Challenging Cases in Cancer:Integration of Findings from ASCO 2007
Colorectal Cancer
Metastatic Colorectal CancerAxel Grothey, MD
Senior Associate Consultant Division of Medical Oncology
Mayo Clinic College of MedicineRochester, MN
Case 3: First-line Colorectal Cancer
• Patient was treated with adjuvant 5-FU/LV after R hemicolectomy for T3N1M0 stage III colon cancer
• Two years later he relapses with rising CEA and 2 lung metastases plus 3 liver metastases
• He is treated with modified FOLFOX6 plus bevacizumab for 12-cycles (six months) but develops grade 3 neuropathy
• CT scan shows all lesions more than 50% smaller
Case 3: First-line Colorectal Cancer
• Which treatment option would you recommend? Continue therapy (unchanged) Hold all treatment until tumor progression Stop oxaliplatin and continue therapy with 5-FU/LV and
bevacizumab Stop oxaliplatin and continue therapy with bevacizumab
alone Switch therapy to an irinotecan-based regimen
Case 3: First-line Colorectal Cancer
• Which treatment option would you recommend? Continue therapy (unchanged) Hold all treatment until tumor progression Stop oxaliplatin and continue therapy with 5-FU/LV and
bevacizumab Stop oxaliplatin and continue therapy with bevacizumab
alone Switch therapy to an irinotecan-based regimen
• Recommended approach – Stop oxaliplatin and continue therapy with 5-FU/LV and
bevacizumab
Pertinent Issues for Case 3
• Metachronous metastases after 2-years to lung and liver– Should always consider resectability even with extrahepatic
disease• In this case situation it was deemed unresectable
• Good response to chemotherapy with FOLFOX + BEV, but grade 3 neurotoxicity after 12-cycles
• Should patient have a “chemo-holiday”?
Definition of “Chemo-Holiday”
• Stop of:– All medical therapy (chemo/biologics), no “maintenance”
(OPTIMOX2)
– Certain components of medical therapy, continuation of “chemo-light” (+/- biologics) (OPTIMOX1, CONcePT)
– Conventional chemotherapeutics, continuation of biologics (DREAM)
Definition of “Chemo-Holiday”
• Stop can occur:– After pre-defined number of cycles
– When “best response” is achieved
– When long-lasting SD has been documented
– When toxicity threshold is reached
• Restart/re-intensify therapy:– After pre-defined interval (OPTIMOX1, CONcePT)
– When “relevant” tumor progression noted (OPTIMOX2)
N9741: FOLFOX4 - TTP and TTF
0
10
20
30
40
50
60
70
80
90
100
0 12 18 24
% E
vent
-fre
e
TTP TTF
6
Time (mos)
9.3 mos
5.8 mos
Green et al., GI ASCO 2005
63% of pts stoppedFOLFOX for otherreasons than PD
OPTIMOX Studies
OPTIMOX-1N = 620
FOLFOX4 until TF
FOLFOX7 FOLFOX7
sLV5-FU2
OPTIMOX-2N = 202
mFOLFOX7 mFOLFOX7
sLV5-FU2
mFOLFOX7 mFOLFOX7
CFI
Tournigand et al, JCO 2006
Maindrault-Goebel et al, ASCO 2007 Abstract #4013
Stop and Go Concept - OPTIMOX1
Tournigand et al., JCO 2006
6x FOLFOX7- 12x sLV5-FU2 - 6x FOLFOX7
FOLFOX4
620 pts
R
Cum. Oxali 780 1,560
(%) FOLFOX4 FOLFOX7
RR 58.5 58.3PFS 9.0 8.7DDC 9.0 10.6OS 19.3 21.2G3/4 NTox 17.9 13.3
Primary endpoint
OPTIMOX2 - 5-FU/LV Maintenance vs Chemo-Free Intervals
MaintenanceN = 99
CFIN = 103
P
Initial RR (%) 60 59
RR reintro. (%) 21 25
PFS (wks) 36 29 0.08
DDC (wks) 52 39 0.39
OS (mos) 26 19 0.0549
Maindrault-Goebel et al, ASCO 2007 Abstract #4013
0 10 20 30 40 50 60 70 80 90 100
0.0
0.2
0.4
0.6
0.8
1.0
36 weeks
29 weeks
Maintenance
CFI
P = 0.08
weeks
OPTIMOX2: Progression-free Survival
Maindrault-Goebel et al, ASCO 2007 Abstract #4013
0 10 20 30 40 50
0.0
0.2
0.4
0.6
0.8
1.0
26 months
19 months
Maintenance
CFI
P = 0.0549
months
Lesson from OPTIMOX2: Don’t stop treatment before progression!
OPTIMOX2: Overall Survival
Maindrault-Goebel et al, ASCO 2007 Abstract #4013
Take-home Messages OPTIMOX2
• A strategy with complete chemotherapy-free intervals (CFI) leads to inferior outcome compared to an induction-maintenance-reintroduction approach
• If PFS is the primary endpoint of your trial, do not stop treatment before progression (see NO16966)
• DDC is NOT an appropriate endpoint in CRC
In advanced CRC, the default treatment strategy should be “treatment to progression”
Recommendation for Case 3
• In palliative situation, goal of therapy is to extend duration and maintain the quality of life as long as possible
• Do not “waste” potentially active agents unnecessarily (no irinotecan here!)
• Maintenance therapy should be default position– Infusional 5-FU/LV + BEV or capecitabine + BEV should be
considered
– No role so far for BEV single agent as maintenance therapy
Case 4: First-line Colorectal Cancer
• 52-year-old healthy restaurant owner presents with increasing pain on bowel movement and complains of several weeks of diarrhea and weight loss of 10 pounds
– Finally cannot move bowels and begins to vomit
• CT scan shows 12 cm mass in the LLQ with multiple liver nodules and an elevated CEA level of 60 ng/mL
• GI evaluation with colonoscopy shows a nearly obstructing sigmoid mass – cannot pass scope – biopsy shows adenocarcinoma
Case 4: First-line Colorectal Cancer
• Undergoes sigmoid colon resection with primary anastomosis and a wedge biopsy of the left lobe of the liver
• Pathology reveals a mucinous adenocarcinoma of the sigmoid colon metastatic to lymph nodes and liver
• Now referred for consideration of chemotherapy
Case 4: First-line Colorectal Cancer
• Which chemotherapy would you recommend? 5-FU/LV or capecitabine FOLFOX CAPOX (XELOX) FOLFIRI IROX FOLFOXIRI
Case 4: First-line Colorectal Cancer
• Which targeted agent would you add? None Bevacizumab Cetuximab Panitumumab Bevacizumab + cetuximab Bevacizumab + panitumumab
Case 4: First-line Colorectal Cancer
• Which targeted agent would you add? None Bevacizumab Cetuximab Panitumumab Bevacizumab + cetuximab Bevacizumab + panitumumab
• Recommended approach– FOLFOX + bevacizumab or FOLFIRI + bevacizumab
Pertinent Issues for Case 4
• Palliative situation with unresectable, scattered liver metastases
• Symptomatic primary (obstruction) → resection of primary warranted
• What is optimal chemotherapy?
• And should a biologic be added upfront?
New Agents Have Significantly Improved Treatment and Patient Outcomes
RegimenFirst Line
Second Line
FDA-Approval Year
5-FU √ √ 1962
Irinotecan (monotherapy) √ 1996
IFL/irinotecan + infusional 5-FU/LV* √ 2000
Capecitabine (monotherapy) √ 2001
Oxaliplatin + infusional 5-FU/LV† √ √Second-line, 2002
First-line, 2004
Cetuximab (with or without irinotecan) √ 2004
Bevacizumab + IV 5-FU-based regimens‡ √ √First-line, 2004
Second-line 2006
Panitumumab (single agent) Salvage 2006
Modified from Venook A. Oncologist. 2005.
More regimens provide more options formultiple lines of therapy to extend survival
* FOLFIRI† FOLFOX‡ IFL, FOLFIRI, FOLFOX, and 5-FU/LV
NCCTG/Intergroup Trial N9741
IFL:Irinotecan +
5-FU/LV
IROX: Irinotecan + oxaliplatin
FOLFOX4: Oxaliplatin + 5-FU/LV
Goldberg et al., JCO 2004
795 patients
RANDOMIZATION
NCCTG/Intergroup Trial N9741Efficacy
Goldberg et al., JCO 2004
IFL FOLFOXP
P-value
OS 15.0 mo 19.5 mo 0.0001
TTP 6.9 mo 8.7 mo 0.0014
RR 31% 45% 0.002
Tournigand Trial (N = 220)
FOLFOXFOLFOX FOLFIRI FOLFIRI FOLFOXFOLFOX (1st line 2nd line) (1st line 2nd line)
N pts 111 69 109 81
RR 54% 4% 56%15%
Resection ofHepatic Metastases 21%21% 9%
PFS (mos) 8.1 2.5 8.5 4.2
Median OS (mos) 20.6 21.5 Tournigand et al., JCO 2004
2nd line:62%
2nd line:74%
Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5,768 Patients
Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5,768 Patients
OS (mos)=13.2 + (% 3 drugs x 0.1), R^2 = 0.85Grothey & Sargent, JCO 2005
0 10 20 30 40 50 60 70 80
Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV
LV5-FU2
FOLFOXIRI
CAIRO
22
21
20
19
18
17
16
15
14
13
12
Med
ian
OS
(m
o)
Patients with 3 drugs (%)
P =.0001
First-Line Therapy
Multivariate analysis:Effect on OS P
First-line doublet 0.69All 3 drugs 0.005
2007
Murine Ab“momab”
ChimericMouse-Human Ab
“ximab”
Humanized Ab“zumab”
Fc
Fab
Human Ab“mumab”
Biologic Agents in Colorectal Cancer Monoclonal Antibodies
(17-1A) Cetuximab Matuzumab Bevacizumab
PanitumumabEGFR
VEGF
Cetuximab as Salvage Therapy for CRC
*P <0.05
Saltz 2001 Saltz 2002 Cunningham 2003
Phase II Phase II Rand. Phase II
Cetux. + CPT Cetux. Cetux. + CPT Cetux.
N 121 57 218 111
RR (%) 22.5 11 23* 11
RR+SD (%) 46 35 56* 32
Med. TTP (mos) -- -- 4.1* 1.5
Med. OS (mos) -- > 4 8.6 6.9
CRYSTAL Study (First-line)
FOLFIRI + Cetuximab
FOLFIRI
EGFR-expressingmetastatic CRC PFS
Stratified by:• Regions• ECOG PS
• Primary Endpoint: PFS (independent review)
• Secondary Endpoints: RR, DCR, OS, Safety, QoL
• Sample Size: 1,217 patients randomized, ITT: 1,198 pts
N = 599
N = 599
Van Cutsem et al., ASCO 2007 Abstract #4000
R
Progression-free survival time (months)
PF
S e
stim
ate
1.0
0.8
0.9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 2 4 6 8 10 12 14 16 18 20
HR = 0.851; 95% CI = [0.726-0.998]
Stratified log-rank P-value = 0.0479
8.9 mo
8.0 mo
FOLFIRI, N = 599
Cetuximab + FOLFIRI, N = 599
1-year PFS rate23% vs 34%
Subjects at risk
FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1Cetuximab + FOLFIRI
599 499 392 298 196 103 58 29 12 5 1
CRYSTAL Trial: Primary Endpoint PFS ITT Population Independent Review
Van Cutsem et al., ASCO 2007 Abstract #4000
CRYSTAL Trial:Independent Assessment of Response
CRYSTAL Trial:Independent Assessment of Response
38.7
46.9
0
10
20
30
40
50
60
Response rate
Pe
rce
nta
ge
(%
)
FOLFIRI alone, N = 599Cetuximab + FOLFIRI, N = 599
P-value* = 0.0038
FOLFIRI
%
Cetuximab
+ FOLFIRI
%
CR
PR
SD
PD
0.3
38.4
46.7
9.0
0.5
46.4
37.4
8.8
ORR95%CI
38.7[34.8 - 42.8]
46.9[42.9 - 51.0]
DCR** 85.5 84.3
*Cochran-Mantel-Haenszel (CMH) test ** DCR: disease control rate Van Cutsem et al., ASCO 2007 Abstract #4000
CRYSTAL Trial:Subgroup Analysis of PFS Time by
On-study Skin Reactions: Cetuximab + FOLFIRI
Skin reaction grade 0 or 1, n=244
*There were no grade 4 skin reactions
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
Progression-free survival time (months)
1.00
0.75
0.50
0.25
0.00
PF
S e
stim
ate
Skin reaction grade 2, n=243
Skin reaction grade 3*, n=112
11.3 mo5.4 mo 9.4 mo
Van Cutsem et al., ASCO 2007 Abstract #4000
KRAS Mutation Status Predictive of Response to Cetuximab?
Lievre et al., Cancer Res 2006
• 30 patients with CRC on cetuximab
• PR: 11/30 patients (37%)• KRAS mutation in
• 0/11 responders• 13/19 non-responders
(68%)• P = 0.0003
• Increased EGFR gene copy number in 10%
• significantly associated with response (P = 0.04)
16.3 mo
6.9 mo
Agents Targeting the VEGF PathwayAgents Targeting the VEGF Pathway
VEGFR-2VEGFR-1P
PPPP
PPP
Endothelial cellSmall-molecule
VEGFR inhibitors (Vatalanib, sunitinib, sorafenib)
Anti-VEGFR antibodies(IMC-1121b)
Soluble VEGF
receptors(VEGF-TRAP)
VEGF
Anti-VEGF antibodies
(bevacizumab)
Phase III Trial of Bevacizumab in MCRC: Efficacy
IFL+ Placebo (N = 411)
IFL+ Bevacizumab(N = 402)
P-value
Median survival (mo) 15.6 20.3 0.00004
PFS (mo) 6.2 10.6 < 0.00001
ORR (%)
CR
PR
35
2.2
32.5
45
3.7
41.2
0.0036
Duration of resp. (mo) 7.1 10.4 0.0014
Hurwitz et al., N Engl J Med 2004
Phase III Trial of IFL ± Bevacizumab in mCRC: Survival
Phase III Trial of IFL ± Bevacizumab in mCRC: Survival
HR = 0.66, P = 0.00004
Median survival: 15.6 vs. 20.3 mo
Duration of survival (mo)
Pro
port
ion
su
rviv
ing
0.2
200 10 30 400
0.8
1.0
0.4
0.6
Treatment Group
IFL + placeboIFL + bevacizumab
Hurwitz et al., N Engl J Med 2004
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 5 10 15 20 25 30
BICC-CPeriod 2: Overall Survival
BICC-CPeriod 2: Overall Survival
Pro
port
ion
of P
atie
nts
Who
Sur
vive
d
Survival Time (months)
RegimenMedian OS (Months)
1 YearHR
(95% CI)P-value
FOLFIRI+ BEV Not Reached 87% -- --
mIFL + BEV 19.2 61% 2.3(1.3,4.1)
0.007
mIFL + bevacizumab
FOLFIRI + bevacizumab
Fuchs et al., ASCO GI 2007
BICC-C: SummaryPeriod 1, no BEV Period 2, + BEV
EfficacyFOLFIRIN = 144
mIFLN = 141
CapIriN = 145
FOLFIRIN = 57
mIFLN = 60
RR (%) 46.6 41.9 38 57.9 53.3
PFS (mo) 7.6 5.9 5.8 11.2 8.3
OS 23.1 17.6 18.9 NR 19.2
G 3/4 (%)
Diarrhea 14 19 48 11 12
Dehydr. 6 7 19 5 2
MI/stroke 0.7 4.4 0 1.8 0
60d mort. 3.4 5.1 3.5 1.8 6.8
NR = not reachedFuchs et al., ASCO GI 2007
XELOX + placebo N = 350
FOLFOX4 + placebo N = 351
XELOX + bevacizumab
N = 350
FOLFOX4 + bevacizumab
N = 350
XELOX N = 317
FOLFOX4 N = 317
Initial 2-arm open-label study (N = 634)
Protocol amended to 2x2 placebo-controled design after bevacizumab phase III data1 became available (N = 1401)
RecruitmentJune 2003 – May 2004
RecruitmentFeb 2004 – Feb 2005
XELOX vs FOLFOX ± Bevacizumab Roche NO16966 Study Design
1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646) Cassidy et al., ESMO 2006
0 5 10 15 20 25 30Months
PF
S e
stim
ate
PFS XELOX Non-inferiority: Primary Objective Met Based on ITT
HR = 1.04 [97.5% CI 0.93-1.16]
1.0
0.8
0.6
0.4
0.2
0
8.58.0
Upper limit ≤ 1.23 (non-inferiority margin)
FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab N = 1017; 826 events
XELOX/XELOX+placebo/XELOX+bevacizumab N = 1017; 813 eventsCassidy et al., ESMO 2006
PFS Chemotherapy + Bevacizumab Superiority: Primary Objective Met
PFS Chemotherapy + Bevacizumab Superiority: Primary Objective Met
0 5 10 15 20 25
Months
PF
S e
stim
ate
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)P = 0.0023
9.48.0
1.0
0.8
0.6
0.4
0.2
0
FOLFOX+placebo/XELOX+placebo N = 701; 547 events
FOLFOX+bevacizumab/XELOX+bevacizumab N = 699; 513 eventsCassidy et al., ESMO 2006
XELOX subgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT)
P = 0.0026
9.37.4
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25
Months
PF
S e
stim
ate
XELOX+placebo N = 350; 270 events XELOX+bevacizumab N = 350; 258 events
FOLFOX subgroupHR = 0.89 [97.5% CI 0.73–1.08] (ITT)
P = 0.1871
9.48.6
FOLFOX+placebo N = 351; 277 events FOLFOX+bevacizumab N = 349; 255 events
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25
Months
PFS Chemotherapy + Bevacizumab Superiority: XELOX and FOLFOX Subgroups
PFS Chemotherapy + Bevacizumab Superiority: XELOX and FOLFOX Subgroups
Cassidy et al., ESMO 2006
NO16966 Response Rate
Saltz et al., ASCO GI 2007
Chemo + Chemo placebo + Bev
FOLFOX+ FOLFOX
placebo + Bev
XELOX+ XELOX
placebo + Bev
Investigator
report
49% 47% 50% 47% 48% 46%
P = 0.90 P = 0.88 P = 0.91
IRC data38% 38% 36% 38% 39% 37%
P = 0.99 P = 0.49 P = 0.48
Why Did BEV Not Increase PFS When Added to FOLFOX in NO16966?
• No synergistic/additive effect with FOLFOX?– No, see E3200 (second-line)
• Ceiling effect of first-line chemotherapy?– Perhaps…
• Failure to OPTIMOXize?– Very likely!
NO16966 Study Drug Exposure – Median Months of Treatment
FOLFOX+Placebo
(N = 336)
FOLFOX+Bev
(N = 341)
XELOX+Placebo
(N = 339)
XELOX+Bev
(N = 353)
Oxaliplatin 6.0 6.0 5.5 5.8
Fluoropyrimidine 6.3 6.7 5.6 6.3
Placebo or Bev 6.3 6.0 5.5 6.0
* Per protocol, patients discontinuing oxaliplatin could continue with a fluoropyrimidine + placebo or bevacizumab. Patients could also remain on a fluoropyrimidine alone or placebo or bevacizumab alone but not oxaliplatin alone
Saltz et al., ASCO GI 2007
NO16966 PFS Subgroup Analyses:On-treatment Population
Saltz et al., ASCO GI 2007
HR = 0.61 [97.5% CI 0.48–0.78]P ≤ .0001
HR = 0.65 [97.5% CI 0.50–0.84]P = .0002
XELOX + placeboFOLFOX4 +
placeboXELOX + Bev
FOLFOX4 + Bev
VS. VS.
XELOX Group FOLFOX Group
Su
rviv
al
1.0
0.8
0.6
0.4
0.2
00 100 200 300 400 500
Study day
1.0
0.8
0.6
0.4
0.2
00 100 200 300 400 500
Su
rviv
al
Study day
10.6 m8.4 m9.5 m7.0 m
Rationale for Combining EGFR- and Angiogenesis- Inhibitors
EGFR Inhibitors• Tumor cell growth • Synthesis of angiogenic
proteins
• Response of endothelial cells to angiogenic proteins
Tumor
Angiogenesis Inhibitors
Angiogenic proteinsbFGFVEGFTGF-
Endothelial cells
Herbst et al., J Clin Oncol. 2005;23:2544.
- - -
Targets
BOND-2 Trial - Efficacy (Historic Comparison with BOND-1)
BOND-1 BOND-2 BOND-1 BOND-2
Cetux.Cetux.+
BEVCetux.+
CPTCetux.+ CPT
+BEV
N pts 111 40 218 41
Previous Oxaliplatin (%) 64 90 62 85
RR (%) 11 20 23 37
TTP (mos) 1.5 5.6 4.1 7.9
Med. OS (mos) 6.9 10.2 8.6 18.0
Saltz et al., ASCO 2005; Lenz et al., ASCO GI 2007
PACCE Study SchemaPACCE: Panitumumab Advanced Colorectal Cancer Evaluation
Randomized, Open-Label, Controlled Phase 3b Trial
Stratification Factors: ECOG score, prior adjuvant Tx, disease site,Ox doses/Iri regimen, number of metastatic organs
Tumor assessments: Q12w until disease progression or intolerability
Panitumumab 6 mg/kg Q2W
Ox-CTBevacizumab
Ox-based CT(e.g., FOLFOX)
N = 800Inv choice
Iri-based CT(e.g., FOLFIRI)
N = 200Inv choice
Ox-CTBevacizumab
Panitumumab 6 mg/kg Q2W
Iri-CTBevacizumab
Iri-CTBevacizumab
RANDOMIZE
1:1
1:1
SCREENING
Hecht et al., World GI Barcelona 2007
Objective Response Rate By Cohort(Central Review)
pmab+ bev/Ox-CT(N = 407)
%
bev/Ox-CT(N = 405)
%
pmab+ bev/Iri-CT(N = 68)
%
bev/Iri-CT(N = 67)
%
Best ORR 39 41 38 31
Complete response 0 <1 0 0
Partial response 39 40 38 31
Stable disease 31 33 26 37
Progressive disease 6 4 9 4
Not done/Unevaluable* 24 22 26 27
ITT set*Included missing and unreadable scans
Oxaliplatin Irinotecan
Hecht et al., World GI Barcelona 2007
Months
413 267 92 21 3
410 298 96 21 1
0 5 10 15 20
Pmab+bev/Ox-CT N
bev/Ox-CT N
Patients at risk:
Limited Update of PFS – Ox-CT Cohort(Central Review, Apr 2007 Data Cutoff)
# PFS events (%)
Median (95%CI), mos
206 (50) 9.0 (8.5-10.4)
172 (42) 10.5 (9.7-11.6)Pmab+bev/Ox-CT
Bev/Ox-CT
HR= 1.29 (95% CI: 1.05-1.58)
Pro
po
rtio
n P
rog
ress
ion
-Fre
e 100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
ITT set Hecht et al., World GI Barcelona 2007
73 10 076 6 0
407 318 194405 333 184
Months
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 4 8 12 16 20
Pmab+bev/Ox-CTbev/Ox-CT
Pts at risk:
413 342 224 85 9 0410 357 234 96 6 0
Pmab+bev/Ox-CTbev/Ox-CT
Months
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 5 10 15 20 25Pts at risk:
Unplanned Interim OS (Ox-CT Cohort)
# OS events (%)
Median(95%CI), mos
127 (31) 18.6 (16.4- 20.6)
95 (23) NE
Pro
po
rtio
n A
liv
e
HR= 1.44 (95% CI: 1.10-1.88)
*Interpretation of statistical significance is limited by the lack of a prespecified significance boundary
Pmab+bev/Ox-CT
Bev/Ox-CT
HR= 1.56 (95% CI: 1.11-2.17)
Oct 2006 Data Cutoff* Apr 2007 Data Cutoff # OS events
(%)Median (95%CI),
mos
83 (20) 18.4 (13.8-NE)
58 (14) NE
Pro
po
rtio
n A
liv
e
Pmab+bev/Ox-CT
Bev/Ox-CT
NE = not estimatable; ITT set
Hecht et al., World GI Barcelona 2007
PACCE: Grade 3/4 AEs of Interest(Ox-CT Cohort)
Pmab+bev/Ox-CT
(N = 401), %
bev/Ox-CT(N = 392), %
Gr 3 Gr 4 Gr 3 Gr 4
Skin toxicity 33 <1 1 0
Diarrhea 21 2 12 1
Dehydration 14 2 4 1
Hypokalemia 8 2 3 1
Hypomagnesemia 3 1 0 0
Neutropenia 12 10 17 7
Neuropathy 9 <1 10 <1
Nausea 10 0 4 <1
Infectionsa 16 2 7 2
Deep venous thrombosis 6 0 7 0
Pulmonary embolismb 0 6 0 4
MedDRA v9.0 preferred terms; Graded per NCI CTCAE v3.0aGrade 5 infections occurred in 2 (1%) pmab + bev/Ox-CT pts and 3 (1%) bev/Ox-CT ptsbGrade 5 pulmonary embolism occurred in 2 (1%) pmab + bev/Ox-CT pts Hecht et al., World GI Barcelona 2007
CALGB/SWOG Intergroup Trial 80405CALGB/SWOG Intergroup Trial 80405
Bevacizumab
Cetuximab
Bevacizumab +Cetuximab
FOLFOXor FOLFIRI
“Dealer’s Choice”
R
N = 2,289 Primary endpoint: OSHR 1.25 (22 vs 27.5 months)
http://www.cancer.gov protocol ID CALGB-80405
Case 5: Previously Treated Colorectal Cancer
• Patient has metastatic colorectal cancer
• Has been treated with FOLFOX and bevacizumab for 4 months but now CEA is rising and CT scan shows new and increasing liver lesions
Pertinent Issues for Case 5
• Palliative situation with unresectable metastases
• Relatively short initial therapy with FOLFOX + BEV, tumor shows PD after 4 months
• Irinotecan-based regimen appropriate
• FOLFIRI or irinotecan-mono?
• Should a biologic be added right away or sequentially?
• If yes, which one?– Cetuximab (or panitumumab)?
– Bevacizumab?
Case 5: Previously Treated Colorectal Cancer
• Which treatment option would you recommend? Irinotecan (or FOLFIRI) until progression followed by
irinotecan and cetuximab FOLFIRI or irinotecan + bevacizimab FOLFIRI or irinotecan + cetuximab FOLFIRI or irinotecan + bevacizumab and cetuximab
Case 5: Previously Treated Colorectal Cancer
• Which treatment option would you recommend? Irinotecan (or FOLFIRI) until progression followed by
irinotecan and cetuximab FOLFIRI or irinotecan + bevacizimab FOLFIRI or irinotecan + cetuximab FOLFIRI or irinotecan + bevacizumab and cetuximab
• Recommended approach – FOLFIRI or irinotecan + cetuximab
NCIC CTG CO.17: Cetuximab vs. BSCProgression-free Survival
CETUXIMAB + BSCCETUXIMAB + BSCCENSOREDCENSORED
BSCBSCCENSOREDCENSORED
Pro
port
ion
Pro
gres
sion
-fre
eP
ropo
rtio
n P
rogr
essi
on-f
ree
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
MONTHSMONTHS
00 33 66 99 1212 1515
HR 0.68 (95% CI =0.57 – 0.80)
Stratified log rank P < 0.0001
Study armStudy arm Med PFS Med PFS (months)(months) 95% CI95% CI
Cetuximab + BSCCetuximab + BSC 1.91.9 1.8 – 2.11.8 – 2.1
BSC aloneBSC alone 1.81.8 1.8 – 1.91.8 – 1.9
Jonker et al., AACR 2007
CETUXIMAB + BSCCENSORED
BSCCENSORED
SUBJECTS AT RISK
CET+BSC 287 217 136 78 37 14 4 0 0 0
BSC 285 197 85 44 26 12 8 2 1 0
Pro
port
ion
Aliv
eP
ropo
rtio
n A
live
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MONTHS
0 3 6 9 12 15 18 21 24 27
NCIC CTG CO.17: Overall Survival
HR 0.77 (95% CI =0.64 – 0.92)
Stratified log rank P = 0.0046
Study armStudy arm MS MS (months)(months) 95% CI95% CI
Cetuximab + BSCCetuximab + BSC 6.16.1 5.4 – 6.75.4 – 6.7
BSC aloneBSC alone 4.64.6 4.2 – 4.94.2 – 4.9
Jonker et al., AACR 2007
Eve
nt-f
ree
Pro
babi
lity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Weeks from Randomization
0 8 16 24 32 40 48 56
Hazard ratio = 0.54 (95% CI: 0.44, 0.66)
Stratified log-rank testP < .000000001
Only a Subgroup of Patients Benefit From EGFR Targeted Therapy
Panitumumab vs. BSC: PFS
Panitumumab
BSC
Van Cutsem et al., JCO 2007
No diff. in OS (75% cross-over!)
EPIC Study (Second-line)
Irinotecan + Cetuximab
Irinotecan
Failure of Oxaliplatin-Based
TherapySurvival
Stratified by:Stratified by:• Study site Study site • ECOG PS (0 - 1, 2)ECOG PS (0 - 1, 2)
• Primary Endpoint: SurvivalPrimary Endpoint: Survival
• Secondary Endpoints: PFS, RR, DCR, Safety, QoLSecondary Endpoints: PFS, RR, DCR, Safety, QoL
• Sample Size: 1,298 patients in 221 centersSample Size: 1,298 patients in 221 centers
N = 648 N = 648
N = 650 N = 650
Sobrero et al., AACR 2007
R
EPIC Results
IrinotecanIrinotecan/ Cetuximab
P-value
RR (%) 4.2 16.4 < 0.0001
PFS (mos) 2.6 4 < 0.0001
OS (mos) 10 10.7 0.71
OS (mos) w/o post-study cetux.
6.2 10.2Exploratory
analysis!
50% cross-over to cetuximab!
Sobrero et al., AACR 2007
If We Cannot Increase First-line PFS, Why Does OS Increase?
10 months 17 months
1st PFS
OS 27 Months
• More effective use of all active agents?• Continuum of care…
• Use of EGFR-mAbs?
• Use of bevacizumab beyond PD?
Post-1st PD Survival
BBP(N = 642)
No BBP(N = 531)
No Post-PD Treatment(N = 253)
Evaluablepatients
(N = 1953)
1st Progression(N = 1445)
BRiTE:Total N = 1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo
Physician decision: no randomization
BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP)
Grothey et al., ASCO 2007 Abstract #4036
BRiTE: Patient Outcome Based on Treatment Post 1st PD
BBP(N = 642)
No BBP(N = 531)
No Post-PD Treatment(N = 253)
# of deaths (%)168
(66%)306
(58%)260
(41%)
Median OS (mo) 12.6 19.9 31.8
1-yr OS rate (%) 52.5 77.3 87.7
OS after 1st PD (mo) 3.6 9.5 19.2
Grothey et al., ASCO 2007 Abstract #4036
Limitations of the Analysis
• Patients were not randomized
• Actual administration dates for BV and CT not collected; missing BV and CT stop dates
• Potential bias that patients who survived longer had a greater potential to be treated with BBP
• Possibility of unmeasured factors that may have biased these results
Grothey et al., ASCO 2007 Abstract #4036
SWOG/NCCTG/NCIC Second-line Trial: S0600/iBET (Intergroup BEV Continuation Trial)
(FOLF)IRI/CETUX
mCRC pretreated with FOLFOX + BEV or CAPOX + BEV orOPTIMOX + BEV
(FOLF)IRI/CETUX+ BEV 10 mg/kg
N = 1,260
Primary endpoint: OS (HR 1.30; 12 15.6 mos)
PIs: Phil Gold, Axel Grothey
(FOLF)IRI/CETUX+ BEV 5 mg/kg
Open since June 15
Treatm
ent Continuum
Patient Potentially Curable?
Induction Ctx (3-4 mos)e.g. FOLF?? + BEV/CETUX
Surgery with curative intent
“Adjuvant” Ctx
yes
Yes
yes
Re-evaluation of resectability
Observation
RR
Induction Ctx (3-4 mos)e.g. FOLF?? + BEV
Maintenance
Re-Induction Ctx
“All 5-drugs”
No
Evaluation oftumor biology
CFI ??
Time, QOL
Curative A
pproach
Conclusion
• Optimize treatment strategies, mainly in the palliative setting with the idea that we should keep patients on some sort of maintenance therapy
• Refined approaches in the adjuvant setting confirming the survival benefit at six years for a stage III patient with FOLFOX
• Proof of efficacy of a perioperative chemotherapy approach in resectable stage IV disease
Future Direction
• mTOR inhibitors
• Biomarker driven trials
• KRAS
• Tailored treatment approaches