Integrating Sirtex in the Clinical Management of Metastatic

SIRFLOX Results Have Changed my Treatment Algorithm
Marwan Fakih, MD
Professor, Medical Oncology
Section Head, Gastrointestinal Oncology
Department of Medical Oncology, City of Hope
Marwan Fakih, M.D.
• Speakers Bureau: Sirtex
• Consultant/Advisory Board: Sirtex/Amgen
Previously Reported Clinical Trials of
Radioembolization in 1st Line MCRC
Study
Experiment Contro
RR
al arml Arm
Y90 C
Y90
Gray et al.
(phase III)
FUDR HAI +
SIR-Spheres
n = 36
van Hazel
et al.
5-FU/LV +
SIR-Spheres
n = 11
Sharma el
al
(phase I)
FOLFOX +
SIR-Spheres
n = 20
FUDR
HAI
n = 34
none
90%
TTP
TTLP
OS
Y90
C
Y90
C
Y90
C
Y90
C
NR
NR
NR
NR
15.9
m
9.7
m
1y = 72%
2y = 39%
3y = 17%
1y =
68%
2y =
29%
3y = 6%
0%
100
%
60
%
18.6
m
3.6
m
NR
NR
29.4 m
12.8 m
NA
100
%
NA
9.3
m
NA
12.3
m
NA
NR
NA
44% 18%
5-FU/LV 73%
n = 10
DCR
RR = response rate; DCR = disease control rate; TTP = time to progression; TTLP = time to liver failure; OS = overall survival; HAI = Hepatic arterial infusion; NR =
not reported; y = year; NA = not applicable
OS Across SIR-Spheres Studies vs. BSC
14
Randomized
Prospective Single Arm
Retrospective
Randomized- BSC Arm
12
10
Median OS Increase with Therapy:
TAS-102 = 7 weeks
Regorafenib = 6 weeks
8
6
4
2
0
Hendliz (44) Cosimelli (50) Sidensticher
(58)
SIR-Spheres
Kennedy
(177/238)
Bester (224) BSC (Correct)
NCI-C017
BSC
Recourse
Pre-SIRFLOX Use of SIR-Spheres
Metastatic Colorectal
Cancer
RAS-WT
(40-45% of Patients)
3 Effective Lines of
Treatment
RAS-MT
(50% of patients)
2 Effective Lines of
Treatment
BRAF-MT
(5-10% of patients)
Poor Prognosis
2 Lines of Treatment
Consider SIR-Spheres® prior to TAS-102 or Regorafenib
SIRFLOX Changes the
Treatment Algorithm
SIRFLOX Study Design
Prospective open-label RCT
Primary endpoint: Progression-Free Survival
Eligible patients
• Non-resectable
liver-only or liverdominant mCRC
• No prior chemo for
advanced disease
• WHO performance
status 0–1
ANZ:
EME:
US:
Stratified by
• Presence of extrahepatic metastases
• Degree of liver
involvement
• Intended use of
bevacizumab
• Institution
n = 263 enrolled
mFOLFOX6 (+ bevacizumab)
(1)
Randomized
1:1
n = 530
280 (53%)
191 (36%)
59 (11%)
n = 267 enrolled
mFOLFOX6 (+ bevacizumab)
(1)
SIRT
1. Bevacizumab allowed at investigator’s
discretion, per institutional practice
ANZ: Australia, New Zealand; AP: Asia Pacific; EME: Europe & Middle East; US: United States
Gibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.
118-EUA-0615
Progression-Free Survival at Any Site
Proportion Not Progressing
1.00
FOLFOX (+ bev)
FOLFOX (+ bev) + SIRT
0.75
n
263
267
Events Median
225
10.2 months
217
10.7 months
HR: 0.93 (95% CI: 0.77–1.12), p=0.43
0.50
0.25
0.00
0
12
24
36
48
60
5
5
2
2
Time from Randomization (months)
Number at risk
FOLFOX
FOLFOX + SIRT
263
267
96
106
29
33
9
11
Gibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.
118-EUA-0615
Progression-Free Survival in the Liver
Probability of Hepatic Progression
0.7
0.6
Liver RR 78.7 vs. 68.8%
0.5
n
263
267
Median
12.6 months
20.5 months
0.4
FOLFOX (+ bev)
FOLFOX (+ bev) + SIRT
0.3
HR: 0.69 (95% CI: 0.55–0.90), p=0.002
0.2
7.9 month improvement in median PFS in the liver
0.1
31% reduction in risk of disease progression in the liver
0.0
0
12
24
36
48
60
5
5
2
2
Time from Randomization (months)
Number at risk
FOLFOX
FOLFOX + SIRT
263
267
96
106
29
33
9
11
Gibbs P et al. Presented at 2015 ASCO Annual Meeting; J Clin Oncol 2015; 33 (Suppl): Abs 3502.
118-EUA-0615
SIR-Spheres delays liver progression, allowing for the delayed
extrahepatic disease progression
Why Are These Results Meaningful?
First Line Integration of Modalities that Improve
Liver Disease Control Can Improve OS
Liver Control Improves OS- Despite Increase in
Extrahepatic Disease Progression: CALGB 9481
Mayo Clinic FU/LV
Metastatic CRC to
Liver
HAI (FUDR)
FU/LV
THF
9.8 m
7.3 m
TEHF
7.7 m
14.8 m
OS
24.4 m
20 m
(67 pts)
HAI FUDR
(68 pts)
Time to Liver progression
Median: 9.8 vs. 7.3 m
THF = time to hepatic failure; TEHF: time to extra-hepatic failure
Overall survival
Median: 24.4 vs. 20 m
Kemeny N. et al. J Clin Oncol 2006: 1395
Liver Control Improves OS- Updated Analysis of
the CLOCC Trial
RFA + FOLFOX +/- Bev
Unresectable Liver MCRC
< 10 lesions, max 4 cm
N =119
FOLFOX +/- Bev
Reurs T, ASCO 2015
Could SIR-Spheres be more effective in the 1st line?
Improvement in Liver PFS across 1st and Refractory Lines of Treatment
First Line (SIRFLOX)
7.9
Refractory (Heindlez)
3.4
0
1
2
3
Refractory (Heindlez)
4
5
First Line (SIRFLOX)
6
7
8
9
Delaying SIR-Spheres to later line of RX may result in a loss of
treatment opportunity: Patient Attrition is a Fact!
Author/ Study
Control Arm
Experimental Arm(s)
Post Progression
Treatment
Saltz, 2000
Study 0038
Bolus 5-FU/LV
IFL (bolus 5-FU/LV + irinotecan)
Single agent irinotecan
52% to 79%
Douillard, 2000
Study V303
Infusional 5-FU either
biweekly (de Gramont)
or weekly (AIO)
Weekly irinotecan + AIO 5-FU/LV or
Biweekly irinotecan + de Gramont
(FOLFIRI)
39.4% to 58.3%
de Gramont, 2000
de Gramont infusional
5-FU/LV (LV5FU2)
LV5FU2 + oxaliplatin (FOLFOX4
regimen)
58.1% to 60.5%
Goldberg, 2004
N9741 Study
Tournigand, 2004
A GERCOR study
IFL
FOLFOX4
IROX (irinotecan + oxaliplatin)
FOLFIRI followed by FOLFOX6
FOLFOX6 followed by FOLFIRI
67% to 75%
N/A
62% to 74%
Fuchs, 2007
BICC-C Study
mIFL (modified IFL, Days
1 & 8, every 21 days)
FOLFIRI
CapeIri (capecitabine + irinotecan)
75% to 77%
Cassidy, 2008
NO16966 Study
N/A
FOLFOX4
XELOX (capecitabine + oxaliplatin)
51% to 53%
Falcone, 2007
A GONO Study
FOLFIRI
FOFOXIRI
73% to 76%
SIRT in Liver-Predominant Colorectal Cancer
Refractory
Disease
Patient in
need of
protracted
chemotherapy
break
Y90
SIRT
Chemotherapy
Intolerant
Nonpotentially
resectable
diseaseacross lines