Supported)by)an)IndependentEducaonal)Grantfrom) · • Validated diet and lifestyle questionnaires prior to treatment • Multivariable analyses using Cox proportional hazards models

Supported by an Independent Educa1onal Grant from Supported by an Independent Educa1onal Grant from

MEETING SUMMARY A S C O G I , S A T U R D A Y J A N U A R Y 1 7 T H 2 0 1 5

B Y D R . G U I L L E M A R G I L E S , B A R C E L O N A , S P A I N

Cancers of the Lower GI Tract

R A I S E : A R A N D O M I Z E D , D O U B L E - B L I N D , M U L T I C E N T E R P H A S E I I I S T U D Y O F I R I N O T E C A N , F O L I N I C A C I D , A N D 5 -

F L U O R O U R A C I L ( F O L F I R I ) P L U S R A M U C I R U M A B O R P L A C E B O I N P A T I E N T S W I T H M E T A S T A T I C

C O L O R E C T A L C A R C I N O M A P R O G R E S S I O N D U R I N G F O R F O L L O W I N G F I R S T - L I N E

C O M B I N A T I O N T H E R A P Y W I T H B E V A C I Z U M A B , O X A L I P L A T I N , A N D A F L U O R O P Y R I M I D I N E

Josep Tabernero*, Allen Lee Cohn, Radka Obermannova, Gyorgy Bodoky, Rocio Garcia-Carbonero, Tudor-Eliade Ciuleanu, David C. Portnoy, Eric Van Cutsem, Axel Grothey, Jana Prausová,

Pilart Garcia-Alfonso, Kentaro Yamazaki, Philip R. Clingan, Vittorina Zagonel, Tae Won Kim, Lorrinda Simms, Shao-Chun

Chang, Federico Nasroulah, Takayuki Yoshino

*On behalf of the RAISE Investigators

RAISE: STUDY DESIGN

Sample size assumptions •  Hazard ratio of 0.8 •  Median overall survival of 10 months in the control arm vs 12.5

months with ramucirumab with a 2-sided a level of 0.05 •  Enrollment of 1050 patients with 756 events for 85% power •  Gatekeeping from OS to PFS to ORR

1:1 Progression during

or after bevacizumab, oxaliplatin, and a fluoropyrimidine

R A N D O M I Z E

Secondary endpoints: PFS, ORR, PRO, Safety, PI, IG

Stratification factors •  Geograpic regions •  KRAS mutation status •  Time to disease progression

after beginning first-line therapy

Treatment until disease progression

or unacceptable toxicity

Primary endpoint: Overall survival

Ramucirumab (8 mg/kg) and FOLFIRI* every 2 weeks per cycle

N=525

Placebo and FOLFIRI* every 2 weeks per cycle

N=525

RAISE: STUDY DESIGN

Time (months) 6 0 3 9 12 15 21 24 27 30

34 22 12 4 0 0 Ram + FOLFIRI 22 10 2 2 1 0 Placebo +

FOLFIRI

33

Patients at risk

Ramucirumab + FOLFIRI N=536

Placebo + FOLFIRI N=536

Median, months (95% CI)

13.3 (12.4, 14.5)

11.7 (10.8, 12.7)

HR (95% CI) 0.84 (0.73, 0.98) (stra1fied)

P-‐value (log-‐rank) 0.0219 (stra1fied)

42 39 36

53 44

78 66

114 108

195 166

269 228

345 329

421 400

497 486

536 536

18

CI, confidence interval; HR, hazard ratio; Ram, Ramucirumab.

0.5

0.4

0.2

0.1

0.0

0.3

0.6

0.7

0.8

0.9

1.0

Ove

rall

su

rviv

al

RAISE: PROGRESSION-FREE SURVIVAL

0.5

0.4

0.2

0.1

Time (months)

Pro

gre

ssio

n-f

ree

surv

ival

6

0.0

0 3 9 12 15 21 24 27 30

5 22 2 1 0 0 Ram + FOLFIRI 1 10 0 0 0 0 Placebo +

FOLFIRI

33

Patients at risk



Median, months (95% CI)

5.7 (5.5, 6.2)

4.5 (4.2, 5.4)

HR (95% CI) 0.79 (0.70, 0.90) (stra1fied)

P-‐value (log-‐rank) 0.0005 (stra1fied)

42 39 36

0.3

0.6

0.7

0.8

0.9

1.0

6 3

11 10

20 17

38 31

77 52

142 92

234 182

381 345

536 536

18

CI, confidence interval; HR, hazard ratio; Ram, Ramucirumab.

TREATMENT-EMERGENT ADVERSE EVENTS (ALL GRADES 20% OR HIGHER, OR GRADE 3-5 5% OR HIGHER IN EITHER TREATMENT ARM)

Any Grade Grade ≥3

Preferred Term





n % n % n % n % Any TEAE 522 98.7 519 98.3 418 79.0 329 62.3 Neutropenia 311 58.8 241 45.6 203 38.4 123 23.3 Fatigue 305 57.7 275 52.1 61 11.5 41 7.8 Diarrhea 316 59.7 271 51.3 57 10.8 51 9.7 Hypertension 136 25.7 45 8.5 57 10.8 15 2.8 Stomatitis 163 30.8 110 20.8 20 3.8 12 2.3 Abdominal pain 140 26.5 139 26.3 18 3.4 19 3.6 Thrombocytopenia 150 28.4 72 13.6 16 3.0 4 0.8 Vomiting 154 29.1 144 27.3 15 2.8 13 2.5 Nausea 262 49.5 271 51.3 13 2.5 14 2.7 Decreased appetite 198 37.4 144 27.3 13 2.5 10 1.9 Anemia 86 16.3 110 20.8 8 1.5 19 3.6 Constipation 151 28.5 120 22.7 5 0.9 8 1.5 Peripheral edema 108 20.4 48 9.1 1 0.2 0 Epistaxis 177 33.5 79 15.0 0 0 Alopecia 155 29.3 165 31.3 0 0

•  The febrile neutropenia rate (any grade) was 3.6% in ramucirumab patients and 2.7% in placebo patients

RAISE: ADVERSE EVENTS OF SPECIAL INTEREST

Any Grade Grade ≥3 Ramucirumab +

FOLFIRI N=529




n % n % n % n % Bleeding/hemorrhage event 232 43.9 120 22.7 13 2.5 9 1.7 Hypertension 138 26.1 45 8.5 59 11.2 15 2.8 Proteinuria 90 17.0 24 4.5 16 3.0 1 0.2 GI hemorrhage 65 12.3 36 6.8 10 1.9 6 1.1 Venous thromboembolic events

44 8.3 34 6.4 22 4.2 11 2.1

Infusion-related reaction 31 5.9 16 3.0 4 0.8 2 0.4 Renal failure 18 3.4 18 3.4 7 1.3 5 0.9 GI perforation 9 1.7 3 0.6 9 1.7 3 0.6 Arterial thromboembolic event 8 1.5 13 2.5 4 0.8 6 1.1 Pulmonary hemorrhage events 7 1.3 3 0.6 0 0 Healing complication 6 1.1 1 0.2 1 0.2 0 Congestive heart failure 4 0.8 3 0.6 4 0.8 3 0.6 Fistula 4 0.8 2 0.4 0 0 RPLS 1 0.2 1 0.2 0 0 Thrombotic microangiopathy 1 0.2 0 1 0.2 0 Hepatic hemorrhage event 0 1 0.2 0 1

GI, gastrointestinal; RPLS, reversible posterior leukoencephalopathy syndrome.

CONCLUSIONS

•  RAISE met its primary endpoint –  Demonstrated a statistically significant improvement

in overall survival for ramucirumab and FOLFIRI vs placebo and FOLFIRI

–  In second-line metastatic CRC patients who progressed after first-line treatment wit bevacizumab, oxaliplatin, and a fluoropyrimidine

•  Consistent survival benefits were observed across subgroups

•  Ramucirumab in combination with FOLFIRI was well tolerated in patients with mCRC. Overall, the adverse events were considered manageable

PREOPERATIVE HEPATIC AND REGIONAL ARTERIAL CHEMOTHERAPY (PHRAC)

REDUCES THE OCCURRENCE OF METACHRONOUS L IVER METASTASIS AFTER CURATIVE COLORECTAL CANCER RESECTION

A P R O S P E C T I V E , M U L T I - C E N T E R , R A N D O M I Z E D C O N T R O L L E D T R I A L

Jianmin Xu Zhongshan Hospital, Fudan University

Shanghai, China

PHRAC

FUDR 650 mg/m2, Oxaliplatin 75 mg/m2, MMC 8 mg/m2 Half in each artery

Right colon cancer

Brain tumor supplying artery chemotherapy

Common hepatic artery chemotherapy

HA

SMA

+

Presented By Jianmin Xu at 2015 Gastrointestinal Cancers Symposium

STUDY DESIGN


PHRAC 7d before primary surgery

(PHRAC arm)

Primary surgery

(Control arm)

CRC patients •  18–75 years old •  cTNM Stage II/III •  No distand

metastases •  No

contraindications to chemo

•  No previous cancer therapy

R

Primary surgery(PHRA

C arm)

Adjuvant therapy(Contr

ol arm)

Adjuvant therapy(PHRA

C arm)

OUTCOMES

Primary outcome •  DFS Secondary outcome •  Cumulative incidence of liver metastasis •  OS •  Safety


PRIMARY OUTCOME–DFS


1.0

Time (months)

Pro

bab

ilit

y o

f su

rviv

al

0.0

0 12 24

341 No. at risk

347

0.8

0.6

0.4

0.2

36 48 60

313 305

282 257

213 169

147 120

82 63

Events n/N (%)

3y-‐DFS 5y-‐DFS

PHRAC 78/341 (22.9%) 80% 75%

Control 120/347 (34.6%) 68% 61%

Hazard ra1o (95% CI)

0.60 (0.45-‐0.80) Log-‐rank p<0.001

PHRAC Control

ITT population 1.0

Time (months)

Pro

bab

ilit

y o

f su

rviv

al

0.0

0 12 24

313 No. at risk

314

0.8

0.6

0.4

0.2

36 48 60

297 292

266 245

202 161

140 117

78 62

Events n/N (%)

3y-‐DFS 5y-‐DFS

PHRAC 66/313 (21.1%) 82% 77%

Control 99/314 (31.5%) 72% 63%

Hazard ra1o (95% CI)

0.62 (0.45-‐0.84) Log-‐rank p<0.002

PHRAC Control

Eligible population

VITAMIN D STATUS AND SURVIVAL OF METASTATIC COLORECTAL CANCER PATIENTS:

RESULTS FROM CALGB/SWOG 80405 (ALL IANCE)

Kimmie Ng, Alan P. Venook, Kaori Sato, Bruce W. Hollis, Donna Niedzwiecki, Cynthia Ye, I-Wen Chang, Bert H. O’Neil,

Federico Innocenti, Heinz-Josef Lenz, Charles D. Blanke, Robert J. Mayer, Charles S. Fuchs, Jeffrey A. Meyerhardt

CALGB/SWOG 80405: FINAL DESIGN ORIGINAL

Presented By Kimmie Ng at 2015 Gastrointestinal Cancers Symposium

Chemo + Cetuximab

Chemo + Bevacizumab

Chemo + Bevacizumab and Cetuximab

FOLFIRI or

FOLFOX

MD choice

N = 1140 2334

Endpoint: Overall Survival

mCRC 1st-line

KP wildtype (con 13

Strata: •  FOLFOX/FOLFIRI •  Prior adjuvant

chemo •  Prior XRT

STATISTICAL METHODS

•  Pre-planned, prospective, observational cohort study

•  Primary endpoint: Overall survival –  Kaplan-Meier method –  Log rank test

•  Plasma 25(OH)D measured by radioimmunoassay prior to treatment

•  Validated diet and lifestyle questionnaires prior to treatment

•  Multivariable analyses using Cox proportional hazards models

•  All P values two-sided and considered significant at the 0.05 level


BASELINE CHARACTERISTICS

Median 25(OH)D = 17.2 ng/mL

Q1 (n=208)

Q2 (n=209)

Q3 (n=208)

Q4 (n=210)

Q5 (n=208)

P

Median 25(OH)D, ng/mL (range)

8.0 2.2-10.8)

13.6 (10.9-15.4)

17.2 (15.4-19.2)

21.4 (19.3-24.0)

27.5 (24.1-72.7) –

Median age, years 59 60 60 61 61 0.07

Male, % 48 64 58 64 55 0.004

Black, % 25 12 6 7 2 <0.0001

ECOG 0 / 1, % 49 / 50 64 / 36 58 / 42 63 / 37 70 / 30 0.002

RAS WT / mut /unknown, %

33 / 30 / 37

31 / 30 / 39

26 / 39 / 35

38 / 29 / 33

37 / 21 / 42 0.02


HIGHER VITAMIN D LEVELS ASSOCIATED WITH BETTER SURVIVAL

0.2

Time (years)

Ove

rall

su

rviv

al p

rob

abil

ity

0.0

0 1 2 15

No. at risk Quintiles 1 & 2 Quintiles 3 & 4

Quintile 5

0.6

0.8

1.0

417 418 208

4


QuinFle mOS (months) 95% CI

1 24.5 21.7-‐28.6

2 30.0 25.8-‐32.2

3 28.4 24.2-‐31.0

4 27.225.0-‐31.5 25.0-‐31.5

5 32.6 27.7-‐36.9

5 6 7

0.2

328 332 171

227 237 137

117 125 76

56 64 41

27 34 22

5 11 1

1 2 0

Log-rank P = 0.01

Documents

Supported)by)an)IndependentEducaonal)Grantfrom) · • Validated diet and lifestyle questionnaires prior to treatment • Multivariable analyses using Cox proportional hazards models