Dra. Margarita Majem

Hospital de la Santa Creu i Sant Pau, Barcelona

Cambio de paradigma del tratamiento de la primera línea del cáncer de pulmón no microcítico metastásico sin

mutaciones driver

INDICE

- INTRODUCCIÓN

- PD-L1> 50%

- CUALQUIER PD-L1

- CA ESCAMOSO

- CA NO ESCAMOSO

- SITUACIONES ESPECIALES

Stage IV NSCLC (no targetable alterations)

PS 0-1 PS 2 PS 3-4

1st

line

PD-L1 < 50%

PD-L1≥ 50%SCC and non-SCC

Pembrolizumab(I,A)(*)

non-SCC

Platinum+Pemetrexed (II,A)Taxol+CBDCA+Bevacizumab (I,A)

Paclitaxel+CBDCA+Bev+Atezolizumab# (I,A)Platinum+Pemetrexed+Pembrolizumab(I,A)

Platinum+Pemetrexed+Atezolizumab#(I,b)

Platinum based-CT (I,A)Platinum+Taxane+Pembrolizumab#

(I,A)Platinum+Taxane+Atezolizumab#(I,

B)

SCC

Single agentCT (I,B)

Carboplatin-based CT (II,A)

BSC (II,B)

(*) combination of immunotherapy + CT may be considered#

• IO MONOTERAPIA

• IO-IO

MONOTHERAPY IN NSCLC PHASE III TRIALS

PFSNivolumab

CT (histology dependent)

PFS PD-L1 ≥5%

1L All histologies NSCLCPD-L1 ≥5% N=541

Checkmate 026

PFS OSDurvalumab

CT (histology dependent)

PFS

OS1L All histologies NSCLCAll comers N=1850

MYSTIC

PFS OSPEM + Platin doublet

Platin/Pem or Platin/GemOS1L All histologies NSCLC

PD-L1 ≥1% N=305IMPower110

Results

PFS OS

Treatment scheme

Pembrolizumab

Platin doubletPFS

Primary endpointsSample

1L All histologies NSCLCPD-L1 ≥50% N=305Keynote 024

PFS OSPembrolizumab

Carbo/pacl or Carbo/PemOS1L All histologies NSCLC

PD-L1 ≥1% N=1274Keynote 042

PFS OSNivolumab

CT (histology dependet)

OS PD-L1>1%1L All histologies NSCLC

All comers N=1739Checkmate 227

Part1

OS

MONOTHERAPY IN NSCLC PHASE III TRIALS

PFSNivolumab

CT (histology dependent)

PFS PD-L1 ≥5%

1L All histologies NSCLCPD-L1 ≥5% N=541

Checkmate 026

PFS OSDurvalumab

CT (histology dependent)

PFS

OS1L All histologies NSCLCAll comers N=1850

MYSTIC

PFS OSPEM + Platin doublet

Platin/Pem or Platin/GemOS1L All histologies NSCLC

PD-L1 ≥1% N=305IMPower110

Results

PFS OS

Treatment scheme

Pembrolizumab

Platin doubletPFS

Primary endpointsSample

1L All histologies NSCLCPD-L1 ≥50% N=305Keynote 024

PFS OSPembrolizumab

Carbo/pacl or Carbo/PemOS1L All histologies NSCLC

PD-L1 ≥1% N=1274Keynote 042

PFS OSNivolumab

CT (histology dependet)

OS PD-L1>1%1L All histologies NSCLC

All comers N=1739Checkmate 227

Part1

OS

PD-L1 ≥ 50%

5-Year Long-Term OS from KEYNOTE 001

Garon et al., ASCO 2019 (LBA 9015)

Reck ESMO 2019

Mok AACR 2019

OS in TC3 or IC3 WT

Spigel ESMO 2019PD-L1 expression (VENTANA SP142 IHC assay) ≥ 1% on TC or IC.

Maintenance therapy

(no crossover permitted)

Arm B

Nsq:

cisplatin/carboplatin +

pemetrexedd

Sq:

cisplatin/carboplatin +

gemcitabinee

4 or 6 cycles

Nsq:

pemetrexed

Sq: best

supportive

care

Su

rviv

al

foll

ow

-up

CPNM

PD-L1 +

R

1:1

Arm A

Atezolizumab

1200 mg q3w

Atezolizumab

1200 mg q3w

PD or

loss of

clinical

benefit

PD

IMpower 110

CM-026

Carbone DP, et al. New Engl J Med 2017;376:2415–26.

Rizvi N, et al. Annals of Oncol. 2018;29:suppl_10(abstr LBA6)

MYSTIC TRIAL

Rizvi N, et al. Annals of Oncol. 2018;29:suppl_10(abstr LBA6)

N = 1189

NIVO + (low-dose) IPIb

n = 396

Chemoc

n = 397

NIVOd

n = 396

R1:1:1

CPNM EGFR ALK WT

PD-L1expression≥

1%

Independent co-primary endpoints: NIVO + IPI vs chemo

• PFS in high TMB (≥10 mut/Mb) populationf

• OS in PD-L1 ≥ 1% populationg

NIVO + IPI(n = 396)

NIVO(n = 396)

Chemo(n = 397)

Median OS, mo 17.1 15.7 14.9

HR (vs chemo)a

CI0.79

0.65–0.96b0.88

0.75–1.04c

OS PD-L1 Expression ≥ 1%

NIVO + IPI

Chemo

NIVO

100

0

40

60

80

20

OS

(%

)

Months0 3 6 9 12 15 18 21 24 27 30 36 3933 42 45

56%

63%

57% 33%

40%

36%

OS PD-L1 Expression ≥ 50%

6 12 18 24 30 36 423 9 15 21 27 33 39

OS

(%

)

00 45

100

80

60

40

20

Months

54%

67%

61%

NIVO + IPI

NIVO

Chemo

NIVO + IPI(n = 205)

NIVO(n = 214)

Chemo(n = 192)

Median OS, mo95% CI

21.2 15.5–38.2

18.114.4–22.1

14.0 10.0–18.6

HR (vs chemo)95% CI

0.700.55–0.90

0.790.63–1.01

36%

48%

42 %

Peters ESMO 2019

CM-227

IO – QTCa no escamosoCa escamoso

Bracci et al., Cell Death and Differentiation 2016

IO – QTCa no escamoso

Bracci et al., Cell Death and Differentiation 2016

Median (95% CI)

24 (8.5–NR)

9.3(6.2–14.9)

Gentzler RD, et al. ASCO 2018

Overall Survival

Crossover~ 73%

Gentzler RD, et al. ASCO 2018

Median (95% CI)

NR (24.5–NR)

21.1 (14.9–NR)

N=616

Gandhi KN-189 AACR 18. Reck IMpower150. ESMO 2017. Papadimitrakopoulou. WCLC 2018. West AACR 2019

KEYNOTE-189: superioridad de Pembro+QT

independientemente de la expresión de PD-L1

Gadgeel et al. ASCO 2019, Abst 9013

Impower 130: Atezolizumab + QT superior en no escamoso

Cappuzzo et al. ESMO 2018West H, et al. Lancet Oncol 2019

Impower 130: Atezolizumab + QT superior en no escamoso en SLP

(SG ?)

Vassiliki A. Papadimitrakopoulou WCLC 2018

IMpower 150: QT+Atezolizumab+ Bev es superior

independientemente de la expresión de PD-L1

Socinski ASCO 2018

IO – QTCa escamoso

Bracci et al., Cell Death and Differentiation 2016

N=559

Paz-Ares ESMO 2019 abstr LBA82Cappuzzo WCLC 2019 abstr OA14.02

Paz-Ares ESMO 2019

KeyNote 407

Cappuzzo WCLC 2019

Impower 131

Treatment until disease

progression, unacceptable toxicity, OR

for 2 years for NIVO + IPI

NIVO 360 mg Q3W +

IPI 1 mg/kg Q6W +

Chemoc Q3W

(2 cyclesd)

Chemoc Q3W

(4 cycles)

Post-Induction

NIVO 360 mg Q3W +

IPI 1 mg/kg Q6W

Optional

Pemetrexed

maintenance

(NSQ histology)

R

1:1

Key Eligibility Criteria

• Stage IV NSCLC

• No prior systemic therapy

• No sensitizing EGFR

mutations or known ALK

alterations

• ECOG PS 0–1

Stratified by PD-L1b(< 1% vs ≥ 1%),

sex, and histology (SQ vs NSQ)

Crossover to immunotherapy from the chemotherapy arm was not permitted per study protocol.

Peters Ann Oncol 2019

PD-L1> 50%

Study

PD-L1

Prevalence

Arms

KN-024(>50%)

30%P vs CT

KN-042>50%46%

P vs CT

IMp-110TC3/IC3

38%A vs CT

MYSTIC>50% (expl)

D vs QT

CM-227>50%54%

N vs QT

CM-227>50%54%

N+I vs CT

MYSTIC> 50% (expl)

D+T VS CT

KN-189(>50%) ≈33%

IO+CT vs CT

IMp-150TC3/IC3

17%IO+CT+Bev vs

CT+Bev

IMp-132TC3/IC3

14%IO+CT vs CT

IMp-130TC3/IC3

19%IO+CT vs CT

RR 45% 39% 38% - 36.9% 44.4% - 61.4% 69% 72% -

mPFS10.3 vs

6mHR 0.5

7.1 vs 6.4m

HR 0.81

8.1 vs 5m

HR 0.63

4.7 vs 5.4m

5.6 vs 5.6mHR 0.75

6.7 vs 5.6 m

HR 0.62

3.9 vs 5.4m

HR 1.0

11.1 vs 4.8m

HR 0.36

12.6 vs 6.8m

HR 0.39

10.8 vs 6.5mHR 0.46

6.4 vs 4.6m

HR 0.51

mOS26.3 vs 14.2m

HR 0.65

20 vs 12.2m

HR 0.70

20.2 vs 13.1m

HR 0.59

18.3 vs 12.7m

HR 0.76

18.1 14m

HR 0.79

21.2 vs 14m

HR 0.70

15.2 vs 12.7mHR 0.77

NR vs 10.1m

HR 0.59

25.2 vs 15m

HR 0.70 (NS)

23.6 vs 14.1m

HR 0.56

17.3 vs 16.9m

HR 0.84 (NS)

MCBSScore

5 - - - - 5 3 - 3

Reck M, et al. NEJM 2016; Reck M, et al WCLC 2019; Mok T, et al. ELCC 2019; Spigel D et al. ESMO 2019; Rizvi N, et al. ASCO 2019;Peters S, et al. ESMO 2019; OA14.01; Gadgeel S.M, ASCO 2019; Socinski MA et al. NEJM 2018; Socinski MA et al, ASCO 2018;PapadimitrakopoulouV.A.,WCLC 2018; Cappuzzo et al ESMO 2018; West H, et al. Lancet Oncol 2019PlanchardD, Updated ESMOGuidelines, Ann Oncol Sept 2019

IO vs CT (All histologies)

IO+CT vs CT (Non-Squamous)

IO+IO (All histologies)

Cortesía Dra G-Campelo

PD-L1> 50%

StudyPD-L1PrevalenceArms

KN-024(>50%)

30%P vs CT

KN-042>50%46%

P vs CT

IMp-110TC3/IC3

38%A vs CT

MYSTIC>50% (expl)

D VS QT

CM-227>50%54%

N vs CT

CM-227>50%54%

N+I vs CT

MYSTIC> 50% (expl)

D+T VS CT

KN-189(>50%) ≈33%

IO+CT vs CT

IMp-150TC3/IC3

17%IO+CT+Bev vs

CT+Bev

IMp-132TC3/IC3

14%IO+CT vs CT

IMp-130TC3/IC3

19%IO+CT vs CT

TRAEs Gr 3/4 26.6% 18% 12.9% 14.6% 19% 33% 22.1% 67% 60% 54% 73%

% Discontin. 7.1% 9% 6.3% 5.4% 7.4% 12% 13.2% 20% (pembro) 34% (any) 15% (atezo) 26.4% (any)

IO vs CT (All histologies)

IO+CT vs CT (Non-Squamous)

IO+IO (All histologies)

Reck M, et al. NEJM 2016; Reck M, et al WCLC 2019; Mok T, et al. ELCC 2019; Spigel D et al. ESMO 2019; Rizvi N, et al. ASCO 2019;Peters S, et al. ESMO 2019; OA14.01; Gadgeel S.M, ASCO 2019; Socinski MA et al. NEJM 2018; Socinski MA et al, ASCO 2018;PapadimitrakopoulouV.A.,WCLC 2018; Cappuzzo et al ESMO 2018

Cortesía Dra G-Campelo

KEYNOTE-1891

(N=607)IMpower1502,3

(N=787)IMpower1324

(N=578)

Pembro+ pem + cis/carb

Pem + cis/carb

Atezo + bev + carb +

pac

Bev + carb +

pac

Atezocarb/cis

pem

Carb/cispem

99.8* 99.0* 94.4 95.4 92 87

67.2* 65.8* 58.5 50 57 42

27.7 14.9 32.63 24.93 24 18

6.7 5.9 2.8 2.3 4 3

KEYNOTE-4075

(N=558)IMpower1316

(N=668)

Pembro + carb + pac/

nab-pac

Carb + pac/ nab-pac

Atezo + carb + nab-

pac

Carb + nabpac

98.2* 97.9* 95 91

69.8* 68.2* 68 57

23.4 11.8 29 17

8.3 6.4 1 1

All TRAEs (%)

Grade 3–5 TRAEs

(%)

Discontinuation

Rate (%) (any

treatment)

Led to death (%)

Nonsquamous Squamous

EA5163/S1709/INSI

GNA

PD-L1 1- 49%

Study

Arms

KN-042P vs CT

CM-227N+I vs CT

KN-189IO+CT vs CT

IMp-150IO+CT+Bev vs CT+Bev

IMp-132IO+CT vs CT

IMp-130IO+CT vs CT

RR - - 49.2 vs 20.7% 58 vs 41% 38 vs 38% -

mPFS - -9.2 vs 4.9m

HR 0.518.3 vs 6.6m

HR 0.566.2 vs 5.7

HR 0.88.3 vs 6mHR 0.61

mOS13.4 vs 12.1mHR 0.9

15.1 vs 15.1m

HR 0.94

21 vs 12m

HR 0.62

20.3 vs 16.4mHR 0.8

-23.7 vs 15.9m

HR 0.70

MCBSScore

- 4 3 - 3

; Mok T, et al. ELCC 2019; Spigel D et al. ESMO 2019; Rizvi N, et al. ASCO 2019; Peters S, et al. ESMO 2019; OA14.01; Gadgeel S.M,ASCO 2019; Socinski MA et al. NEJM 2018; Socinski MA et al, ASCO 2018; PapadimitrakopoulouV.A.,WCLC 2018; Cappuzzo et alESMO 2018; PlanchardD, Updated ESMO Guidelines, Ann Oncol Sept 2019

IO vs CT (All histologies)

IO+CT vs CT (Non-Squamous)

IO+IO (All histologies)

PD-L1<1%

Study

Arms

CM-227N+I vs CT

KN-189IO+CT vs CT

IMp-150IO+CT+Bev vs CT+Bev

IMp-132IO+CT vs CT

IMp-130IO+CT vs CT

RR 27.3 vs 23% 32.3 vs 14.3% 51 vs 36% 44 vs 27% -

mPFS5.1 vs 4.7m

HR 0.736.2 vs 5.1m

HR 0.647.1 vs 6.9m

HR 0.778.5 vs 4.9m

HR 0.456.2 vs 4.7m

HR 0.72

mOS17.2 vs 12.2m

HR 0.62

17 vs 10m

HR 0.52

17.1 vs 14.1m

HR 0.82

15.2 vs 12m

HR 0.81

MCBSScore

- 4 3 - 3

IO+CT vs CT (Non-Squamous)

IO+IO (All

histologies)

Peters S, et al. ESMO 2019; OA14.01; Gadgeel S.M, ASCO 2019; Socinski MA et al. NEJM 2018; Socinski MA et al,ASCO 2018; PapadimitrakopoulouV.A.,WCLC 2018; Cappuzzo et al ESMO 2018; PlanchardD, Updated ESMOGuidelines, Ann Oncol Sept 2019

Pembrolizumab Plus Chemotherapy For Advanced NSCLC Without Tumor PD-L1 Expression: Pooled Analysis of KN021G, KN189 and KN407

1Fox Chase Cancer Center, Philadelphia, PA, USA; 2Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 3Hospital Universitario 12 de Octubre, Madrid, Spain; 4Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; 5Montefiore Einstein Center for Cancer Care, New York City, NY, USA; 6The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 8Mid North Coast Cancer Institute, Port Macquarie Base Hospital, Port Macquarie, NSW, Australia; 9Kansai Medical University Hospital, Osaka, Japan; 10Jilin Cancer Hospital, Changchun, China; 11Merck & Co., Inc., Kenilworth, NJ, USA; 12Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA

Hossein Borghaei,1 Corey Langer,2 Luis Paz-Ares,3 Delvys Rodríguez-Abreu,4 Balazs Halmos,5

Vassiliki A. Papadimitrakopoulou,6 Marina C. Garassino,7 Baerin Houghton,8 Takayasu Kurata,9

Ying Cheng,10 Jianxin Lin,11 M. Catherine Pietanza,11 Bilal Piperdi,11 Shirish Gadgeel12

0 3 6 9 12 15 18 21 24 27 30 33

0

10

20

30

40

50

60

70

80

90

100

Time, months

OS

, %

No. at risk

Pembrolizumab +chemotherapy

Chemotherapy alone

221243 186 153 117 92 79 49 29 13 2 0

165185 127 83 56 34 26 16 7 5 4 1

66%

47%

52%

29%

Events, n HR (95% CI)

Pembrolizumab + CT

112 0.56(0.43‒0.73)

CT 110

Median (95% CI) OS

19.0 (15.2‒24.0) mo

11.0 (9.2‒13.5) mo

Hossein Borghaei WCLC 2019

• IO monotherapy in previously untreated NSCLC PD-L1 ≥50% is a winner: efficacy, safety, and QoL positive data

compared to conventional chemotherapy (KN-024, KN-042, IMpower110)

• It´s also true today: IO+CT can be considered a new standard of care for previously untreated advanced NSCLC,

independently of PD-L1 status

• PD-L1 testing is still valid and mandatory when enough tumor material… from the beginning

• For those PD-L1 ≥50% IO monotherapy and IO+QT are valid treatment options, so far I would consider a

personalize decision…but today a regulatory decision

• Not direct prospective comparison available IO vs IO+CT

• After IO monotherapy, still you have opportunities for platinum doublets

• Not so clear for me the role of IO+IO

• Toxicity issues, patient preference… must be taken into account

✓ PD-L1✓ TMB✓ SKT-11/KEAP1✓ TIL > 10%✓ dNLR/LIPI

CLINICAL FACTORS