comers All comers All comers All comers All comers

Primary

Endpoint(s)PFS, OS PFS, OS PFS, OS PFS, OS PFS, OS PFS, OS

Study Arms Pembro

pem

cis/carb

Pem

cis/carb

Atezo

bev

carb

pac

(Arm B)

Bev

carb

pac

(Arm C)

Atezo

carb/cis

pem

Carb/cis

pem

Atezo

carb

nab-pac

Carb

nab-pac

Pembro

carb

pac/

nab-pac

Carb

pac/

nab-pac

Atezo

carb

nab-pac

(Arm B)

Carb

nab-pac

(Arm C)

Cross-trial comparisons are not intended. *Nonsquamous: pemetrexed + cisplatin or carboplatin, Q3W for ≤4 cycles, with optional pemetrexed maintenance following chemotherapy or nivo lumab + pemetrexed maintenance following nivolumab + chemotherapy; squamous: gemcitabine + cisplatin, or gemcitabine + carboplatin, Q3W for ≤4 cycles.1. Gandhi L et al. N Engl J Med. 2018;378(22):2078-2092. 2. Socinski MA et al. N Engl J Med 2018;378(24):2288-2301. 3. Papadimitrakopoulou VA et al. Oral presentation at WCLC 2018. OA05.07. 4. Paz-ares L, et al. N Engl J Med. 2018; doi: 10.1056/NEJMoa1810865. 5. Jotte et al. Oral presentation at ASCO 2018. LBA9000. 6. Capuzzo et al. ESMO 2018.

MSD MSDRoche Roche RocheRoche

Presented By Luis Paz-Ares at 2018 ASCO Annual Meeting

Beneficio independiente de la expresión de PD-L1

KN407

Jotte IM131 ASCO 2018

First interim OS in the ITT population

42% in control arm received immunotherapy

Jotte IM131 ASCO 2018

No escamosoEscamoso

Terapias dirigidas (EGFR, ALK, ROS1, BRAF…)

Quimioterapia: Pemetrexed, mantenimiento

Antiangiogénicos: Bevacizumab, nintedanib

Inmunoterapia

Inmunoterapia

2L: Nivolumab (Pembrolizumab, Atezolizumab)

New SoC

KN-407

Carcinoma escamoso de pulmón avanzado: Necesidad médica no cubierta

IMPOWER 1501 400 400 0.62 [0.52;0.74]

TrialNo. patients

Immuno Control

HR [95% CI]

Immuno vs. control

IMPOWER 132 292 286 0.60 [0.49;0.72]

KEYNOTE 189 410 206 0.52 [0.43;0.64]

IMPOWER 130 451 228 0.64 [0.54;0.77]

Total 1553 1120 0.60 [0.54;0.65]

p<0.0001

0.2Heterogeneity : p=0.42, I²=0%

1 paclitaxel + carboplatin + bevacizumab + atezolizumab versus paclitaxel + carboplatin + bevacizumab

1.0 2.0

Immuno better | Control better

CT + Immuno - PFS

Besse and Pignon ESMO 2018

IMPOWER 1501 400 400 0.78 [0.64;0.96]

TrialNo. patients

Immuno Control

HR [95% CI]

Immuno vs. control

IMPOWER 1502 402 400 0.88 [0.72;1.08]

IMPOWER 132 292 286 0.81 [0.64;1.03]

KEYNOTE 189 410 206 0.49 [0.38;0.64]

IMPOWER 130 451 228 0.79 [0.64;0.98]

Total 1955 1520 0.76 [0.69;0.83]

p<0.0001

0.2

% of cross over

37.1%

41.3%

59.2%

31.7%

Heterogeneity : p=0.007, I²=71%1 paclitaxel + carboplatin + bevacizumab + atezolizumab versus paclitaxel + carboplatin + bevacizumab

2 paclitaxel + carboplatin + atezolizumab versus paclitaxel + carboplatin + bevacizumab

1.0 2.0


CT + Immuno - OS


IMPOWER 1501 191 205 0.77 [0.61;0.99]

TrialNo. patients

Immuno Control

HR [95% CI]

Immuno vs. control

IMPOWER 132 88 75 0.45 [0.31;0.64]

KEYNOTE 189 127 63 0.75 [0.53;1.05]

IMPOWER 130 235 121 0.72 [0.56;0.91]

Total 641 464 0.69 [0.60;0.80]

p<0.0001

Heterogeneity : p=0.10, I²=52%0.2 1.0 2.0



PD-L1 NEGATIVE - PFS


IMPOWER 1501 191 205 0.82 [0.62;1.08]

TrialNo. patients

Immuno Control

HR [95% CI]

Immuno vs. control

KEYNOTE 189 127 63 0.59 [0.38;0.92]

IMPOWER 130 235 121 0.81 [0.61;1.08]

Total 553 389 0.77 [0.64;0.92]

p=0.005

0.2

% of cross over

41.3%

59.2%

31.7%

Heterogeneity : p=0.42, I²=0%


1.0 2.0


PD-L1 NEGATIVE - OS


TrialNo. patients

Immuno ControlHR [95% CI]

Immuno vs. control

Chemotherapy

± immuno

320 205

0.39 [0.25;0.60]

0.46 [0.22;0.96]

0.36 [0.25;0.52]

0.51 [0.34;0.85]

0.42 [0.33;0.52]

0.64 [0.57;0.72]

p<0.0001

0.2


IMPOWER 1501

IMPOWER132

KEYNOTE 189

IMPOWER130

Subtotal

Chemotherapy

vs. immuno

KEYNOTE 042

KEYNOTE 024

CheckMate 026

Subtotal

Total 861 782

Heterogeneity : p<0.0001, I²=82%

Interaction : p<0.0001

75

25

132

88

73

20

70

42

299

154

88

300

151

126

0.81 [0.67;0.99]

0.50 [0.37;0.68]

1.07 [0.77;1.49]

541 577 0.76 [0.66;0.88]

1.0 2.0


PD-L1 ≥ 50% - PFS


TrialNo. patients

Immuno Control

HR [95% CI]

Immuno vs. control

295 185

0.70 [0.43;1.13]

0.42 [0.26;0.68]

0.84 [0.51;1.39]

0.62 [0.47;0.82]

762

0.2

% of

cross over

IMPOWER 1501

KEYNOTE 189

IMPOWER130

75

132

88

73

70

42

31.7%

41.3%

59.2%

300

151

126

Low

43.7%

60.0%

0.69 [0.56;0.85]

0.63 [0.47;0.86]

0.90 [0.63;1.29]

541 577 0.71 [0.61;0.82]

0.69 [0.60;0.79]

p<0.0001

1.0 2.0


PD-L1 ≥ 50% - OS

Chemotherapy

± immuno

Subtotal

KEYNOTE 042 299

Chemotherapy KEYNOTE 024 154

vs. immuno CheckMate 026 88

Subtotal

Total 836

Heterogeneity : p=0.21, I²=31%

Interaction : p=0.43



Anti-drug Antibodies (ADAs)% of ADAs

Maximum rate reported

13 2.1 3.2 4.1 4.5

48

26

10080604020

0

Circulating ADAs may

▪ Neutralize drugs

▪ Enhance drug clearance

▪ Different sensitivity of assays and cut-off explain discrepancies

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761049s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s009lbl.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s035lbl.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761034s012lbl.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125527s000lbl.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s067lbl.pdf

Maio M, Lancet Oncol 2017; Kverneland, Oncoimmunology 2018; Agrawal, J Clin Pharmacol. 2016; Tolcher CCR 2017, Shimizu Invest New Drugs 2016,

Besse ESMO 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf








Ipilimumab in melanoma

Kverneland, Oncoimmunology 2018

Serum level of ADAsN=31

26% positive for ADA

The FDA and EMA have previously reported frequencies of 5% and <2% respectively.

Besse ESMO 2018

Category No. Entered Hazard Ratio HR [95% CI]

0.80 [0.70;0.91]

(a) ITTITT 1225

(b) TC-IC subgroups

TC3-IC3 174TC1/2/3-IC1/2/3 684TC0-IC0 531

0.45 [0.30;0.67]0.77 [0.64;0.93]0.84 [0.69;1.02]

(c) ADA subgroups

ADA+ADA-

118442

0.89 [0.61;1.30]0.68 [0.55;0.84]

0.2 1.0 5.0Atezolizumab better| Docetaxelbetter

OAK – exploratory analysis

ADAs testedin 560 pts118 (21%)

Positive at 4 weeks


Besse ESMO 2018


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

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

In patients withTMB <10mut/Mb on nivo + ipi vs chemo, the

HRwas1.07 (95%CI: 0.84, 1.35)d

Hellman et al: AACR 2018: NEJM

CM-227: Co-primary Endpoint PFS With Nivolumab + Ipilimumab vs

Chemotherapy in Patients With High TMB (≥10 mut/Mb)a

Results by Histology

Exploratory analysisa95% CI: nivo + chemo (4.3, 9.1 mo), nivo + ipi (2.7, NR mo), chemo (4.0, 6.8 mo); b95% CI: nivo + chemo (4.2, 6.9 mo), nivo + ipi (1.6, 5.4 mo), chemo (3.9, 6.2 mo)

Nivolumab +

chemotherapy

Nivo +

chemo

(n = 54)

Nivo + ipi(n = 52)

Chemo

(n = 59)

Median PFS,b mo 4.7 3.1 4.7

HR (vs chemo)(95% CI)

0.87 (0.57, 1.33)

1.17(0.76, 1.81)

Nivolumab + ipilimumab

1-y PFS = 18%1-y PFS = 18%

Months

Chemotherapy1-y PFS = 16%

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

Nivolumab +

chemotherap

y

Months

1-y PFS = 45%

1-y PFS = 27%

Nivo +

chemo

(n = 43)

Nivo + ipi(n = 38)

Chemo

(n = 48)

Median PFS,a mo 6.2 7.7 5.3

HR (vs chemo)(95% CI)

0.56(0.35, 0.91)

0.48 (0.27, 0.85)

Nivo + chemo

No. at risk

Nivo + ipi 38 20 16 15 10 8 4 1

43 36 21 14 9 5 2 0

48 30 16 4 1 1 1 0Chemo

0

20

40

60

80

100

0 6 12 183 9 15 21

Chemotherapy

1-y PFS = 8%

PF

S (

%)

No. at risk

Nivo + ipi 52 22 12 7 5 3 1 0

59 39 16 6 6 3 1 0Chemo

Nivo + chemo 54 38 19 13 6 3 0 0

Nivolumab + ipilimumab

0

20

40

60

80

100

0 6 12 183 9 15 21

CheckMate 227: Progression-free survival by tumor mutation

burden and PD-L1 expression

Borghaei H, et al. ASCO2018.Abstract9001.

Platinum Chemotherapy is just as effectiveas Nivo+Ipi or Nivo+Chemo in <1% + TMB<10

patient population

• MYSTIC

1st Line TMB high TMB low Other Charact.

PDL1 Neg

Chemo

Chemo-IO / IO-IO

Chemo

Chemo-IO

?

PDL1 ≥1%

Chemo

Chemo-IO / IO-IO

Chemo

Chemo-IO

?

PDL1 ≥ 50%

IO

Chemo-IO / IO-IO

IO

Chemo-IO

Agressive

Disease ?

IO in First Line NSCLC

In 2019!!

La inmunoterapia es el estándar de tratamiento en primera línea de cáncer de pulmón no microcítico

avanzado/metastásico

• Monoterapia: Menos tóxica vs QT; reservada para PD-L1 ≥50%

• ¿Cuándo asociar quimioterapia?

• PD-L1 sea desconocido o <50% (otros?, Biología agresiva?)

• ¿Son todas las QT intercambiables? De momento, faltan datos

• ¿Cuándo asociar anti-CTLA4?

• TMB alto (≥10 mut/Mb) – Perfil toxicidades diferentes a la QT

• Familiarizarse con irAEs (Guías ESMO, NCCN/ASCO)

• Mejoría en parámetros de calidad de vida, control sintomático y funcional y retraso en el tiempo del deterioro clínico del paciente.

Take Home MessagesInmunoterapia en primera línea de Cáncer de Pulmón

Inmunoterapia en primera línea de cancer de pulmón

no microcítico: ¿sola o en combinación?

[email protected]

Gracias por vuestra

atención!

inmunoterapia en primera línea de cancer de pulmón no ......ph3 rct. un oncólogo ante el cáncer...

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