Neo- and Adjuvant treatment for Gastric cancer and GE junction Cancer

Andrés CervantesProfessor of Medicine

DISCLOSURE SLIDE

Employment: None; Stock Ownership: None

Consultant or Advisory Role: Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas.

Research Funding: Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Sierra Oncology, Astra Zeneca, Medimmune, BMS, MSD

Speaking: Merck Serono, Roche, Angem, Bayer, Servier, Foundation Medicine. Grant support: Merck Serono, Roche.

Others: Executive Board member of ESMO, Chair of Education ESMO, General and Scientific Director INCLIVA, Associate Editor: Annals of Oncology and ESMO Open, Editor in chief: Cancer Treatment Reviews.

Classical approach to localised gastric cancer

� Surgical resection

� Pathology assessment and estimation of risk

� Treatment based upon classical TNM stage

� Postoperative chemotherapy of limited value

� Postoperative chemoradiation in US

The Gastric Group. JAMA 2010;303:1729–37

Meta-analysis of individual data of trials involving adjuvant chemotherapy versus surgery alone for gastric cancer

Noh SH, et al. Lancet Oncol 2014;15:1389–1396, © (2014), with permission from Elsevier

Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy versus surgery alone: 5-year follow -up of a randomised phase III trial

SURGERYNO TREATMENT

STRATIFICATION

T 1–4NODES CT+ CT-RT + CT0, 1–3, >3

MacDonald JS, et al. N Engl J Med 2001;345:725–730

The role of radiation in the postoperative setting: Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: A randomised Phase III Trial

Study design

Smalley S, et al. J Clin Oncol 2012;30:2327–2333

Adjuvant chemoradiotherapy for gastric cancer after surgery versus surgery alone: Long term data of a randomised Phase III Trial

ARTIST: The role of Radiation in the Postoperative SettingAdjuvant Cisplatin and Capecitabine versus Chemoradiation forGastric Cancer after Surgery: A Randomized phase III Trial

Park SH, et al. J Clin Oncol 2015; 33: 3130-3136

CRITICS TRIALDesign: 788 pts: 393 CT and 395 CRT

Tissuebanking

QoL

Chemoradiation

3x EC/OC q 3 wks

D1 + surgery

D1 + surgeryPreoperative chemotherapy3x EC/OC q 3 wks

Preoperative chemotherapy3x EC/OC q 3 wks

R

45 Gy/25 fx + / capecitabine

cisplatin-

Stratified for:- Center- Histological type- Localisation of tumor

Cats A, et al. Lancet Oncol 2018; 19:616-628

Final Results from CRITICS

/

-

Cats A, et al. Lancet Oncol 2018; 19:616-628

Eligible patients:� Adenocarcinoma of the stomach

or lower third of the oesophagus (from 1999), suitable for curative resection

� Non-metastatic disease� Stage II or greater

Chemotherapy (ECF):Epirubicin 50 mg/m2, IV day 1Cisplatin 60 mg/m2, IV day 15-FU 200 mg/m2/day, continuous infusion, days 1-21(cycles repeated every 3 weeks)

PrimaryOverall survival

SecondaryProgression-free survivalSurgical resectabilityQuality of Life

Recruitment: July 1994-April 2002

Study entry and randomisation

S armN=253

CSC armN=250

3-6 weeks

6-12 weeks

Cunningham D, et al. N Engl J Med 2006;355:11–20

MAGIC: Study design

Pre-operative chemotherapy:ECFx3

Post-operative chemotherapy:ECFx3

Surgery

Surgery

MAGIC Trial results

Logrank p-value = 0.0001Hazard Ratio = 0.66

(95% CI 0.53 - 0.81)

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

163 250190 253

EventsTotalCSCS

Logrank p-value = 0.009Hazard Ratio = 0.75

(95% CI 0.60 - 0.93)

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 250170 253

EventsTotalCSCS

2 year survival

5 year survival

Median survival

CSC 50% 36% 24 mo

S 41% 23% 20 mo

Benefit to CSC arm

9% 13% 4 mo

PFS* Overall

� On multivariate analysis, treatment effect unchanged after adjustment for age, performance status, site of primary and gender

� Hazard ratio for death � Adjusted: 0.74 (95%CI: 0.59-0.93) � Unadjusted: 0.75

Cunningham D, et al, N Engl J Med 2006;355:11–20. Copyright © (2006) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

Trial CTNo. pts control

No. ptsCT

5-year survival control

5-year survival CT

HR(CI at 95%)

CunninghamN Eng J Med 2006

ECF253

No CT250 23% 36 %

0.750.60-0.93p=0.009

YchouJ Clin Oncol 2011

CDDP5-FU

111No CT

113 24% 38%0.69

0.50-0.95p=0.021

AllumJ Clin Oncol 2009

CDDPFU

402No CT

40017,6% 25.5%

0.840.72-0.98P=0.03

Summary of trials of perioperative chemotherapy for localized Oesophago-gastric cancer with a surgical only controlled arm

1. Cunningham D, et al, N Engl J Med 2006;355:11–20.2. Ychou M, et al. J Clin Oncol 2011;29:1715-1726.3. Allum W, et al. J Clin Oncol 2009; 27:5062-5067. Only esophageal cancer

Classification of gastric adenocarcinoma: Pathology

� Intestinal versus diffuse subtypes

Lauren P. et al. Acta Pathol Microbiol Scand 1965;64:31–49

Cancer Genome Atlas Research Network. Nature 2014;513:202–209

9%

22%20%

50%

No effect of Preoperative ECF in MSI-H Gastric Cancer Patients

Smyth EC, et al. JAMA Oncol 2017; 3:1197-2003.

Preoperative ECF in Gastric and GE Junction Patients The role TRG.

Smyth EC, et al. J Clin Oncol 2016; 32:2721-2727.

Preoperative ECF in Gastric and GE Junction Patients The role TRG and ypNstatus

Smyth EC, et al. J Clin Oncol 2016; 32:2721-2727.

ECX versus CF

Alderson D, et al. Lancet Oncol 2017: 18:1249-1260.

CF vs EXC

ECX versus CF

Alderson D, et al. Lancet Oncol 2017: 18:1249-1260.

mOS 23.4 months for CFmOS 26.1 months for ECXHR:0.90 (95% CI: 0.77-1.05; p:0.19)

ECX versus BEV -ECX

Cunningham D, et al. Lancet Oncol 2017: 18:357-370.

FLOT-4 Study

FLOT x4 - RESECTION - FLOT x4

ECF/ECX x3 - RESECTION - ECF/ECX x3

• Gastric or EGJ cancer typ I-III

• Medically and anatomically operable

• cT2-4/cN-any/cM0 or cT-any/cN+/cM0

R

n=716

STRATIFIKATION

FLOT: Docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1; Leucovorin 200 mg/m², d1; Oxaliplatin 85 mg/m², d1, q2w

ECF/ECX: Epirubicin 50 mg/m2, d1; Cisplatin 60 mg/m², d1; 5-FU 200 mg/m² (or Capecitabin 1250 mg/m² p.o.geteilt in 2 doses d1-d21), q2w

Stratification: ECOG (0 or 1 vs. 2), localization(GEJ Type I vs. Type II/III vs. Gastric), age (< 60 vs. 60-69 vs. ≥70 years) and nodal status (cN+ vs. cN-).

Randomized, multicenter, Phase II/III Study

23% had Siewert type I33% had Siewert type II/III

FLOT Regimen

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

Chemo Related Toxicity 1

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

Chemo Related Toxicity 2

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

Survival ECF/ECX versus FLOT

Al-Batran et al. J Clin Oncol 2017; 35(suppl): #4004

ECF/ECX FLOT

mOS 35 months 50 months[27-46] [38-na]

HR 0.77 [0,63 – 0,94] p=0.012 (log rank)

2y. 59% 68% 3y. 48% 57% 5y. 36% 45%

OS rate* ECF/ECX FLOT

*projected OS-rates

Median follow-up time: 43 months

Trial CTNo. pts control

No. ptsCT

5-year survival control

5-year survival CT

HR(CI at 95%)

CunninghamN Eng J Med 2006

ECF253

No CT250 23% 36 %

0.750.60-0.93p=0.009

YchouJ Clin Oncol 2011

CDDP5-FU

111No CT

113 24% 38%0.69

0.50-0.95p=0.021

AllumJ Clin Oncol 2009

CDDPFU

402No CT

40017,6% 25.5%

0.840.72-0.98P=0.03

Al-BatranASCO 2017

FLOT360ECF

356FLOT

36% 45%0.77

0.63-0.94P=0.012

Summary of trials of perioperative chemotherapy for localized Oesophago-gastric cancer

1. Cunningham D, et al, N Engl J Med 2006;355:11–20.2. Ychou M, et al. J Clin Oncol 2011;29:1715-1726.3. Allum W, et al. J Clin Oncol 2009; 27:5062-5067. Only esophageal cancer4. Al-Batran SA, et al 2017; 35(suppl): #4004

ESMO MAGNITUDE OF THE CLINICAL BENEFIT SCALE

FLOT vs ECF trial: GRADE A

- -

�Absolute increase in 5-year survival 9%

Cheny NI et al. Ann Oncol 2015; 27:1547-1573

X

TrialCT

ExperimentalNo. pts

pCRControl vs

Experimental

5-year survival

Control vsExp

HR(CI at 95%)

CunninghamN Eng J Med 2006

ECF 503 0% vs 8% 23% vs 36 %0.75

0.60-0.93p=0.009

Al-BatranASCO 2017

FLOT 716 5,8% vs 15,6% 36% vs 45%0.77

0.63-0.94P=0.012

Alderson +Lancet Oncol 2017

ECX 897 3% vs 11% 39% vs 42%*0.90

0.77-1.050.19

CunninghamLancet Oncol 2017

BEV-ECX 1063 8% vs 11% 50% vs 48%*1.09

0.91-1.290.36

Perioperative chemotherapy for localized Oesophago-gastric cancer: a new standard

1. Cunningham D, et al, N Engl J Med 2006;355:11–20.2. Al-Batran SA, et al 2017; 35(suppl): #40043. Alderson D. et al Lancet Oncol 2017 on line +Only Esophageal, *3 year OS4. Cunningham D, et. Lancet Oncology 2017; 18:357-370

Neoadjuvant chemotherapy in gastric cancer: Conclusions

� Perioperative chemotherapy:� Induces downstaging� May increase the R0 resection rate� Prolongs disease free survival� Improves overall survival

� Evidence level I based upon 2 well designed and properly conducted randomised trials.

� FLOT is current standard of care� Preoperative therapy is better tolerated than postoperative� Localised gastric cancer requires a multidisciplinary team approach� Further research on biological predictive factors is needed

Currently recommended approach to localised gastric cancer

� Clinical assessment and staging

� Multidisciplinary team discussion

� FLOT preoperative treatment in clinical stage II and III patients

� Surgical resection after FLOT chemotherapy

� Pathology assessment and estimation of risk

� Postoperative chemotherapy if tolerated

� Radiotherapy still experimental

� No biological agents (Bevacizumab) to be used in this setting

Treatment for localised gastric cancer: What is standard of care? ESMO guidelines

Gastric Cancer (Adenocarcinoma)

Operable Stage > T1N0

Preoperativechemotherapy

Consider endoscopic /

limited resection

Operable Stage T1N0

SurgeryAdjuvant

chemotherapyAdjuvant

chemoradiation

Surgery

Post-operative chemotherapy

Preferred pathway