esophageal and gastric cancer...esophageal and gastric cancer peter c. enzinger, md director, center...

Esophageal and Gastric Cancer

Peter C. Enzinger, MD

Director, Center for Esophageal and Gastric Cancer

Dana-Farber Cancer Institute

Associate Professor, Harvard Medical School

Disclosures:

• Consultant:

• Astellas

• Celgene

• Five Prime

• Lilly

• Loxo

• Merck

• Taiho

Cancer Site Incidence Deaths

Esophagus

Stomach

16,940

28,000

15,690

10,960

Esophagogastric Cancer 2017

USA

Males in USAFemales in USA

Incidence of Gastric Adenocarcinoma

CA Cancer J Clin ‘08

Brown. J. Natl. Cancer Inst. 2008

Trends in Esophagogastric Cancer:

++++ > 8-fold risk

+++ 4-8-fold risk

++ 2-4-fold risk

+ < 2-fold risk

+/- Conflicting studies

--- No proven risk

Risk Factor SCC ADC Tobacco +++ ++ ETOH +++ --- Barrett’s Esophagus --- ++++ Weekly Reflux Symptoms --- +++ Obesity --- ++ Poverty ++ --- Achalasia ++++ Caustic injury to esophagus ++++ --- Tylosis (NEPPK) ++++ --- Plummer-Vinson syndrome ++++ --- History of head & neck cancer ++++ --- H/o breast ca treated with radiotherapy +++ ++ Frequent consumption of hot beverages + --- HPV (China, Japan, South Africa) +/- --- Beta blocker --- +/- Anticholinergics --- +/- Aminophylines --- +/-

Risk Factors:

Esophageal CA

Enzinger & Mayer. N Engl J Med 2003

0

2

4

6

8

10

12

14

16

18

0 20-29 30-39 40 + 0 3.5 11 14.5 25 28.5 36+

Adenocarcinoma

Squamous Cell Carcinoma

Adenocarcinoma

Squamous Cell Carcinoma

Cigarettes per Day Drinks per Week

Data from Takezaki 2000, Wu 2001 and Brown 2001

Tobacco/Alcohol and Esophageal Cancer

1-19

Squamous

epitheliumMetaplasia

Low-

Grade

Dysplasia

High-

Grade

DysplasiaADC METS

Oxidative stress

Inflammation

G1&G2

COX-2

BCL-2

4%/yr

0.5%/yr

1%/yr

5%/yr10%

GERD1:7 Americans

0.005%/yr

Early Genetic Events:

17pLOH p53; 9pLOH p16

cyclin D1

2nd Tier Genetic Events:

p53 mutation; p16 mutation/methylation

EGF(R), telomerase RNA

Late Genetic Events:

4 N (G2) aneuploidy of 5q/13q

and LOH of 5q/13q(Rb)/18q

?

c-erbB2

E-cadherin-catenin

85+%

Neoplastic Progression of Barrett’s Esophagus

Risk Factors

for

Gastric

Adenocarcinoma

• Nutritional

– Low fat or protein consumption

– Salted meat or fish

– High nitrate consumption

• Environmental

– Poor food preparation (smoked)

– Lack of refrigeration

– Poor drinking water (well water)

– Occupation (rubber, coal workers)

– Smoking (1.6x)

– Low social class

• Medical

– Prior gastric surgery

– Helicobacter pylori infection (2x)

– Gastric atrophy and gastritis

Helicobacter pylori

N=0

mutagens

Higher pH

Bacterial growth + nitrate

Gastric

ascorbic acid

B-carotene

Proposed Cascade of

Pathologic Events in

Gastric Adenocarcinoma

Salt

Normal Superficial

gastritis

Atrophic

gastritisMetaplasia Dysplasia Carcinoma

Salt N-nitroso Chronic inflammation

carcinogens and reactive oxygen species

inhibition

promotion

Adapted from Correa

Hereditary Gastric Cancer• 1-3% of all gastric cancers:

• Hereditary Diffuse Gastric Cancer (HDGC):

– E-cadherin/CDH1 Germline Mutation

– Autosomal dominant

• families with > 2 patients with gastric cancer at any age, one confirmed DGC

• individuals with DGC before the age of 40

• families with diagnoses of both DGC and LBC (one diagnosis < age 50)

– 70% risk of DGC; 40% risk of lobular breast cancer (LBC)

– Prophylactic total gastrectomy

• Li-Fraumeni syndrome Lynch syndrome

• Peutz-Jeghers syndrome Hereditary breast and ovarian cancer

• Familial adenomatous polyposis Juvenile polyposis syndrome

• MUTYH-associated adenomatous polyposis (MAP)

• PTEN hamartoma tumor syndrome (Cowden syndrome)

Van der Post, RS. J Med Genet. 2015 Jun; 52(6): 361–374.

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

Genomic Characterization of Esophagogastric Cancer

CIN: chromosome instability

EBV: ebstein-barr virus

MSI: microsatellite instability

GS: genomically stable

Presented by: Peter C. Enzinger, MD


Genomic Characterization of Esophagogastric Cancer

The Cancer Genome Atlas Research Network. Nature . 2017; 1–9


Mutations, copy #, & translocations across gastric molecular subtypes



Localized Esophageal Cancer

What Can Surgery

Accomplish?

Localized Esophageal Cancer Treated With Surgery

Rice, Blackstone, Rusch. Ann Surg Oncol 2010


Does (Neo)Adjuvant

Chemotherapy

Improve Surgical Outcomes?

Neoadjuvant Chemotherapy Compared with Surgery

Alone for Localized Esophageal Cancer

Sjoquist et al. Lancet Oncol 2011;12(7):681-92


Does Neoadjuvant

Chemoradiation

Therapy Improve

Surgery Outcomes?

All-Cause Mortality Estimates for Neoadjuvant C/RT Compared with Surgery Alone

Sjoquist et al.

Lancet Oncol 2011;

12(7):681-92

CROSS Study: Schema

• Chemoradiotherapy regimen: • Paclitaxel 50mg/m2 + Carboplatin AUC=2 on days 1, 8, 15, 22 and 29• Concurrent radiotherapy of 41.4 Gy in 23 fractions of 1.8 Gy

• Surgery within 6 weeks after completion of chemoradiotherapy (THE/TTE)

Van Hagen et al. N Engl J Med 2012;366:2074-84.

CROSS Study: Overall survival

Van Hagen et al. N Engl J Med 2012;366:2074-84.

HR, 0.657; 95% CI 0.495-0.871

24.0 mo 49.4 mo

POET: Schema

Arm A

Week

Arm B

PLF I PLF III (3 weeks)

15 x 2 Gy in 3 weeks

PE (1 week)

Surgery

Surgery

1 1314 17 20-21

PLF: Cisplatin 50mg/m2, 1h, d 1,15,29. Leukovorin/5-FU 500mg/m2 2h / 2g/m2 24h, d1,8,15,22,29,36

PE: Cisplatin 50 mg/m2, 1h, d 2+8. Etoposide 80 mg/m2, 1h, d 3-5

PLF II

6 7

PLF I PLF II

Stahl M, et al. J Clin Oncol.2009;27:851-856.

POET: Overall Survival (Long-term Results)

Stahl M, et al. J Clin Oncol.2009;27:851-856.

Stahl M, et al. Eur J Cancer.2017;183-190.

Median Survival:

C→C→S C→C/RT→S

21.1 mo 30.8 mo

3yr 5yr

47% 40%

26% 24%

Can Surgery Improve

the Outcome of

Chemoradiation?


Schema

tumor size

histology

weight loss

2 x Cisplatin (75 mg/m2)

+

5-fluorouracil (1000 mg/m2/d CI x 4d)

+

radiation therapy (5000 cGy)

R

A

N

D

O

M

I

Z

E

radiation therapy (6400 cGy)

Herskovic A, et al. N Engl J Med. 1992;326:1593-1598.

al-Sarraf M, et al. J Clin Oncol. 1997;15:277-284.

Prospective Randomized Intergroup Study:Radiation Therapy vs Chemotherapy + Radiation Therapy for Localized SCC or ADC of the Esophagus

Herskovic A, et al. N Engl J Med. 1992;326:1593-1598. al-Sarraf M, et al. J Clin Oncol. 1997;15:277-284.

Intergroup Study

Stratification :

• adenocarcinoma vs squamous cell vs adenosquamous

• pretreatment weight loss < 10% vs ≥ 10%

• performance status: 0 vs 1 vs 2

• center

Inoperable

esophageal

cancer

R

A

N

D

O

M

I

Z

E

50 Gy/5 weeks

+ Folfox, 3 cycles

50 Gy/5 weeks +

5FU/cisplatin, 2 cy.

Folfox, 3

cycles

5FU/cisplatin, 2

cycles

Conroy et al. Lancet Oncol. 2014 Mar;15(3):305-14.

Prodige 5 - ACCORD 17 - Schema

FOLFOX: more gr. 1-2 PN, fewer toxic & sudden deaths, less mucositis, less alopecia,

decreased renal toxicity, shorter chemotherapy (12 days vs 16-20 days) in an outpatient

setting. Conroy et al. Lancet Oncol. 2014 Mar;15(3):305-14.

Prodige 5 - ACCORD 17 - Survival

• A total of 455 patients with localized esophageal cancer were given 2 courses of 5-FU/cisplatin plus radiation therapy.

• 259/455 patients experienced a “partial response”, were considered operative candidates, and entered the randomized component of the trial.

Bedenne. J Clin Oncol. 2007;25:1160-1168.

Chemoradiation Therapy With or Without Surgery: French Phase III Trial

Survival

3-month mortality median 2-year

5-FU/CDDP x 3

+

1%

Radiation therapy

19.3

months

40%

P=0.56

Surgery 9% 17.7 months

34%

Partial Response

R

A

N

D

O

M

I

Z

E

(259 pts)

Bedenne. J Clin Oncol. 2007;25:1160-1168.

Chemoradiation Therapy With or Without Surgery: French Phase III Trial

Patients:

(N = 177)

uT3-4,N0-1, M0

with SCC

R

A

N

D

O

M

I

Z

E

3 cycles:

5-FU/LV +

Cisplatin +

Etoposide

Chemoradiation:

Cisplatin + Etoposide

+ 40 Gy RT

→ Surgery

Chemoradiation:

Cisplatin + Etoposide

+ > 60 Gy RT

Stahl. J Clin Oncol. 2005;23:2310-2317.

Chemoradiation Therapy With or Without Surgery:German Phase III Trial - Schema

Arm Completed

Treatment

Treatment

Mortality

3-yr Local

Recurrence

Median

Survival

3-Year Survival

Induction Chemo

All Responder

Arm A:

C/RT →S 62% 12.8% 41% 16 mo. 31% 54%

Arm B:

C/RT 85% 3.5%

(P = 0.03)

64%

(P = 0.004)

15 mo. 24%

(P = 0.02)

54%


Chemoradiation Therapy With or Without Surgery:German Phase III Trial - Results


Median survival (N = 172):

Arm A (C/RT →S) -16.4 months

Arm B (C/RT only)-14.9 months

31.3% (P = 0.02)

24.4%

Chemoradiation Therapy With or Without Surgery:German Phase III Trial - Survival

Localized Esophageal

Pre-operative cisplatin/5-FU chemotherapy offers a

small survival advantage in distal esophageal and GE

junction cancer.

Neoadjuvant platinum-based chemoradiation (esp. w.

carbo/tax) offers a greater survival advantage with

better local control but increased surgical morbidity.

Surgery may not be needed in patients who have a

clinical response to chemoradiation. FOLFOX may

be the best choice for these patients.

Conclusions from these Studies

What Can Surgery

Accomplish?

Localized Gastric Cancer

Survival for Resected Localized Gastric Cancer

Survival for 10,601 patients with resected gastric cancer

using SEER data 1973-2005 and AJCC 7th ed.Washington. Ann Surg Oncol 2010

What are Proven Strategies to

Enhance Outcomes for

Surgical Resection?

Localized Gastric Cancer

Stratify

depth of tumor

penetration 5-FU/leucovorin x 1

5-FU/leucovorin

+

4500 cGy

radiation

5-FU/leucovorin x 2

number involved

nodes

location of tumor observation

extent of surgery

R

A

N

D

O

M I

Z

E

Macdonald JS, et al. N Engl J Med. 2001;345(10):725-730.

Intergroup Protocol 0116Adjuvant Therapy for Gastric Cancer

Macdonald JS, et al. N Engl J Med. 2001;345:725-730.

Smalley SR, et al. J Clin Oncol. 2012; 30:2327-2333

Chemoradiotherapy

Surgery Only

50%

41%

3 years

Intergroup Protocol 0116

ECF x 3 q3/52

3-6 weeks

Resection

ECF x 3 q3/52

6-12 weeks

CSC S

Follow-up

Within 6 weeks

Resection

Cunningham D, et al. N Engl J Med. 2006;355:11-20. 503 Patients:

15% Lower Third12% GE Junction

MAGIC Trial: Schema

MAGIC: Survival

FLOT4 Study Design

FLOT x4 - RESECTION - FLOT x4

ECF/ECX x3 - RESECTION - ECF/ECX

x3

• Gastric cancer or

adenocarcinoma of

the gastro-esophageal

junction type I-III

• Medically and

technically operable

• cT2-4/cN-any/cM0 or

cT-any/cN+/cM0

R

n=716

S

T

RA

T

I

F

I

CA

T

I

O

N

FLOT: docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1;

leucovorin 200 mg/m², d1; oxaliplatin 85 mg/m², d1, every

two weeks

ECF/ECX: Epirubicin 50 mg/m2, d1; cisplatin 60 mg/m², d1;

5-FU 200 mg/m² (or capecitabine 1250 mg/m² p.o. divided

into two doses d1-d21), every three weeks

Stratification: ECOG (0 or 1 vs. 2), location of primary (GEJ type I vs.

type II/III vs. stomach), age (< 60 vs. 60-69 vs. ≥70 years) and nodal

status (cN+ vs. cN-).

Presented by: Salah-Eddin Al-Batran

Randomized, multicenter, investigator-initiated, phase II/III study

FLOT4: Progression-Free Survival

ECF/ECX FLOT

mPFS 18 months 30 months

[15-22] [21-41]

HR 0.75 [0.62-0.91]

p=0.004 (log rank)

2y 43% 53% 3y 37% 46% 5y 31% 41%

PFS rate* ECF/ECX FLOT

*projected PFS rates


FLOT4: Overall Survival

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


FLOT 4: Toxicity

Grade 3-4 >5% ECF/ECX (N=354) FLOT (N=354) P-value (Chi-Square)

Diarrhea 13 (4%) 34 (10%) 0.002

Vomiting 27 (8%) 7 (2%)

Localized Gastric:

Post-operative 5-FU-based chemoradiation therapy remains

one standard of care for muscle-invasive or LN positive

disease.

The peri-operative FLOT4 regimen appears to be an

improvement over MAGIC/ECF and should be considered

for patients of better performance status.

Conclusions from these Results

What are the Active Agents and

Combinations for this Disease?

Metastatic Esophagogastric Cancer

Evolution of Therapy in Advanced Esophagogastric Cancer

FAM < FAMTX

CF = ELF = FAMTX > EAP

5-FU < FAM

PELF = FAMTX < ECF

ECF > MCF

ECF = ECX = EOF = EOX

DCF > CF CF = FOLFIRIFOL = CFFOX

DC < DCF IP < FOLFIRI

Randomized Phase III

Randomized Phase II

Multi-center Phase II

FOLFOX

FOLFIRI = EOXmDCFFOL =ECFFOX

CALGB 80403 / ECOG E1206: Schema

Stratification:

ECOG 0-1 vs 2

ADC vs. SCC

ARM A: (ECF + cetuximab); 1 cycle = 21 days

Cetuximab 400 → 250mg/m2 IV, weekly

Epirubicin 50 mg/m2 IV, day 1

Cisplatin 60mg/m2 IV, day 1

Fluorouracil 200mg/m2/day, days 1-21

ARM B: (IC + cetuximab); 1 cycle = 21 days


Cisplatin 30 mg/m2 IV, days 1 and 8

Irinotecan 65 mg/m2 IV, days 1 and 8

ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days


Oxaliplatin 85 mg/m2 IV, day 1

Leucovorin 400 mg/m2, day 1

Fluorouracil 400 mg/m2 IV bolus, day 1

Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

Enzinger. J Clin Oncol 2016

CALGB 80403 / E1206: Survival

FOLFOX-C has similar efficacy to ECF-C in Esophageal and GEJ Cancer

Progression-Free Survival Overall Survival

0 5 10 15 20 25 30

Months from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y O

vera

ll S

urv

ival

67 55 38 23 14 10 473 56 33 21 13 10 5

73 61 41 24 14 6 5

Number of Patients at Risk

ECF-CIC-C

FOLFOX-C

Events n/N (%)

Median months

95% CI

ECF-C 63/67 (94.0%) 11.6 8.1-13.4

IC-C 68/73 (93.2%) 8.6 6.0-12.4 FOLFOX-C 65/73 (89.0%) 11.8 8.8-13.9

Log-rank test p=0.61

0 5 10 15 20 25 30

Months from Study Entry

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity

Pro

gre

ss

ion

-fre

e S

urv

iva

l

67 41 17 7 5 5 3

73 35 11 5 4 1 073 47 22 8 8 3 2

Number of Patients at Risk ECF-C

IC-CFOLFOX-C

Events n/N (%)

Median months

95% CI

ECF-C 65/67 (97.0%) 7.1 4.5-8.4

IC-C 72/73 (98.6%) 4.9 3.9-6.0 FOLFOX-C 70/73 (95.9%) 6.8 5.4-8.1

Log-rank test p=0.09

Treatment modifications:

FOLFOX-C (73%) vs IC-C (85%) vs ECF-C (91%) (χ2, p=0.013).

Discontinued treatment for adverse event or treatment-related death:

FOLFOX-C (11%) vs. ECF-C (19%) vs IC-C (26%) (χ2, p=0.17).Enzinger. J Clin Oncol 2016

Time to Progression Overall Survival

Grade 3-4 Toxicity DCF CF

Neutropenia 82% 57%

Febrile Neutropenia 29% 12%

Stomatitis 21% 27%

Diarrhea 19% 8%

Vomiting 14% 17%

Van Cutsem et al.

J Clin Oncol 2006

Phase III: DCF vs CF for Esophagogastric Cancer

Shah et al. JCO 2015;33:3874-3879

Grade 3-4 Toxicity mDCF DCF

Neutropenia w GCSF 56% 45%

Febrile Neutropenia 9% 16%

Stomatitis 0 13%

Diarrhea 6% 3%

Vomiting 2% 19%

Randomized PII: Modified DCF vs. DCF for Met Gastric

Guimbaud. J Clin Oncol 2014

Phase 3: FOLFIRI vs ECX for Met Gastric/GEJ

Previously

untreated patients

with locally

advanced or

metastatic

oesophago-

gastric cancer

R

A

N

D

O

M

I

S

A

T

I

O

N

Epirubicin

Cisplatin

Fluorouracil

Epirubicin

Cisplatin

Xeloda (capecitabine)

Epirubicin

Oxaliplatin

Fluorouracil

Epirubicin

Oxaliplatin

Xeloda (capecitabine)Stratified for:

- Center (63 centers, mainly UK, 2 Aus)

- Locally advanced vs metastatic

- PS 0/1 vs 2

2 x 2 design

Cunningham D, et al. N Engl J Med. 2008;358:36-46.

REAL-2: Schema

0

20

40

60

80

100

0 1 2 3Time since randomisation (years)

Pro

bab

ilit

y of

su

rviv

al (

%)

ECF EOF ECX EOX

Arm OS (m) 1-year survival

(95% CI)

P-value HR

(95% CI)

ECF

EOF

ECX

EOX

9.9

9.3

9.9

11.2

37.7 (31.8-43.6)

40.4 (34.2-46.5)

40.8 (34.7-46.9)

46.8 (40.4-52.9)

0.612

0.389

0.020

1

0.96 (0.79-1.15)

0.92 (0.76-1.11)

0.80 (0.66-0.97)

Cunningham D, et al. N Engl J Med. 2008;358:36-46.

EOX

ECF

REAL-2: Survival (ITT)

IntelliDose chemotherapy order entry (COE) platform:Trends in metastatic gastric cancer chemotherapy treatment* (2005-2016 )

Year of initiation of first-line therapy

N=4,333

Year of initiation of second-line therapy

N=1,822

2005-09 2010-12 2013-14 2015-16 2005-09 2010-12 2013-14 2015-16

N 1,073 1,357 948 883 N 465 604 424 329

FOLFOX (%) 12.0 21.2 35.1 41.0 FOLFOX (%) 13.3 13.1 17.2 16.4

ECF/EOX (%) 13.8 23.0 11.6 10.2 ECF/EOX (%) 11.2 7.9 5.4 3.0

DCF (%) 22.9 14.3 11.8 8.4 DCF (%) 15.7 9.3 7.3 2.1

CF (%) 12.6 10.8 7.9 7.2 CF (%) 4.3 4.6 3.3 3.3

TAX (%) 4.8 4.1 3.8 6.3 TAX (%) 11.8 11.4 21.0 22.8

C+Irinotecan (%) 9.0 2.8 1.1 1.5 FOLFIRI (%) 11.2 9.1 12.0 9.7

C+TAX (%) 9.8 12.2 15.6 14.6 C+TAX (%) 7.1 19.7 7.5 7.6

FU mono (%) 9.2 7.5 8.1 6.5 FU mono (%) 9.2 112.1 13.0 22.2

Other (%) 5.9 4.1 5.0 4.3 Other (%) 14.8 11.9 13.0 11.9

FOLFOX=fluoropyrimidine (FU) + oxaliplatin ; ECF/EOX=epirubicin + platinum + FU ; DCF=docetaxel (D) + cis/carboplatin (C) + FU ;

CF=C + FU; TAX=taxane; DF = D + FU* With or without biologic agents

Abrams T et al. GI Cancers Symposium 2018

HER2-positive

advanced GC

(n = 584)

5-FU or capecitabine

+ cisplatin

(n = 290)

R

aChosen at investigator’s discretion

GEJ, gastroesophageal junction

5-FU or capecitabinea

+ cisplatin

+ trastuzumab

(n = 294)⚫ Stratification factors

− Advanced vs metastatic

− GC vs GEJ

− Measurable vs non-measurable

− ECOG PS 0-1 vs 2

− Capecitabine vs 5-FU

Phase III, randomized, open-label, international, multicenter study

Bang, Y-J et al. Lancet 2010; 376:687

3807 patients screened1

810 HER2-positive (22.1%)

ToGA - Schema

(HER2 3+ or 2+/FISH+)

ToGA: Overall Survival

2.7 mo.

Is 2nd line therapy of benefit?

Metastatic Esophagogastric Cancer

R

A

N

D

O

M

I

Z

E

Docetaxel 75

mg/m2 q 3 weeks

Best supportive

care

168 patients :

Primary Endpoint:

Overall

Survival

Ford et al. Lancet Oncol. 2014 Jan;15(1):78-86.

Cougar-02: Randomized Trial of Docetaxel vs. BSC in

Relapsed Esophagogastric Adenocarcinoma

3.6 mo 5.2mo

HR: 0.67, 95% CI 0.49–0.92;

p=0.01

Ford et al. Lancet Oncol. 2014 Jan;15(1):78-86.

Cougar – 02: 2nd line Docetaxel vs. BSC: Overall Survival

Ramucirumab 8 mg/kg

q2wk

+

BSC (n = 238)

R

A

N

D

O

M

I

Z

E

Placebo q2wk

+

BSC (n = 117)

S

C

R

E

E

N

Treatment until disease progression

or intolerable

toxicity

Tumor assessment, survival, and safety follow-

up

N = 355

• Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial

• Gastric or GEJ adenocarcinoma

• Stratification factors: region, weight loss (≥10% vs.

Months

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 27 28

Overa

ll S

urv

ival

0.0

0.2

0.4

0.6

0.8

1.0

Ramucirumab

Placebo

Censored

Censored

Ram 238 154 92 49 17 7 3 0 0

Plcb 117 66 34 20 7 4 2 1 0

No. at Risk

HR (95% CI) = 0.776 (0.603, 0.998)

Log rank P-value (stratified) = 0.0473

Ramucirumab Placebo

Patients / Events 238 / 179 117 / 99

Median (mos) (95% CI) 5.2 (4.4, 5.7) 3.8 (2.8, 4.7)

6-month OS 42% 32%

12-month OS 18% 11%

REGARD: Overall Survival

Δ mOS = 1.4 months

Fuchs et al. Lancet. 2014 Jan 4;383(9911):31-9.

Treat until

disease

progression

or intolerable

toxicity

• Important inclusion criteria:- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma- Progression after 1st line platinum/fluoropyrimidine based chemotherapy

•Stratification factors:- Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)

Ramucirumab 8 mg/kg day 1&15

+ Paclitaxel 80 mg/m2 day 1,8 &15

of a 28-day cycle

N = 330

Placebo day 1&15

+ Paclitaxel 80 mg/m2 day 1,8 &15

N = 335

S

C

R

E

E

N

R

A

N

D

O

M

I

Z

E

Survival and

safety follow-

up

RAINBOW: Study Design

* GEJ= gastroesophageal junction; gastric and GEJ will be summarized under the term GC

1:1

Wilke et al. Lancet 2014; 15: 1224-35

RAINBOW: Overall Survival

RAM + PTX 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0

PBO + PTX 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0

No. at risk

Wilke et al. Lancet 2014; 15: 1224-35

HR (95% CI) = 0.807 (0.678, 0.962)

Stratified log rank p-value = 0.0169

RAM + PTX PBO + PTX

Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38)

6-month OS 72% 57%

12-month OS 40% 30%

Major Response Rate 28% 16%

Duration of Response 4.4mo 2.8mo

Δ mOS = 2.3 months

Censored

No benefit for angiogenesis inhibitors in frontline:

AVAGAST: Bevacizumab AVATAR: Bevacizumab

RAINFALL: Ramucirumab ZAMEGA: Ziv-Aflibercept

ONO-4538-12 (Attraction-2): Phase 3 Study of Nivolumabvs Placebo in Patients With Refractory GC

Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471.

Study Design and Endpoints

Key eligibility criteria:•Age ≥20 years•Unresectable advanced or recurrent GC or GJC•Histologically confirmed adenocarcinoma•Prior treatment with ≥2 regimens and refractory to/intolerant of standard therapy•ECOG PS of 0 or 1

Nivolumab3 mg/kg IV Q2W

R

2:1

• Stratification based on:– Country (Japan vs Korea vs Taiwan)– ECOG PS (0 vs 1)– Number of organs with metastases (

ONO-4538-12 (Attraction-2): Response & Survival

Kang YK et al. Lancet 2017 Dec 2;390(10111):2461-2471.

KEYNOTE-059: Phase 2 Study of Pembrolizumab for Advanced Gastric or GEJ Adenocarcinoma

Primary end point: ORR per RECIST v1.1 by central review

aThe first 40 patients enrolled regardless of PD-L1 expression. Enrollment after the first 40 patients will be determined based on the results of an interim analysis. b20 patients from Asian sites and 20 patients from non-Asian sites will be enrolled. Analysis cut-off date: Nov. 10, 2014.

Pembrolizumab 200 mg + Cisplatin + 5FU, all Q3W

Pembrolizumab200 mg Q3W

Pembrolizumab200 mg Q3W

COHORT 2

• PD-L1+ or PD-L1–

• No prior systemic therapy

N = 40b

COHORT 1

• PD-L1+ or PD-L1–

• ≥2 prior systemic treatments

N = 180a

COHORT 3

• PD-L1+ only• No prior systemic therapy

N = 50

Fuchs CS et al. JAMA Oncol 2018 [Epub ahead of print]

Cohort 1: Response by PD-L1 & MSI Expression

ResponseaPD-L1 Positive

(n = 148)

PD-L1 Negative

(n = 109)

% 95% CI % 95% CI

ORR (CR + PR) 15.5 10.1–22.4 6.4 2.6–12.8

CR 2.0 0.4–5.8 2.8 0.6–7.8

PR 13.5 8.5–20.1 3.7 1.0–9.1

DCRb 33.1 25.6–41.3 19.3 12.3–27.9

ResponseaMSI-High

(n = 7)

Not MSI-High

(n = 167)

% 95% CI % 95% CI

ORR (CR + PR) 57.1 18.4–90.1 9.0 5.1–14.4

CR 14.3 0.4–57.9 2.4 0.7–6.0

PR 42.9 9.9–81.6 6.6 3.3–11.5

DCRb 71.4 29.0–96.3 22.2 16.1–29.2Fuchs CS et al. JAMA Oncol 2018 [Epub ahead of print]

Cohort 1: Treatment Exposurea and Duration of Response

Median DoR

mos (95% CI)

All patients 8.4 (1.6+b to 17.3+)

PD-L1 positive 16.3 (1.6+ to 17.3+)

PD-L1 negative 6.9 (2.4 to 7.0+)

Con

firm

ed r

esp

on

der

s (n

= 3

0)

Time since first dose (months)

CR

PR

Progressive disease

Death

Ongoing pembrolizumab treatment

0 2 4 6 8 10 12 14 16 18 20 22 24

aPatients with measurable disease per RECIST v1.1 by central review at baseline who had ≥1 post-baseline assessment

were included (n = 30). Bar length indicates time to last imaging assessment. bNo progressive disease at last disease

assessment.

Data cutoff on January 16, 2017.Fuchs CS et al. JAMA Oncol 2018 [Epub ahead of print]

Conclusions from these Results

Metastatic Esophagogastric:

The most active single agents are the fluoropyrimidines, platinum

analogues, taxanes, and irinotecan.

1st Line: Fluoropyrimidine & platinum combos are standard.

Trastuzumab should be added for HER2/neu 3+ or FISH+ tumors.

Pts should receive at least 2-3 lines of therapy for their dz.

2nd Line: Paclitaxel + Ramucirumab is probably the best choice for

most patients. Checkpoint inhibitors should be given for MSI-H.

Checkpoint inhibitors should be offered to all PD-L1 positive pts.

References:

• Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003; 349 (23): 2241-52. PMID: 14657432

• Enzinger PC et al. CALGB 80403 (Alliance) /E1206: A Randomized Phase II Study of Three Chemotherapy Regimens Plus Cetuximab in Metastatic Esophageal and Gastroesophageal Junction Cancer. J Clin Oncol. 2016 Aug 10;34(23):2736-42. PMID: 27382098

• Van Hagen P et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. PMID: 22646630

• Bang YJ et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. The Lancet , Volume 376 , Issue 9742 , 687 – 697 PMID: 20728210

• Fuchs CS et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018 Mar 15. doi: 10.1001/jamaoncol.2018.0013. [Epub ahead of print] PMID: 29543932

PMID:

20728210
https://www.ncbi.nlm.nih.gov/pubmed/29543932

esophageal and gastric cancer...esophageal and gastric cancer peter c. enzinger, md director, center...

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