supported)by)an)independenteducaonal)grantfrom) · • validated diet and lifestyle questionnaires...
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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
Ramucirumab + FOLFIRI N=536
Placebo + FOLFIRI N=536
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
Ramucirumab + FOLFIRI N=529
Placebo + FOLFIRI N=528
Ramucirumab + FOLFIRI N=529
Placebo + FOLFIRI N=528
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
Placebo + FOLFIRI N=528
Ramucirumab + FOLFIRI N=529
Placebo + FOLFIRI N=528
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
Presented By Jianmin Xu at 2015 Gastrointestinal Cancers Symposium
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
Presented By Jianmin Xu at 2015 Gastrointestinal Cancers Symposium
PRIMARY OUTCOME–DFS
Presented By Jianmin Xu at 2015 Gastrointestinal Cancers Symposium
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
Presented By Kimmie Ng at 2015 Gastrointestinal Cancers Symposium
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
Presented By Kimmie Ng at 2015 Gastrointestinal Cancers Symposium
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
Presented By Kimmie Ng at 2015 Gastrointestinal Cancers Symposium
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