Inmunoterapia en cáncer esófago-gastrico - SEOM

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Inmunoterapia en cáncer esófago-gastrico Fernando Rivera Herrero

Hospital Universitario Marqués de Valdecilla. IDIVAL. Santander

Disclosure Information

Consultant or Advisory Role: Roche, Merck-Serono, Amgen, MSD, BMS, Lilly, Celgene, Sanofi-Aventis, Servier, Astra-Zeneca, Bayer

Research Funding: Roche, Merck-Serono, Amgen, MSD, Lilly, Celgene, Sanofi-Aventis, Servier, Bayer

Speaking: Roche, Merck-Serono, Amgen, MSD, BMS, Lilly, Celgene, Sanofi-Aventis, Servier, Bayer

Grant support: Amgen

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Inmunoterapia en cáncer esófago-gástrico

GUION

.- Introducción

.- Cáncer esofágico

- E. Resecable

- E. Avanzada

.- Adenocarcinoma gástrico

- E. Resecable

- E. Avanzada

.- Conclusiones

Cáncer Esófago-Gástrico Grupo heterogéneo de enfermedades

Cáncer de esófago - Ca. Epidermoide

- Adenocarcinoma

Adenocarcinoma de la UEG

Adenoca. Gástrico

Gradations of molecular subtypes of gastro-esophageal carcinoma

The Cancer Genome Atlas Research Network. Nature 2017

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GUION

.- Introducción


- E. Resecable

- E. Avanzada


- E. Resecable

- E. Avanzada

.- Conclusiones

CheckMate 577

CheckMate 577 study design

7

• CheckMate 577 is a global, phase 3, randomized, double-blind, placebo-controlled triala

Placebo

Q2W × 16 weeks then Q4W

Key eligibility criteria

• Stage II/III EC/GEJC

• Adenocarcinoma or squamous cell

carcinoma

• Neoadjuvant CRT + surgical resection

(R0,b performed within 4-16 weeks

prior to randomization)

• Residual pathologic disease

– ≥ ypT1 or ≥ ypN1

• ECOG PS 0–1

Primary endpoint:

• DFSe

Secondary endpoints:

• OSf

• OS rate at 1, 2, and

3 years

R

2:1

Nivolumab

240 mg Q2W × 16 weeks

then 480 mg Q4W N = 794

n = 532

n = 262

Stratification factors

• Histology (squamous vs adenocarcinoma)

• Pathologic lymph node status (≥ ypN1 vs ypN0)

• Tumor cell PD-L1 expression (≥ 1% vs < 1%c)

Kelly RJ et al, ESMO 2020

Total treatment duration

of up to 1 yeard

• Median follow-up was 24.4 months (range, 6.2–44.9)g

• Geographical regions: Europe (38%), US and Canada (32%), Asia (13%), rest of the world (16%)

794 pts incluidos - 15% asiáticos - 29% C epidermoides - 40% UEG - 17% PDL1-TPS >1%

CheckMate 577

Disease-free survival

8

aPer investigator assessment; b6-month DFS rates were 72% (95% CI, 68-76) in the nivolumab arm and 63% (95% CI, 57-69) in the placebo arm; cThe boundary for statistical significance at the pre-specified interim analysis required the P value to be less than 0.036.

• Nivolumab provided superior DFS with a 31% reduction in the risk of recurrence or death and a doubling in median DFS versus placebo

Nivolumab

(n = 532)

Placebo

(n = 262)

Median DFS, mo 22.4 11.0

(95% CI) (16.6–34.0) (8.3–14.3)

HR (96.4% CI) 0.69 (0.56–0.86)

P value 0.0003c

Months 0 45 42 39 36 33 30 27 24 21 18 15 12 9 6 b 3

532 0 3 4 8 22 41 68 92 147 181 212 249 306

0 1 2 5 12 17 28 38 53 65 80 96 126

364 430

0

20

40

100

80

60

DFS

a (

%)

Nivolumab

Placebo

No. at risk

Placebo 262 214 163

Nivolumab

CheckMate 577

Disease-free survival by subgroups

9

• DFS favored nivolumab versus placebo across these pre-specified subgroups

Overall (N = 794) 22.4 11.0 0.70

Age, years < 65 (n = 507) 24.4 10.8 0.65 65 (n = 287) 17.0 13.9 0.80

Sex Male (n = 671) 21.4 11.1 0.73 Female (n = 123) Not reached 11.0 0.59

Race White (n = 648) 21.3 10.9 0.71 Asian (n = 117) 24.0 10.2 0.70

ECOG PS 0 (n = 464) 29.4 11.1 0.73 1 (n = 330) 17.0 10.9 0.66

Disease stage II (n = 278) 34.0 13.9 0.72 at initial diagnosis III (n = 514) 19.4 8.5 0.68

Tumor location EC (n = 462) 24.0 8.3 0.61 GEJC (n = 332) 22.4 20.6 0.87

Histology Adenocarcinoma (n = 563) 19.4 11.1 0.75 Squamous cell carcinoma (n = 230) 29.7 11.0 0.61

Pathologic lymph ypN0 (n = 336) 27.0 0.74 node status ypN1 (n = 457) 14.8 7.6 0.67

Tumor cell PD-L1 1% (n = 129) 19.7 14.1 0.75 expression < 1% (n = 570) 21.3 11.1 0.73

Indeterminate/nonevaluable (n = 95) 9.5 0.54

0.25

Nivolumab better Placebo better

4 1 0.5 2

Subgroup Nivolumab

Median DFS, months

Placebo Unstratified HR

Unstratified HR (95% CI)

Not reached

Not reached

CM-577 nivolumab adyuvante tras QT/RTCx en C esofágico resecado

10

Es un estudio claramente positivo

…pero con algunas DUDAS:

.- Mayor seguimiento y datos de Sv

.- ¿adenoca de la UEG?

.- Selección de pacientes

¿CPS en vez de TPS? ¿Otros BM: TMB …?

.- ¿Nivo tras QT/RT definitiva?, ¿o tras QT perioperatoria?

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GUION

.- Introducción


- E. Resecable

- E. Avanzada


- E. Resecable

- E. Avanzada

.- Conclusiones

Pembrolizumab en cáncer esofágico

628 pts incluidos - 39% asiáticos - 64% C epidermoides - 35% PDL1-CPS >10

3 obj primarios: - Sv ITT - Sv en C epidermoides - Sv en PDL1-CPS>10

1- Kojima et al. J Clin Oncol 2019

P. III KN 181 1: Pembro vs Chemo in 2nd line Esop.Cancer: Final Analysis

2nd line Advanced Esophageal Cancer: Pembrolizumab

628 pts 401 pts (64%)

222 pts (35%)


prespecificado

p<0,0077

prespecificado

p<0,0077

prespecificado

p<0,0085


P. III KN 181 1: Pembro vs Chemo in 2nd line Esop.Cancer: Final Analysis

2nd line Advanced Esophageal Cancer: Pembrolizumab

On July 30, 2019, the Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck) for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy

749 pts incluidos - 52% asiáticos - 92% metastásicos - 73% C epidermoides - 50% PDL1-CPS >10

17

P. III KN 590 1: Chemo-Pembro vs Chemo-pcb in 1st line Esop.Cancer

1st line Advanced Esophageal Cancer: CT+ Pembrolizumab

1- Kato et al. ESMO 2020

286 pts (38%) 548 pts (73%) 383 pts (51%) 749 pts

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GUION

.- Introducción


- E. Resecable

- E. Avanzada


- E. Resecable

- E. Avanzada

.- Conclusiones

MONEO Perioperative G/EGJ II FLOT + avelumab 40 DANTE Perioperative G/EGJ R II FLOT 295 DFS/PFS NCT03421288 FLOT + Atezolizumab

Selected Ongoing trials with Inmunotherapy in resectable G/EGJ Adenoca

EGJ: preop CT-RT

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GUION

.- Introducción


- E. Resecable

- E. Avanzada


- E. Resecable

- E. Avanzada

.- Conclusiones

Immuno Checkpoint Inh in AdGC

1st line manteinance 2nd line ≥ 3rd line

KN 059. Coh 1

ATTRACTION-02

Javelin 300

KN 061 KN 062

Pem

bro

lizum

ab

Niv

olu

mab

Ave

Promising P. II

Rand P. III +

Rand P. III -

Ongoing P III

KN 811

KN 859

Javelin 100 manteinance

ATTRACTION-04

CM 649

Nivolumab (Anti PD-1) A positive asian P III in refractory disease

1.- Lancet. 2017 Dec 2;390(10111):2461-2471

2- Kang YK, et al. ASCO-GI 2017 . Abst 1 ;

3.- Boku N et al, ESMO 2017

P. III ATTRACTION-02 / ONO-4538 1,2,3

Advanced Gastric cancer, refractory to standard therapy (> 2 lines)

493 pts (rand 2/1)

Placebo Nivolumab 3 mg/kg / 14 d Primary Endpoint:OS

Pembrolizumab (Anti PD-1) P II KEYNOTE 059 (Cohort 1: > 2nd line)

1- Fucks CS et al, JAMA Oncol, 2018

259 pts (PD-L1 + 57%; Asian 13% )

RR 12%, DC 27% Dur of Resp: 8.4 m

Higher activity in PD-L1 + CPS>1 vs CPS <1

RR: 15% 6%

Dur of Resp 16,3 m 6,9 m

1 y OS: 26%

Avelumab (Anti PD-L1)

Bang YJ et al. Annals of Oncol 2018

OS

PFS

No valor predictivo de PD-L1 (TPS)



KN 059. Coh 1

ATTRACTION-02

Javelin 300

KN 061 KN 062

Pem

bro

lizum

ab

Niv

olu

mab

Ave

Promising P. II

Rand P. III +

Rand P. III -

Ongoing P III

KN 811

KN 859


ATTRACTION-04

CM 649

Pembrolizumab in 2nd line AGC A negative P III in 2nd line

1.- Fuchs CS. ASCO 2018

P. III KN 0611

2nd line Advanced Gastric canc

592 pts

Paclitaxel Pembrolizumab Primary Endpoint:

PFS and OS in PD-L1+ (CPS ≥1) OS (median) 9.1 m vs 8.3 m HR 0.82 (0.66-1.03 ) p 0.042 (0.0135)

PFS (median) 1.5 m vs 4.1 m HR 1.37 (1.03-1.57) p NS

P. III KN 0611,2

1.- Fuchs CS. ASCO 2018 2.- Fuchs CS, ASCO 2020

Overall Survival by PD-L1 (CPS)

33% of pts

67% of pts 18% of pts 29% of pts

P. III KN 0611


MSI-H: 27 pts (4% of pts)

RR

Overall Survival by MSI

P. III KN 061: tTMB predictive value 1


- tTMB >175 in 18% of pts - predictive value of tTMB is independent of MSI-H and PDL1/CPS



KN 059. Coh 1

ATTRACTION-02

Javelin 300

KN 061 KN 062

Pem

bro

lizum

ab

Niv

olu

mab

Ave

Promising P. II

Rand P. III +

Rand P. III -

Ongoing P III

KN 811

KN 859


ATTRACTION-04

CM 649

Avelumab (Anti PD-L1)

805 pts 499 pts

Primary endpoints: - OS in ITT pts - OS in PD-L1+

(TPS>1%

Moehler MH, et al. ASCO-GI-2020



KN 059. Coh 1

ATTRACTION-02

Javelin 300

KN 061 KN 062

Pem

bro

lizum

ab

Niv

olu

mab

Ave

Promising P. II

Rand P. III +

Rand P. III -

Ongoing P III

KN 811

KN 859


ATTRACTION-04

CM 649

P III Pembrolizumab in 1st line AGC P. III KN 062

1st line Advanced G/EGJ canc

HER 2 -; PD-L1 + (CPS >1)

763 pts

1º endp.; OS/PFS in CPS>1 and CPS>10

Cisplatin-FU/X Placebo

Pembrolizumab Cisplatin-FU/X

Pembrolizumab

K Shitara et al, JAMA Oncol 2020

OS: P vs CT in CPS ≥ 1 .- Non inferiority demonstrated .- Superiority no demonstrated

OS: P vs CT in CPS ≥ 10 .- Superiority of P no tested …. But seems to be better with P

Treatment-Related AEs: P vs C (CPS ≥1)

Presented By Josep Tabernero at 2019 ASCO Annual Meeting

P III in 1st line AGC: QT+Anti-PD1 vs QT+Pcb: PFS P. III KN 062 1

HER 2 -;PD-L1 -CPS >1 (38% CPS>10)

Asian 25%,EGJ 30%, M1 95%

1º endp: OS/PFS in CPS>1, CPS>10

2L/3L Immuno in control arm: 15%

Cispl-FU/X Placebo

Pembro Cispl-FU/X Pembro

/X

1.- K Shitara et al, JAMA Oncol 2020;

507 pts

HR 0,84 p 0,03

(>p 0.001)

HR 0,73

P III in 1st line AGC: QT+Anti-PD1 vs QT+Pcb: PFS P. III KN 062 1

HER 2 -;PD-L1 -CPS >1 (38% CPS>10)

Asian 25%,EGJ 30%, M1 95%



Cispl-FU/X Placebo


/X

P. III CM 649 2

HER 2 -; PD-L1 + /- (60%CPS >5)

Asian 25.%, EGJ/EA 20%, M1 96%

1º endp: OS/PFS in CPS>5 (2º CPS>1, all pts)


FOLFOX/XELOX Placebo

Nivo.Ipi FOLFOX/XELOX Nivo

P. III ATTRACTION-04 3

HER 2 -; PD-L1 +/-

Asian 100% , EGJ 11%,

1º endp: PFS/OS


Oxali-X/S1 Placebo

Oxali-X/S1 Nivo /X

1.- K Shitara et al, JAMA Oncol 2020; 2.- M Moehler et al, ESMO 2020; 3.- Boku N et al, ESMO 2020

/X

1581 pts 507 pts 724 pts

HR 0,84 p 0,03

HR 0,73 HR 0,68 p 0,0001

HR 0,74 HR 0,77 HR 0,68 p 0,0007

CPS >1 CPS >10 CPS >5 CPS >1 All pts All pts

P III in 1st line AGC: QT+Anti-PD1 vs QT+Pcb: OS P. III KN 062 1

HER 2 -;PD-L1 -CPS >1 (38% CPS>10)

Asian 25%,EGJ 30%, M1 95%



Cispl-FU/X Placebo


/X

P. III CM 649 2

HER 2 -; PD-L1 + /- (60% CPS >5)

Asian 25.%, EGJ/EA 20%, M1 96%






HER 2 -; PD-L1 +/-

Asian 100% , EGJ 11%,

1º endp: PFS/OS


Oxali-X/S1 Placebo

Oxali-X/S1 Nivo /X


/X

1581 pts 507 pts 724 pts

HR 0,85 p NS

HR 0,85 P NS

HR 0,71 p 0,0001

HR 0,77 P 0,0001

HR 0,8 P 0,0002

HR 0,9 p 0,25

CPS >1 CPS >10 CPS >5 CPS >1 All pts

All pts

P III in 1st line AGC: QT+Anti-PD1 vs QT+Pcb: OS P. III KN 062 1

HER 2 -;PD-L1 -CPS >1 (38% CPS>10)

Asian 25%,EGJ 30%, M1 95%



Cispl-FU/X Placebo


/X

P. III CM 649 2

HER 2 -; PD-L1 + /- (60%CPS >5)

Asian 25.%, EGJ/EA 20%, M1 96%






HER 2 -; PD-L1 +/-

Asian 100% , EGJ 11%,

1º endp: PFS/OS


Oxali-X/S1 Placebo

Oxali-X/S1 Nivo /X


/X

1581 pts 507 pts 724 pts

HR 0,85 p NS

HR 0,85 P NS

HR 0,71 p 0,0001

HR 0,77 P 0,0001

HR 0,8 P 0,0002

HR 0,9 p 0,25

Ongoing P III Pembrolizumab in 1st line AGC

P. III KN 811

1st line Advanced G/EGJ C

HER 2 + 700 pts

CT-Herceptin

Pembrolizumab CT-Herceptin

P. III KN 859

1st line Advanced G/EGJ canc

HER 2 -; PD-L1 + (CPS >1) and -

1542 pts Platin-FU Placebo 1º Endpoint: OS / PFS

Platin-FU

Pembrolizumab

1º Endpoint: OS / PFS

P III KN-062 Pembrolizumab in 1st line AGC

MSI-H (7% of pts)

Shitara K , ESMO 2019

P III CM-649 Nivolumab in 1st line AGC

MSI-H (4% of pts)

Pembrolizumab in 1st line in MSI-H G/GEJC?

P III KN-062 Pembrolizumab in 1st line AGC

MSI-H (7% of pts)

Shitara K , ESMO 2019

P III CM-649 Nivolumab in 1st line AGC

MSI-H (4% of pts)

Pembrolizumab in 1st line in MSI-H G/GEJC?

P. III KN-177: Pembro vs CT in 1st line MSI_H mCRC

Andre T et al, ASCO 2020

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GUION

.- Introducción


- E. Resecable

- E. Avanzada


- E. Resecable

- E. Avanzada

.- Conclusiones

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CONCLUSIONES. Ca de esófago

.- Carcinoma epidermoide y adenocarcinoma de esófago son dos entidades muy distintas que deberían estudiarse por separado

.- Enf. Resecable: CM-577: papel de nivolumab adyuvante tras QT/RTCx

.- 2ª línea: KN-181: pembro aprobado por FDA para epidermoides + CPS>10

.- 1ª línea: KN -590: pembro+QT superior a QT (claro en CPS>10; más dudoso en CPS<10)

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CONCLUSIONES. Ca Gástrico .- En marcha estudios en enfermedad resecable

.- Enf refractaria: Nivo aprobado en Japón (ATTRACTION-2) y Pembro en CPS>1 por FDA (KN 059)

.- 2ª línea: Pembro fase III KN-061 negativo (pero posible beneficio en CPS>10, MSI-H y TMB alto)

.- En 1ª línea

- KN 062: Pembro equivalente a QT en CPS >1; posiblemente superior en CPS>10; menos tox

- antiPD-1+QT vs QT (KN-062, CM 649, ATTRACTION-4):

- KN 062 com pembro negativo (tendencia a mejor SLP y SV) F III en marcha

- CM-649: con Nivo mejor SLP y Sv en CPS>5 (posible beneficio pero menor en CPS<5)

- ATTRACTION-4: con Nivo mejor SLP pero no Sv (¿2-3L inmuno en 27% pts del control?)

.- En MSI-H posible papel de los anti PD1 en 1ª línea (¿monoterapia o combinados con QT?)

GRACIAS

Inmunoterapia en cáncer esófago-gastrico - SEOM

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