gastric cancer chemotherapy first - iweventos€¦ · four gastric cancer genomic subsets: tcga...

GASTRIC CANCER Chemotherapy First

David H. Ilson, M.D., Ph.D.

Attending Physician

Memorial Sloan-Kettering Cancer Center

New York

Disclosure

Consulting

– AMGEN

– Bayer

– Lilly

– Pieris

– Roche Genentech

– Astra Zeneca

– Bristol Myers Squibb

– Astellas

– Pfizer

Optimal Surgery for Gastric Cancer?

D2 resection is the standard of care in Asia

Increasingly in the West D2 resection is considered the standard

Update of Dutch D1 vs D2 resection at 15 years supports D2

Songun I et al Lancet Oncol 11: 439; 2010

Adjuvant Therapy in Gastric Cancer Improves OS

Pre and post op chemo (U.K.) without RT

– Preferred approach in the West

– ECF, MAGIC:

13% ↑ 5 yr OS, HR 0.75

Post op chemo (Asia): 2 trials, 2000 pts, D2 resection, no RT

– S-1 (Oral 5-FU), ACTS-GC:

10% ↑ 5 yr OS, HR 0.67 (2011 update)

– Cape-Oxali , CLASSIC Trial:

9% ↑ 5 yr OS, HR 0.66

Post op RT + chemo (U.S.), less than a D1-2 resection

– 5FU-LV + RT, INT 116:

10% ↑ 5 yr OS, HR 0.65

Macdonald NEJM 345:725; 2001 Cunningham NEJM 355: 11; 2006 Sasako JCO 29: 4387; 2011 ; Noh

Lancet Oncol 15: 1389; 2014

Why Give Chemo First?

Surgery First: 30-40% of patients don’t get to the point of adjuvant therapy

Better therapy tolerance

– After surgery and preop chemo only 50-60% start any post op therapy

Potential for downstaging, enhance resection

Assess response to preop therapy

Negatives:

– Risk of POD on therapy

– Treating early stage patients who are mistakenly staged T3 or N1

Gastric Cancer, Pre and Post Op ECF MAGIC Trial

ECF: Epirubicin, cisplatin, CIV 5-FU

3 Pre / 3 Post Op cycles ECF vs Surgery

Primary: Overall Survival

Cunningham et al, NEJM 2006

MAGIC Trial: Overall Survival

Patients at risk

Logrank p-value = 0.009

Hazard Ratio = 0.75

(95% CI 0.60 - 0.93)

CSC

S

250 168 111 79 52 38 27

253 155 80 50 31 18 9

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months from randomisation

0 12 24 36 48 60 72

149 250

170 253

Events Total

CSC

S

13% OS

MAGIC TRIAL: Preop Chemo in Gastric Cancer

Survival Improved + 13%, without RT

Modest T and N Down staging

– T1-2: 52% vs 37%

– N0: 31% vs 27%

– No improvement in rate of R0 resection (66-69%)

Supports pre and post op chemo as a standard of care

FLOT4 Study Design

Presented By Salah-Eddin Al-Batran at 2017 ASCO Annual Meeting

FLOT Regimen


Baseline 1


Baseline 2


Surgery 1


Surgery 2


Histopathology (ypTN)


FLOT4: Progression-Free Survival


FLOT4: Overall Survival


A Multicenter Randomized Phase III Trial of Neo-adjuvant Chemotherapy Followed by Surgery and Chemotherapy or by Surgery and Chemoradiotherapy in Resectable Gastric Cancer

Presented By Marcel Verheij at 2016 ASCO Annual Meeting

Does RT Add Benefit after Preop Chemo?

Trial design


Results: Overall Survival


Sasako et al. J Clin Oncol 29: 4387-4393; 2011

S1 for 1 yr after D2 resection: 1000 ptsOverall and Relapse-free Survival

10% OS

CLASSIC: Surgery vs 6 mos XELOX after D2

Noh et al Lancet Oncol 15: 1389-1396; 2014

5 yr OS: 78% vs 69%,

9%, HR 0.66, P =

0.0015

5 yr DFS: 68% vs 53%,

HR 0.58, P < 0.001

DOES RT ADD TO D2 RESECTION and Post op Chemo?

Adjuvant ChemoRadiotherapy Trial In Stomach Tumors

(ARTIST)

1 Lee J, J Clin Oncol 2011

• D2 resected

gastric

adenocarcinoma

• pStage Ib to IV(M0)

• Stratified by (1)

stage, (2) type of

surgery (STG v TG)

XP

RANDO MIZATION

XP

X: capecitabine 2,000

mg/m2/d D1-D14

P: cisplatin 60 mg/m2 D1

XRT: capecitabine 1,650

mg/m2/d daily

concurrently with RT 45

Gy for 5 weeks

XP

XP

XP XP XP XP

XP XPXRT

XP arm (6 cycles of XP)

XPRT arm (2XP/XRT/2XP)

Primary endpoint:

3-y DFS

Park JCO 33; 2014

Overall Survival

0 6 12 18 24 30 36 42 48 54 600.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bilit

y

XPRT

XP

Months

Pt

at

ris

k

XP

RT

23

0

220 20

1

184 178 171

XP 22

8

217 20

4

191 179 166

130 death events occurred

Hazard ratio 1.130 (95% CI,

0.775-1.647)

P=0.5272

Overall Survival: INT 116

Macdonald NEJM 345: 725-730; 2001

INT 116: Gastric Cancer Conclusions

Biggest impact in decreasing local recurrence

Surgical resection: Only 10% had a D2 resection

– 54% had less than a D1 resection

Standard of care for gastric cancer in <D1 resection

Impact of Postop RT in Gastric Cancer Depends on Surgical Quality

INT 116

– 54% < D1 resection

– 10% had D2

ARTIST

– 100% D2 resection

– ? Benefit in intestinal, N+

CRITICS

– 87% D1-D2 resection

Macdonald NEJM 345:725; 2001; Park JCO 33:

3030; 2015 Verheij JCO 34: 2016 (Abs 4000)

Gastric Cancer Adjuvant Therapy: Chemo, RT or Both?

Preop and post chemo with ECF improves OS (MAGIC)

– FLOT superior to ECF

– CRITICS: post op RT added no benefit

Post op chemo S1, Cape-Ox improves OS after D2 resection (Japan, Korea)

– ARTIST: No Benfit for RT after D2

Post op chemo 5-FU + RT improves OS (U.S. INT)

– Pts with less than a D1-2 resection

Four Gastric Cancer Genomic Subsets: TCGA

Genomically unstable (50%)

– 95% of Esophageal, GEJ tumors

– p53 mutation, RTK amplification

– VEGFA, Cell cycle pathway amplification

MSI high (22%)

– Promoter hypermethylation

Genomically stable (20%)

– Diffuse histology

– CHD-1 and RHOA mutation

Epstein-Barr virus (9%)

– PIK3CA mutation, PD-L1 and 2 amplification

Nature Genetics 24: 2903; 2014

MAGIC: MSI High 20 of 303 patients (7%)

Smith JAMA Oncol 3: 1197 ; 2017

MAGIC: dMMR protein status

Smith JAMA Oncol 3: 1197 ; 2017

HER2 Targeted Neoadjuvant Trials

RTOG 1010 (NCT01196390): Esophageal and GEJ Cancers, Carbo/Pac/RT + / - Trastuzumab

TRAP (NL) (NCT02120911): Phase II Carbo/Pac/Tras/Pertuz + RT

PETRARCA (NCT02581462): FLOT + / -Trastuzumab + Pertuzumab, gastric and GEJ

INNOVATION (EORTC) (NCT02205047): FU or Cape/Cisplatin + Trastuzumab + / - Pertuzumab, gastric and GEJ

Immunotherapy Neoadjuvant/Adjuvant Trials

Adjuvant nivolumab vs placebo after chemo + RT + surgery

– 760 pts, esophageal and GEJ cancer (NCT02743494)

ECOG: Carboplatin/Paclitaxel/RT + / -Nivolumab Surgery

– Observation vs Nivolumab + Ipilimumab

AIO: Dante: FLOT4 + / - Atezolizumab

Merck: Cape or FU/Cis periop + / -Pembrolizumab

Pilots: combining anti PD-1 or PDL-1 agents with chemo + RT

Local Recurrence Rates: Gastric Cancer Trials

U.S. Post Op 5-FU/RT (10% D2 resection)

– Surgery: 29%

– Chemo + RT: 19%

MAGIC: Periop ECF (40% D2)

– Surgery: 21%

– Chemo + Surgery: 14%

S-1 (100% D2)

– 2-3% with or without chemo

CLASSIC (100% D2)

– 4-9% with, without chemo

ARTIST (100% D2)

– 7% for chemo + RT, 13% for chemo alone

gastric cancer chemotherapy first - iweventos€¦ · four gastric cancer genomic subsets: tcga...

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