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Personalized Therapy in Colorectal Cancers
J. Randolph Hecht, MD
Professor of Clinical Medicine
Director, UCLA GI Oncology Program
David Geffen School of Medicine at UCLA
Biomarker
• NIH Definition: a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.
• Predictive: (Ex: HER-2, BRAF, cytogentic abnormalities)
• Prognostic: (Ex: HER-2, KRAS)
Evaluating Predictive Biomarkers: Trial Design
Patient Population R
Biomarkerpositive
Biomarkernegative
Receive treatment
Do not receive treatment
Receive treatment
Do not receive treatment
Biology of Colorectal Cancers
• Subgroup Analysis– Breast cancer does it, is it time for CRC?
• CIN vs MSI vs CIMP+– CIN: Majority of tumors MSS, APC mutation– MSI: Abnormal DNA mismatch repair
• ~15%• Most Sporadic (BRAF mut); others HNPCC
• Molecular Subgroup Analysis
Survival Rates of by Stage of Adenocarcinoma of the Colon
Edge SB, et al. AJCC cancer staging manual. 2010. Data from the SEER 1973-2005 Public Use File diagnosed in years 1998-2000.
Su
rviv
al R
ate
0
20
0
40
60
80
100
1 2 3 4 5
30
50
70
90
10
100100100100100100100100
IIIAIIBIICIIIAIIIBIIIC
IV
91.489.985.466.098.383.471.939.9
87.083.477.852.588.070.850.319.7
82.677.869.145.383.659.339.011.3
78.272.062.941.579.151.732.97.6
74.066.558.637.373.146.328.05.7
Yrs From Diagnosis
Other Putative Biomarkers:
• Molecular pathology• CTCs• Molecular abnormalities
– Mutations– microRNAs
• Gene expression profiles
Where Would Biomarkers Be Most Useful?
• Adjuvant– Treat those who would benefit– Don’t treat those that won’t
• Metastatic Disease– We have multiple agents. How can we
choose for safety and efficacy?
Stage II Colon Cancer
• Which stage II colon cancer patients should be treated with adjuvant chemotherapy?– 75% to 80% cured with surgery alone– Benefit of chemotherapy is small and no
consensus on whom to treat or on how to identify whom to treat
• Decision to give chemotherapy based on– Clinical/pathologic markers of risk– Molecular biomarkers – Not informative for majority of patients
1.0
0.8
0.6
0.4
0.2
0
Stage II Stage III
Follow-up (Yrs)
Surgery alone: 66.8%
Surgery + FU-based chemotherapy: 72.2%
Surgery alone: 42.7%
Surgery + FU-based chemotherapy: 53.0%
0 1 2 3 4 5 6 7 8
1.0
0.8
0.6
0.4
0.2
0
Sargent D, et al. J Clin Oncol. 2009;27:872-877.
∆ = 5.4%P = .026
0 1 2 3 4 5 6 7 8
∆ = 10.3%P < .0001
Adjuvant Therapy Increases OS:ACCENT Database of 20,898 Patients
Pro
bab
ilit
y o
f S
urv
ival
Pro
bab
ilit
y o
f S
urv
ival
Determining Who Benefits From Adjuvant Therapy in CRC
• Risk assessment in stage II (III) CRC: prognostic factor(s) of recurrence of disease and predictive factor(s) to the treatment.– High-risk prognostic factors[1]
• Stage II: T4, tumor perforation, bowel obstruction, poorly differentiated tumor, venous invasion, or < 10 examined nodes
• Stage III: age, lymph node involvement, T stage, tumor obstruction, differentiation
– Defective mismatch repair and microsatellite instability[2-5]
1. André T, et al. J Clin Oncol. 2009;27:3109-3116. 2. Hutchins G, et al. J Clin Oncol. 2011;29:1261-1270. 3. Sargent DJ, et al. J Clin Oncol. 2010;28:3219-3226. 4. Sinicrope FA, et al. J Natl Cancer Inst. 2011;103:863-875. 5. Ribic CM, et al. N Engl J Med. 2003;349:247-257.
MOSAIC: Exploratory Analysis of DFS and OS in “High-Risk” Stage II CRC
André T, et al. J Clin Oncol. 2009;27:3109-3116.
0.4 0.6 0.8 1.0 1.2 1.4 1.6
Stage II
High-risk stage II
Stage III
Stage II
High-risk stage II
Stage III
OS at 6 Yrs
DFS at 5 Yrs
HR
Favors FOLFOX4 Favors LV5FU2
MMR-D (MSI) Is a Favorable Prognostic Marker in Stage II (and III) Colon Cancer
Study StageTreatment
EndpointMMR-D vs MMR-P
HR (95% CI; P Value)
Ribic et al[1] II/IIISurgery alone OS 0.31 (0.14-0.72; .004)
Roth et al(PETACC-3)[2]
II5-FU/LV ± irinotecan
Relapse-free survival
OS
0.27 (0.10-0.72; .0094)0.14 (0.03-0.64; .011)
Sargent et al[3] II/IIISurgery alone
DFSOS
0.46 (0.22-0.95; .03*)0.51 (0.24-1.10; .06*)
Gray et al(QUASAR)[4]
IISurgery alone
Recurrence-free interval
0.31 (0.15-0.63; < .001)
1. Ribic CM, et al. N Engl J Med. 2003;349:247-257. 2. Roth AD, et al. J Clin Oncol. 2010;28:466-474. 3. Sargent DJ, et al. J Clin Oncol. 2010;28:3219-3226. 4. Gray R, et al. J Clin Oncol. 2011;29:4611-4619.
5-FU Not Beneficial and Survival Longer in Stage II Patients With MMR Deficiency
Sargent DJ, et al. J Clin Oncol. 2010;28:3219-3226.
No Adjuvant 5-FU Chemotherapy
Adjuvant 5-FU Chemotherapy
HR for OS: 0.47 (95% CI: 0.26-0.83;
P = .004)
HR for OS: 0.78 (95% CI: 0.49-1.24;
P = .28)
Per
cen
t A
live
an
dP
rog
ress
ion
Fre
e
Yrs0 21 3 4 5
0
20
40
60
80
100
MMR-d (n = 86)MMR-p (n = 426)
HR: 0.79 (95% CI:0.49-1.25; P = .30)
Per
cen
t A
live
an
dP
rog
ress
ion
Fre
e
Yrs0 21 3 4 5
0
20
40
60
80
100
MMR-d (n = 79)MMR-p (n = 436)
HR: 0.51 (95% CI:0.29-0.89; P = .009)
• Gene signatures provide prognostic, not predictive, information• 12-gene recurrence score assay validated for recurrence risk in
stage II patients
– QUASAR: 12% (low risk) vs 22% (high risk) 3-yr recurrence risk[1]
– CALGB 9581: 13% (low risk) vs 21% (high risk) 5-yr recurrence in T3, MMR proficient disease[2]
1. Gray RG, et al. J Clin Oncol. 2011;29:4611-4619. 2. Venook AP, et al. ASCO 2011. Abstract 3518.
Genomic Tests for CRC Risk Stratification
Ris
k o
f R
ecu
rren
ce
at
5 Y
rs (
%)
Colon Cancer Recurrence Score0 2010 30 40 50 60
0
5
10
15
20
25
30
35
70
Risk
95% CI
Ris
k o
f R
ecu
rren
ce
at
3 Y
rs (
%)
Recurrence Score0 2010 30 40 50 60
0
5
10
15
20
25
30
35
70
P = .004
Personalized Therapy For Metastatic Disease
• Cytotoxics
• Anti-EGFR Antibodies
• Anti-VEGF Pathway Agents
Cytotoxic Agents
• Fluoropyrimidines– TS: A target. No clear evidence for choosing therapy– DPD: Dihydropyrimidine dehydrogenase deficiency
associated with severe FP toxicity• Testing only in patients with toxicity
• Irinotecan– UGT1A1*28 (10% of North Americans)
• Originally associated with diarrhea but later studies with neutropenia instead
• In package insert, but not used– Topo 1: Conflicting data
• Oxaliplatin– ERCC1: Unproven for efficacy
EGFR Signaling Pathway
Extracellular
Intracellular
Ligand
EGFR
PI3K
Akt
Ras
Raf
MEK
MAPK
Cell motility
MetastasisAngiogenesis
Proliferation
Cell survivalDNA
PTEN
KRAS as a Biomarker for Panitumumab Response in Metastatic CRC
• PFS log HR significantly different depending on KRAS status (p < .0001)• Percentage decrease in target lesion greater in patients with wild-type KRAS receiving
panitumumab• Approved in EU in KRAS WT
Patients With Mutant KRAS
Meanin Wks
Stratified log rank test: P < .0001
115/124 (93)
Patients With Wild-Type KRAS
1.0
0.9
Pro
po
rtio
n W
ith
PF
S
0.8
0.70.60.50.4
0.3
0.20.1
00 2 4 6 8 10
Events/N (%)Medianin Wks
Pmab + BSCBSC alone
114/119 (96)
12.37.3
19.09.3
HR: 0.45 (95% CI: 0.34–0.59)
12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50 52
Weeks
Pro
po
rtio
n W
ith
PF
S
1.0
0.90.8
0.70.60.50.4
0.30.20.1
00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50
Weeks
Pmab + BSCBSC alone Mean
in Wks
76/84 (90)
Events/N (%)Medianin Wks
95/100 (95)
7.47.3
9.910.2
HR: 0.99 (95% CI: 0.73–1.36)
52
Amado et al., JCO 2008.
EGFR Signaling Pathway
Extracellular
Intracellular
Ligand
EGFR
PI3K
Akt
Ras
Raf
MEK
MAPK
Cell motility
MetastasisAngiogenesis
Proliferation
Cell survivalDNA
PTEN
BRAF
– V600E mutation relatively common in CRC (5-15%)
– Poor prognostic factor (Van Cutsem ASCO GI, 2010)• FOLFIRI+cetuximab PFS: 25.1 vs 14.1 months
– Inhibitors: sorafenib, PLX4032 (vemurafenib)
– PLX4032: 70% RR in V600E melanoma, but 5% in CRC
CI, confidence interval; CT, chemotherapy; HR, hazard ratio; mt, mutant; OS, overall survival; wt, wild-type
32 25 16 12 8 5 2 2 2 038 24 14 6 6 3 3 1 0 0
00CT
CT + cetuximab
Pro
bab
ility
of
over
all
surv
ival
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
180 6 12 24 6030 36 42 48 54Time (months)Number of patients
349 317 268 225 163 120 80 63 19 4381 350 283 212 149 107 63 46 17 2
00CT
CT + cetuximab
KRAS wt/BRAF wtHR [95% CI]: 0.840 [0.710–0.993]p=0.041 FOLFIRI / FOLFOX4 + cetuximab: (n=349) median 24.8 months FOLFIRI / FOLFOX4: (n=381) median 21.1 months
KRAS wt/BRAF mtHR [95% CI]: 0.633 [0.378–1.060]p=0.079 FOLFIRI / FOLFOX4 + cetuximab: (n=32) median 14.1 months FOLFIRI / FOLFOX4: (n=38) median 9.9 months
Bokemeyer
Pooled analysis of OS in patients with KRAS wt/BRAF mt tumors
Other Markers (Unknown Benefit)
• Rare KRAS mutations• NRAS• Ligands (amphiregulin, epiregulin)• Copy Number
Molecular Profiling
• Multiple Targets (Caris, Foundation Medicine)• Sequencing• Explants
• No Evidence of Clinical Benefit• Hours of Physician Time
We are on the verge of truly personalized therapy for colorectal cancer
• We need to be able to identify subgroups by genetic alterations and activated pathways
• We need to validate molecular tests before selling them to the public
• We need to identify new targets for new drugs• We may have to find ways to do trials in small
subsets
Agents Targeting the Vascular Endothelial Growth Factor (VEGF) Pathway
VEGFR-2VEGFR-1P
PPPP
PPP
Endothelial cell Small-moleculeVEGFR inhibitors
(PTK787, sunitinib, sorafenib, regorafenib, axitinib)
Anti-VEGFR antibodies(IMC-1121b)
Soluble VEGF
receptors(VEGF-TRAP/ aflibercept)
VEGFAnti-VEGF antibodies
(bevacizumab)
Golden Age of CRC Therapeutics: Bevacizumab
Hurwitz H et al. N Engl J Med. 2004;350:2335-2342.
HR = 0.66, P <.001
Per
cen
t S
urv
ivin
g
Duration of Survival (months)
1.0
0.8
0.6
0.4
0.2
0.0
0 10 20 30 40
IFL/bevacizumab IFL/placebo
20.315.6
10.6
100
80
60
40
20
0
0 10 20 30
Pro
gre
ssio
n-f
ree
Su
rviv
al (
%)
Progression-Free Survival (months)
6.2
(n = 402)
(n = 411)
HR = 0.54, P <.001
What About Angiogenesis Inhibition After First Line Therapy?
• Bevacizumab• Aflibercept• Regorafenib
E3200: Overall SurvivalP
r o
b a
b i
l i
t y
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
OS (months)
0 3 6 9 12 15 18 21 24 27 30 33 36
ALIVEDEAD MEDIANTOTAL
A:FOLFOX4 + bevacizumab 289 246 43 12.9B:FOLFOX4 290 257 33 10.8C:bevacizumab 243 216 27 10.2
HR = 0.76
A vs B: p = 0.0018
B vs C: p = 0.95
Giantonio BJ, et al. ASCO 2005
No first line bev!
BEV + standard first-line CT (either
oxaliplatin oririnotecan-based)
(n=820)
Randomise 1:1
Standard second-line CT (oxaliplatin or irinotecan-
based) until PD
BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-
based) until PD
PD
ML18147 (TML) study design
CT switch:
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
CT switch:
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
Study conducted in 220 centres in Europe and Saudi Arabia
Primary endpoint • Overall survival (OS) from randomisation
Secondary endpoints included
•Progression-free survival (PFS)•Best overall response rate•Safety
Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based)• First-line PFS (≤9 months, >9 months)• Time from last BEV dose (≤42 days, >42 days)• ECOG PS at baseline (0/1, 2)
Arnold 2012
OS: ITT populationO
S e
stim
ate
Time (months)
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42 48
No. at riskCT 410 293 162 51 24 7 3 2
0BEV + CT 409 328 188 64 29 13 4 1
0
CT (n=410)BEV + CT (n=409)
9.8 mo 11.2 mo
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)
p=0.0062 (log-rank test)
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)
p=0.0211 (log-rank test)
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
PFS: ITT populationP
FS
est
imat
e
Time (months)
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42
No. at riskCT 410 119 20 6 4 0 0 0BEV + CT 409 189 45 12 5 2 2 0
CT (n=410)BEV + CT (n=409)
4.1 mo 5.7 mo
Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) p<0.0001 (log-rank test)
Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)
p<0.0001 (log-rank test)
aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
What else does TML teach us?
• Affirms the limited utility of Registry studies regarding interventions and outcomes:– BRITE: 9.5 v. 19.2 OS beyond PD– TML: 9.8 v. 11.2
BRiTE findings not replicated; the publication* could be cited as an example of the pitfalls of Registry data
* Grothey et al, JCO, 2008 Venook 2012
Aflibercept (VEGF-TRAP)• Fully human fusion protein and
soluble recombinant decoy VEGF receptor composed of Domain 2 of VEGFR1 and Domain 3 of VEGFR2 fused to the Fc of IgG1
• Higher affinity for VEGF-A than bevacizumab and also blocks PlGF; T1/2 17 days
• EFC10262 (VELOUR )– Phase III Trial 2nd Line
FOLFIRI +/- VEGF-TRAP (Aflibercept)
• Where has it been?
VELOUR Study Design
Primary endpoint: overall survival
Sample size: HR=0.8, 90% power, 2-sided type I error 0.05
Final analysis of OS: analyzed at 863rd death event using a 2-sided nominal significance level of 0.0466 (α spending function)
Metastatic Colorectal Cancer
RANDOMIZE
Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks
Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks
Placebo IV, day 1+ FOLFIRIq2 weeks
Placebo IV, day 1+ FOLFIRIq2 weeks
1:1 Disease Progression Death
600
600Stratification factors:• ECOG PS (0 vs 1 vs 2)• Prior bevacizumab (Y/N)
VELOUR Study
• Overall results– Adding aflibercept to FOLFIRI in mCRC patients previously treated with an
oxaliplatin-based regimen resulted in significant OS and PFS benefits
Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.
OS PFS
TML/VELOUR
• Is aflibercept better than bevacizumab second-line?
• ? Differences in toxicity than bevacizumab
• What about anti-EGFR Ab? SPIRITT trial (KRAS WT) pending
Small Molecule TKIs
• Both Abs and TKIs may inhibit the “classic” VEGF-A/VEGFR-2 pathway
• Inhibition of multiple VEGF receptors may be important
• Inhibition of other receptors (Clean vs. Dirty)• c-kit, PDGF-R, RET, FGF-R
MAb
TKI
Godzilla vs. Mothra 1964
CRC: Graveyard of VEGFR TKIs
Negative Randomized Trials: 6365+ pts
SU5416 719
CONFIRM 1 1168
CONFIRM 2 855
HORIZON II/III 1050/1614
SUN1122 768
SUN1104 191
TKI
TKI
TKI
TKITKI
VEGFR TKIs: Take 2
• Negative in combination with chemotherapy
• New studies with chemo free regimens
• Front-line vs salvage
Regorafenib:
• Small molecule inhibitor of VEGFR and FGFR-1
• CORRECT Trial Grothey et al. 760 pts 2:1• Chemorefractory mCRC vs BSC, interim
analysis• PFS: 1.9 v 1.7m (HR=0.493) p<0.000001• OS: 6.4 v 5.0m (HR=0.773) p=0.0051• Positive but is it clinically significant?
Overall survival (primary endpoint)
Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p<0.009279 at approximately 74% of events required for final analysis)
1.00
0.50
0.25
0
0.75
200100500 150 300250 400350 450
Days from randomization
Sur
viva
l dis
trib
utio
n fu
nctio
n
Placebo N=255Regorafenib N=505
Median 6.4 mos 5.0 mos95% CI 5.9–7.3 4.4–5.8
Hazard ratio: 0.77 (95% CI: 0.64–0.94)
1-sided p-value: 0.0052
Regorafenib Placebo
Grothey 2012
1.00
0.50
0.25
0
0.75
200100500 150 300250 350
Days from randomization
Sur
viva
l dis
trib
utio
n fu
nctio
n
Placebo N=255Regorafenib N=505
Regorafenib Placebo
Median 1.9 mos 1.7 mos95% CI 1.9–2.1 1.7–1.7
Hazard ratio: 0.49 (95% CI: 0.42–0.58)
1-sided p-value: <0.000001
Progression-free survival (secondary endpoint)
Grothey 2012
Overall response and disease control rates(secondary endpoints)
*DCR = PR + SD; p<0.000001
Grothey 2012
Why these results?
• Possibly benefit from long term anti-VEGF inhibition (BRITE)
• Can anti-VEGF therapy worsen post-therapy outcome? (Bevacizumab Addiction)– Bevacizumab only leads to modest improvement in OS– VEGF inhibition may up-regulate other parts of pathway and other pathways– Preclinical models of increased metastasis with VEGFR-2 inhibition (Rip-
TAG Paez-Ribes, 2009 and sunitinib conditioning Ebos, 2009)– Differences between PFS and OS with PTK/ZK (Hecht JCO 2010)