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Treatment Beyond Progression-is there a new standard of care
for wt kras?
Heinz-Josef Lenz
Associate Director, Clinical Research
Kathryn Balakrishnan Chair for Cancer Research
Co-Director, USC Center for Molecular Pathways and Drug Discovery
Co-Leader GI Oncology Program
USC/Norris Comprehensive Cancer Center
Options for wt kras…wt ..
• Continue Anti VEGF therapy (bevacizumab, aflibercept)
• Switch to anti EGFR AB
Acquired Functional
Capabilities of Cancer Cells
Self-sufficiency in growth signals
Insensitivity to antigrowth
signals
Tissue invasion and metastasis
Limitless potential to
replicate
Sustained angiogenesis
Evading apoptosis
Hallmarks of Cancer – Therapeutic Targeting
EGFR inhibitors
Cyclin-dependent kinase inhibitors
Inhibitors of HGF/c-Met
Telomerase inhibitors
Inhibitors of VEGF signaling
Proapoptotic BH3 mimetics
VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; HGF, hepatocyte growth factor.Hanahan D, et al. Cell. 2011;144:646-674. 15
Genetic Changes in CRC
Cancer Genome Atlas Network. Nature. 2012;487:330-337.
Genomics: Cancer Genome Atlas
Cancer Genome Atlas Network. Nature. 2012;487:330-337.
VEGF expression throughout tumour life cycle1
Pre-clinical data suggest continuous VEGF suppression is key to achieving and maintaining tumour control2
VEGF = vascular endothelial growth factor
bFGF = basic fibroblast growth factor
TGFb-1 = transforming growth factor b-1
PD-ECGF = platelet-derived endothelial cell growth factor
Tumour evolution
VEGFbFGF
TGFb-1
VEGF
bFGFTGFb-1
PIGF
VEGF
bFGFTGFb-1
PIGFPD-ECGF
VEGFPIGFPD-ECGFPleiotrophin
bFGFTGFb-1
VEGF
1. Folkman. Cancer: Principles and Practice of Oncology, 7th ed. 20052. Bagri et al. Clin Cancer Res 2010
VEGF-A, VEGF-B, and PlGF are involved in multiple pathways of angiogenic response
ENDOTHELIAL CELLSurvival, Migration, Proliferation
VEGF-A
VEGF
R-1
STROMAL CELLPERICYTE, SMC
MigrationProliferation
sVEGFR-1
MACROPHAGERecruitment and activation
Release of angiogenic factors
BM PROGENITORS LEUKEMIC CELLProliferation, Migration, Survival
VEGF-A
DENDRITIC CELLSuppression ofantigen recognition
VEGF-A
TUMOR CELLProliferationand migrationChemoprotection
PlGF
VEGF-B
VEGF
R-2
Adapted from Fischer. Nat Cancer Rev. 2008;8:942–956.
5Courtesy of Heinz-Josef Lenz, MD.
Pharmacologic Approaches to Blocking Angiogenesis
• Neutralizing VEGF activity(e.g., bevacizumab, aflibercept)1,2
• Inhibition of receptorkinase activity (e.g., sunitinib,sorafenib, pazopanib, etc.)3-5
• Reducing expression of VEGFby inhibiting tumor growth pathways(e.g., anti-EGFR therapies)6-9
THREE GENERAL MECHANISMS OF ANGIOGENESISINHIBITORS THAT BLOCK THE VEGF PATHWAY
1. Avastin PI. 2010. Genentech Inc. 2. Holash. PNAS. 2002;99:11393–11398. 3. Sutent PI. 2010. 4. Nexavar PI. 2010. 5. Votrient PI. 2010. 6. Petit. Am J Pathol. 1997;151:1523–1530. 7. Tarceva PI. 2010. 8. Erbitux PI 2010. 9. Vectibix PI. 2010
Block VEGF receptor•Anti-VEGFR-2 TKIs
(sunitinib, etc)
VEGF
Neutralize VEGF•Aflibercept
•Bevacizumab
Extracellular
VEGFR-2Tumorcell
Block VEGFexpression•Erlotinib
•Cetuximab•Panitumumab
Intracellular
ANGIOGENESIS INHIBITORS
VEGFR-1
(Flt-1)
NRP-1/NRP-2 NRP-
2
VEGF-D
VEGF-CVEGF-B VEGF-A
PlGF
VEGFR-2(Flk-
1/KDR)
VEGFR-3
(Flt-4)
VasculogenesisAngiogenesis
Lymphangiogenesis
BEVACIZUMAB*
VEGF-TRAP
18F1 1121B
TG-403
Tyrosine Kinase InhibitorsSunitinib*Sorafenib*Pazopanib*
Axitinib*MotesanibCedirinibBrivanib
Many, many others
VEGF Targeted Agents in the Clinic or In Clinical Trials
Ellis, Hicklin Nat Rev Ca. 2008
* FDA approved agents
Do we see improved outcomes in patients treated with agents that target
PlGF/VEGFR-1?
• Patients treated with FOLFOXIRI-bevacizumab* were screened for VEGF, PlGF levels
Biomarker profiles may indicate resistance against VEGF inhibition
Loupakis F et al, BJC, 2011, 104: 1262-9* Masi G et al, Lancet Oncol, 2010: 11, 845-52
Cytokine increase on BEV therapy
Kopetz et al., JCO 2010
EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/-
VEGF-TRAP (Aflibercept)
Stratification factors:Prior bevacizumab (Y/N)ECOG PS (0 vs 1 vs 2)
1:1
mCRC afterfailure of an oxaliplatin
based regimenR
600 ptsAflibercept 4 mg/kg
IV+ FOLFIRI q 2 weeks
600 pts Placebo + FOLFIRIq 2 weeks
13
30% of patients had prior BEVPIs: Allegra, Van Cutsem
2L aflibercept plus FOLFIRI significantly improved OS and PFS compared with FOLFIRIImprovement in OS and PFS with aflibercept appears to be independent
of prior treatment with bevacizumab
VELOUR: phase III trial of second-line aflibercept plus FOLFIRI – efficacy (ITT)
Van Cutsem, et al. JCO 2012*Stratified, cut-off date = February 7, 2011†Stratified, cut-off date = May 6, 2011
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Aflibercept + FOLFIRI (n=612)
Placebo + FOLFIRI (n=614)
0 3 6 9 12 15 18 21 24 27 30
PF
S e
stim
ate1
12.1 13.5 4.7 6.9
OS* PFS†
Aflibercept + FOLFIRI (n=612)
Placebo + FOLFIRI (n=614)
OS
est
imat
e1
1.0
0.8
0.6
0.4
0
0.2
1.0
0.8
0.6
0.4
0
0.2
Time (months)Time (months)
HR*=0.82 p=0.0032
HR*=0.76 p=0.00007
Strata (as per UVRS) N HR (95.34% CI) HRInteraction
P
All patients 1,226 0.817 (0.713-0.937)
Prior bevacizumab No Yes
853
3730.788 (0.669-0.927)0.862 (0.673-1.104)
.5668
0 1 2 3
Favors placeboFavors aflibercept
Strata (as per UVRS) N HR (95% CI) HRInteraction
P
All patients 1,226 0.758 (0.661-0.869)
Prior bevacizumab No Yes
853
3730.797 (0.679-0.936)0.661 (0.512-0.852)
.1958
0 1 2 3
Favors placeboFavors aflibercept
Overall Survival
Progression-Free Survival
Aflibercept: VELOUR Phase III: OS and PFS Stratified by Prior Bevacizumab
Adapted from Van Cutsem E, et al. J Clin Oncol. 2012 Sep 4. [Epub ahead of print].
Primary Endpoint
Allegra Abstract
#3505
Response Rates
Van Cutsem et al., JCO 2012
Safety – Most frequent AEs, with ≥ 5% difference in incidence between treatment arms, excluding anti-VEGF class events
Safety Population, % of patients
Placebo, N = 605 Aflibercept N = 611
All Grades Grade 3-4 All
Grades Grade 3-4
Diarrhea 56.5 7.8 69.2 19.3
Neutropenia** Complicated neutropenia
56.3 29.52.8
67.8 36.75.7
Asthenic conditions (HLT) 50.2 10.6 60.4 16.9
Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7
Thrombocytopenia** 33.8 1.7 47.4 3.3
Infections (SOC) 32.7 6.9 46.2 12.3
Decrease appetite 23.8 1.8 31.9 3.4
Weight decreased 14.4 0.8 31.9 2.6
Palmar plantar erythrodysaesthesia 4.3 0.5 11.0 2.8
Skin hyperpigmentation 2.8 0 8.2 0
Dehydration 3.0 1.3 9.0 4.3
AEs leading to treatment discontinuation:AFL: 26.6%PL: 12.1%
Van Cutsem et al., JCO 2012
Meyerhardt JA, Mayer RJ. N Engl J Med. 2005;352:476-487; Venook A. Oncologist. 2005;10:250-261.
Survival (anti-
apoptosis)
Gene transcriptionCell-cycle progression
MYC
MYC Cyclin D1
FOSJUN
PP
Cyclin D1
AngiogenesisInvasion andmetastasis
Chemotherapy/radiotherapy resistance
Proliferation/maturation
MAPK
MEK
RAS RAFSOS
GRB2
PTEN AKTSTAT
P13KpY
pY
Ligand: AREG, EREG
EGFR-TKTarget for EGFT-TK inhibitor
pY
EGF Receptor: A Rational Target for CRC Therapy
CRYSTAL PRIME OPUS COIN NORDIC CAIRO2 181 PICCOLO
-20
-15
-10
-5
0
5
10
15
20
25
30
17
7
24
7
-1
11
25
22
-5
0
-16
-3
9
-13
-1
-5
KRAS wtKRAS mut
Ch
ang
es i
n r
esp
on
se r
ates
(%
)
2nd Line 1st Line
IRI OX OX OX OX OX IRI IRI
PFS/DFS for EGFR inhibitors improves across lines of therapy in KRAS WT mCRC
CR
YS
TAL
5
CO
IN3
PR
IME
4
NO
RD
IC V
II2
CO
.17
9
Am
ad
o8
N0
14
71
1- H
R
1L 2L Salvage (single agent)
Adjuvant
0.7
0.5
0.3
0.2
–0.1
–0.2
–0.31
817
PIC
CO
LO
6
0.6
0.4
0.1
0
Cetuximab
Panitumumab
1. Alberts, et al. JAMA 2012; 2. Tveit, et al. JCO 2012; 3. Maughan, et al. Lancet 2011 4. Douillard, et al. JCO 2010; 5. Van Cutsem, et al. JCO 2011; 6. Seymour, et al. ASCO 2011
7. Peeters, et al. JCO 2010; 8. Amado, et al. JCO 2008; 9. Karapetis, et al. NEJM 2008
181 vs EPIC181
(n = 1083; 597 WT)WT only
EPIC(n = 1298) WT + Mut
Pmab-FOLFIRI
FOLFIRI Cetux-Iri Iri
OS median(mo)
14.5 12.5 10.7 10.0
OS HR (p) .92 (.37) .98 (.7)
PFS median(mo)
6.7 4.9 4.0 2.6
PFS HR* (p) .82 (.023) .69 (<.001)
RR (%) 36.0 9.8(p<.001)
16.4 4.2(p<.0001)
Subsequent EGFR Ab (%)
12 34 ~0 46.9
A Sobrero et al. GI Symposium 2012A Sobrero et al. J Clin Oncol 2008. 26:2311-2319.
181: FOLFIRI +/- PanitumumabPFS and OS
Median (95% CI), months
6.7 (5.8, 7.4)
4.9 (3.8, 5.5)FOLFIRI alone
Panitumumab + FOLFIRI
PFS
Median (95% CI), months
14.5 (13.0, 16.1)
12.5 (11.2, 14.2)FOLFIRI alone
Panitumumab + FOLFIRI
MonthsMonths
OS
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
0
20
40
60
80
100
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Panitumumab + FOLFIRI (n=303)
FOLFIRI alone (n=294)
Panitumumab + FOLFIRI (n=238)
FOLFIRI alone (n=248)
Adapted from: A Sobrero et al. GI Symposium 2012
* PFS “on treatment” HR = .73; p= .001
Hazard ratio (95% CI): 0.82 (0.69, 0.97)
P-value: 0.023
Hazard ratio (95% CI): 0.92 (0.78, 1.10)
P-value: 0.37
SWOG 0600/iBET: A Phase III of Irinotecan and Cetuximab With or Without Bevacizumab in Patients With mCRC That Progressed During First-Line Therapy
Gold, Grothey et al..
• Primary endpoint: OS
• Secondary endpoints: PFS, objective tumor response, tolerability, and safety
• June 2007 – October 2010
Second line
PD
RANDOMIZE
CT + dual biologic arm removed
mCRCKRAS
wild-typepreviously
treated with Bevacizumab
and oxaliplatin- based CT(n=1260)
Bevacizumab 5 mg/kg +(FOLFIRI or Irinotecan +
Capecitabine)
Cetuximab +(FOLFIRI or Irinotecan +
Capecitabine)N = 68
PEAK study: FOLFOX + Pmab vs. FOLFOX + Beva
Pmab+FOLFOX 6
Bev+FOLFOX6
HR(95% CI)
P-value
RAS wtNPAT 80 80
Median OS
Mo (95% CI)
n.r.(28,8 – nr)
29,0(24,3 – nr)
0.55(0.3 – 1,01)
0.06
Median PFSMo
(95%CI)
13.1(10.7 – 15.1)
9.5(7.9 – 12.7)
0.63(0.43 – 0.94)
0.02
Schwartzberg L et al ASCO 2013
CO.20 Trial: Cetuximab +/- BrivanibK-Ras WT Chemo-refractory CRC
Cetuximab + Placebo
Cetuximab + Brivanib
P Value
PFS 3.4 5.0 <0.0001 (HR=0.72)
RR 7.2 13.6 0.044Siu et al
Conclusions• Anti Angiogenesis Therapy effective through all
lines of therapy (1.4 months!) • Not only kras exon 12/13 but all other codons
and nras may be used to select patients for second line anti EGFR Therapies (prior to resistant!?)
• Emergent Mechanisms of Resistance in EGFR and VEGF pathways may be a key for combination therapies
Are All KRAS Mutations Created Equal? – G13D
Tejpar et al., ASCO 2011Pooled analysis of OPUS and CRYSTAL