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Metastatic Colon Cancer: Today

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Tanios Bekaii-Saab, MD Medical Director, GI Oncology The Ohio State University-James Cancer Hospital Anti-VEGF Agents Proposed Mechanisms of Action Based on ... – PowerPoint PPT presentation

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Title: Metastatic Colon Cancer: Today


1
Metastatic Colon Cancer Todays and Tomorrows
Target
  • Tanios Bekaii-Saab, MD
  • Medical Director, GI Oncology
  • The Ohio State University-James Cancer Hospital

2
Anti-VEGF Agents Proposed Mechanisms of Action
Based on Preclinical Models
1. Lee CG, Heijn M, di Tomaso E, et al. Cancer
Res. 2000605565-5570. 2. Inai T, Mancuso M,
Hashizume H, et al. Am J Pathol. 200416535-52.
3. Gerber HP, Ferrara N. Cancer Res.
200565671-680. 4. Jain RK. Science.
200530758-62. 5. Tong RT, Boucher Y, Kozin S,
et al. Cancer Res. 2004643731-3736. 6. Hicklin
DJ, Ellis LM. J Clin Oncol. 2005231011-1027.
3
First-Line Bevacizumab in MCRC Progression-Free
Survival
NO16966
AVF2107g
TREE-2
BICC-C
a
b
c
PFS or TTP (mo)
aPlt0.001 bP0.0023 cP0.003 vs mIFL. Fuchs et
al. ASCO, 2007. Abstract 4027 Hochster et al.
ASCO, 2006. Abstract 3510 Hurwitz et al. N Engl
J Med. 20043502335 Saltz et al. J Clin Oncol.
2008262013.
4
First-Line Bevacizumab in MCRC Overall Survival
NO16966
AVF2107g
TREE-2
BICC-C
b
a
OS (mo)
aPlt0.001 bP0.0769. Fuchs et al. ASCO, 2007.
Abstract 4027 Hochster et al. ASCO, 2006.
Abstract 3510 Hurwitz et al. N Engl J Med.
20043502335 Saltz et al. J Clin Oncol.
2008262013.
5
NO66 Bevacizumab in Combination With
Oxaliplatin-Based Chemotherapy
PFS
OS
CapeOx/FOLFOX4 bevacizumabn699 513 events
CapeOx/FOLFOX4 bevacizumabn699 420 events
CapeOx/FOLFOX4 placebon701 547 events
CapeOx/FOLFOX4 placebon701 455 events
HR0.83 (97.5 CI, 0.72-0.95)
HR0.89 (97.5 CI, 0.76-1.03)
P0.0023
P0.0769
Proportion of patients
Proportion of patients
8.0
9.4
19.9
21.3
Months
Months
Saltz et al. J Clin Oncol. 2008262013.
6
PIIR study of FOLFOX/Sunitinib vs
FOLFOX/bevacizumab
  • Higher toxicity with sunitinib

Hecht et al , ASCO 2010
7
VEGFR TKIs in CRC
Agent mCRC Trials CRC Patients
Cediranib AZD2171 2 Phase III 3,194
Semaxinib SU5416 2 Phase III 2,084
Vatalanib PTK787 2 Phase III 2,050
Sunitinib SU11248 Phase III 1,623
Brivanib BMS-582664 Phase III 926
Regorafenib BAY 73-4506 Phase III 730
Sorafenib BAY 43-9006 Phase IIB 814
Vandetanib ZD6474 Phase IIB 356
Axitinib AG-013736 Phase IIB 299
Linifanib ABT-869 Phase IIB 147
Vargateg BIBF 1120  Phase II 166
Tivozanib AV-951 Phase II 80
Motesanib AMG-706 Phase IB 148
Pazopanib GW786034 Phase IB 94
gt10,000
  • Courtesy of Scott Kopetz

8
EGFR Activation
EGFR Activation
Metastatic Spread
Tumor
Angiogenesis
Angiogenesis
Cell Survival
Tumor
Proliferation
Rowinsky EK. Annu Rev Med. 200455433. Ritter
CA, Arteaga CL. Semin Oncol 2003303. Mendelsohn
J. J Clin Oncol, 2002201S. Herbst RS, Shin DM,
Cancer, 2002941593-1611. Woodburn JR. Pharmacal
Ther. 199982241.
9
Colon Cancer Has Many Biologic Subsets That
Differ in Response to EGFR-Targeted Agents
EREG or AREG
Low expression of EGFR ligands ? decreased
response to EGFR targeted agents
EGFR
Mutant KRAS ? decreased response to EGFR-targeted
agents
PIP1
PI3K
KRAS
PTEN
PTEN loss of expression ? decreased response to
EGFR-targeted agents
Mutant BRAF ? ?decreased response to
EGFR-targeted agents
PIP3
BRAF
Signaling to the nucleus
10
COIN Trial design
Maughan et al
gt80 patients genotyped for KRAS, NRAS and
BRAF 43 KRAS mutation 4 NRAS mutation 8 BRAF
mutation
.
Maughan et al Abs 3502, ASCO 2010
11
OS and PFS among KRAS wild-type patients
Arm A Arm B Diff.
Median OS mo 17.9 17.0 -0.92
2-year survival rates 36.1 34.4 -1.66
Arm A Arm B Diff.
Median PFS mo 8.6 8.6 0.07
2-year survival rates 8.83 9.55 0.72
1.00
HR point estimate 1.038 95 CI (0.90,
1.20) ?2 0.18 p 0.68
HR point estimate 0.959 95 CI (0.84,
1.09) ?2 0.27 p 0.60
0.75
0.50
Survival
0.25
Arm A (OxFp)
Arm A (OxFp)
Arm B (OxFp cetux)
Arm B (OxFp cetux)
0.00
0
6
12
18
24
30
36
42
0
6
12
18
24
30
36
42
Time (months)
Time (months)
Overall Survival
Progression-free Survival
Maughan et al Abs 3502, ASCO 2010
12
PRIME Study FOLFOX /- Panitumumab in 1st Line
mCRC
Endpoints
Hypothesis
Study Description
Primary Endpoint PFS Secondary Endpoints OS,
ORR, TTP, DOR, Safety Tertiary/Exploratory
Endpoints TTR, Biomarkers, PRO
The addition of panitumumab to chemotherapy
(FOLFOX) will increase progression-free survival
(PFS) compared to chemotherapy (FOLFOX) alone as
first-line treatment of mCRC among subjects with
wild-type KRAS tumors and subjects with mutant
KRAS tumors.
A Randomized, Multicenter, Phase 3 Study to
Compare the Efficacy of Panitumumab in
Combination with Oxaliplatin/ 5-fluorouracil/
leucovorin to the Efficacy of Oxaliplatin/
5-fluorouracil/ leucovorin Alone in Patients with
Previously Untreated Metastatic Colorectal Cancer
12
13
WT KRAS Progression-Free Survival
Eventsn () Median (95 CI) months
Panitumumab FOLFOX 199 (61) 9.6 (9.211.1)
FOLFOX 215 (65) 8.0 (7.59.3)
HR 0.80 (95 CI 0.660.97) P-value 0.02
14
WT KRAS Overall Survival (Interim Analysis)
Eventsn () Median (95 CI) months
Panitumumab FOLFOX 106 (33) NE (20.3, NE)
FOLFOX 124 (37) 18.8 (17.2, NE)
HR 0.83 (95 CI 0.641.08) P-value 0.16 HR 0.83 (95 CI 0.641.08) P-value 0.16 HR 0.83 (95 CI 0.641.08) P-value 0.16
15
Summary of published Phase III 1st line CT
anti-EGFR combination data in KRAS WT patients
CRYSTAL1(FOLFIRI Cmab)(from meta-analysis) CRYSTAL1(FOLFIRI Cmab)(from meta-analysis) COIN3 (FOLFOX/XELOX Cmab) COIN3 (FOLFOX/XELOX Cmab) PRIME4 (FOLFOX Pmab) PRIME4 (FOLFOX Pmab)
Cmab (n 316) Control (n 350) Cmab (n 668) Control (n 652)
KRAS Ascertainment Rate 89 89 81 81 93 93
RR () 57.3 39.7 49 45 55 48
Median PFS (mos) (95 CI) 9.9 8.4 8.6 8.6 9.6 8.0
Hazard Ratio (95 CI) 0.696(0.558 to 0.867, p 0.0012) 0.696(0.558 to 0.867, p 0.0012) 0.959 (0.84 to 1.09 p 0.60) 0.959 (0.84 to 1.09 p 0.60) 0.8 (0.84 to 1.09 p 0.60) 0.8 (0.84 to 1.09 p 0.60)
Median OS (mos) (95 CI) 23.5 20.0 17.0 (22.2 to 27.8) 17.9 (19.2 to 25.7) NE (20.3 - NE) 18.8 (20.3 - NE)
Hazard Ratio (95 CI) 0.796 (0.670 to 0.946, P 0.0094) 0.796 (0.670 to 0.946, P 0.0094) 1.038 (0.90 to 1.20 p 0.68) 1.038 (0.90 to 1.20 p 0.68) 0.83 (95 CI 0.641.08) 0.83 (95 CI 0.641.08)
1. Van Cutsem E, et al Eur J Can (suppl)a6.077,
3. Update from ECCO-ESMO , 2. Bokemeyer C, et al.
Eur J Can(Supp)a6.079, 3. Saltz L, et al. J Clin
Onc 2008262013-2019, 4. Douillard et al ESMO
2009
16
Summary of 2nd line CT anti-EGFR combination
data in KRAS WT patients
EPIC1(Irinotecan Cmab) KRAS WT Population EPIC1(Irinotecan Cmab) KRAS WT Population 1834(FOLFIRI /- Pmab) KRAS WT 1834(FOLFIRI /- Pmab) KRAS WT
Cmab(n 97) Control (n 95) FOLFIRI Pmab FOLFIRI
KRAS Ascertain-ment Rate 23 23 92 92
RR () (95 CI) 10.3 7.4 35 10
PFS (mos) (95 CI) 3.98 2.79 5.9 3.9
Hazard Ratio (95 CI) 0.77(0.57 to 1.04) 0.77(0.57 to 1.04) 0.73 (0.59 to 0.90 p0.004) 0.73 (0.59 to 0.90 p0.004)
OS (mos) (95 CI) 10.94 11.56 14.5 12.5
Hazard Ratio (95 CI) 1.28(0.89 to 1.85) 1.28(0.89 to 1.85) 0.94 (0.76 to 1.15 p0.55) 0.94 (0.76 to 1.15 p0.55)
17
Conclusions
  • The current standard of care for first line
    treatment of eligible patients with MCRC remains
    F-based chemotherapy Bevacizumab.
  • Is Bevacizumab optimally used in combination with
    chemotherapy?
  • FOLFIRI/XELIRI Yes ( 5 mg/Kg qowk/7.5 mg/Kg
    q3wks)
  • XELOX ? Yes (7.5 mg/Kg q3wks)
  • FOLFOX ? Unclear in first line at 5 mg/Kg qowk
    ?10 mg/Kg qowk? (ECOG 3200)
  • Effect of bevacizumab on PFS and OS is
    independent of KRAS status
  • In advanced CRC, evidence suggests that treating
    to progression may improve survival.
  • Balance effect with added risk of toxicity

18
Conclusions
  • A role for EGFR inhibitors in first line
    treatment of select patients with potentially
    resectable disease is justifiable (KRAS WT).
  • Anti-EGFR antibody therapy when added to
    oxaliplatin based therapy for patients with KRAS
    mutant tumors might be detrimental with respect
    to RR, PFS and OS. When combined with irinotecan
    , there is no added benefit to justify the added
    toxicities.
  • Are EGFR inhibitors optimally used in combination
    with chemotherapy?
  • Irinotecan ? Cetuximab Yes
  • ? Panitumumab Yes
  • Oxaliplatin ? Cetuximab No
  • ? Panitumumab Yes
  • Can Bevacizumab be safely combined with anti-EGFR
    mAbs?
  • Cetuximab No ( 1st line (CAIRO-2)
  • Panitumumab No (PACCE)

19
COIN Mutations in Kras, Nras, Braf
distribution and prognostic significance
Prognostic effect of mutational status
NRAS-mut n50 (4)
KRAS-mut n565 (43)
Arm A
Arm B
12
All-wt n581 (44)
BRAF-mut n102 (8)
Median PFS (months)
6
39
0
11
18
102
554
12
Total n1316 (81)
Median OS (months)
6
0
40
Population N Arm A Arm B
ITT 1630 815 815
Assessed for mutations 1316 648 668
of which - KRAS mutation - NRAS mutation - BRAF mutation 565 (43) 50 (4) 102 (8) 268 18 57 297 32 45
KRAS wt 729 (55) 367 306
KRAS/NRAS/BRAF-wt All wild-type 581 (44) 289 292
30
2-year OS ()
20
10
0
N
815
815
Mutation status
BRAF mutation
All patients
Any mutation
KRAS wild-type
KRAS mutation
All wild-type
20
Mutations in Kras, Nras, Braf distribution and
prognostic significance
Prognostic effect of mutational status
Arm A
Arm B
12
Median PFS (months)
6
0
BRAF mutation poorest prognosis KRAS wt
superior prognosis compared to KRAS mut
18
12
Median OS (months)
6
0
40
30
2-year OS ()
20
10
0
N
815
815
Mutation status
BRAF mutation
All patients
Any mutation
KRAS wild-type
KRAS mutation
All wild-type
21
Conclusions
  • Strong prognostic effect of KRAS, BRAF and NRAS
    mutation status independent of the use of
    cetuximab
  • Limitation ? No observation arm ( not really
    feasible)

22
N0147 Is K-ras prognostic in FOLFOX treated
patients?
K-ras Status 3 Year Rates (95 CI) HR (95 CI) P-value
WT N902 75.8 (72.1-79.6) 0.7 (0.5-0.9) 0.04
Mut N374 67.2 (61.4-73.5) 0.7 (0.5-0.9) 0.04
23
BRAF status is prognostic for OS but not RFS
KRAS
BRAF
Relapse free survival (RFS)
Overal survival (OS)
Roth, A. D. et al. J Clin Oncol 28466-474 2010
24
Cetuximab with chemotherapy (CT) as first-line
treatment for metastatic colorectal cancer
(mCRC) Analysis of the CRYSTAL and OPUS studies
according to KRAS and BRAF mutation status
  • In this pooled analysis, a significant
    improvement in OS is demonstrated for patients
    with KRAS WT tumors receiving cetuximab plus
    chemotherapy vs. chemotherapy alone
  • Patients with BRAF mutations appear to benefit
    from cetuximab, although a mutation in BRAF would
    appear to be an indicator of poor prognosis ?
    BRAF is perhaps prognostic but not necessarily
    predictive.

C. Bokemeyer, C.-H. Köhne, P. Rougier, C. Stroh,
M. Schlichting, E. Van Cutsem
25
KRAS mutation Predictive and/or prognostic ?
  • PREDICTIVE response to therapy
  • KRAS mutation predicts non-response to EGFR
    inhibitor antibodies
  • PROGNOSTIC outcome independent of treatment
  • NO
  • PETACC 3
  • 3rd line Cetuximab / Panitumumab monotherapy
    trials
  • CAIRO-2 1st line oxaliplatin / bevacizumab /-
    cetuximab stage IV
  • PACCE 1st line chemo / bevacizumab /-
    panitumumab stage IV
  • YES
  • RASCAL stage II/III colon cancer
  • FOCUS 1st line sequential treatment stage IV
  • COIN 1st line oxaliplatin / cetuximab stage IV
  • N0147 Adjuvant FOLFOX /- cetuximab
  • MAYBE
  • CRYSTAL 1st line FOLFIRI / cetuximab stage IV

26
BRAF mutation Predictive and/or prognostic ?
  • BRAF mutation is present in less than 10 of MCRC
  • BRAF mutation does not predict for EGFR
    resistance
  • BRAF mutation is prognostic for overall survival
    in MCRC ( including relapsed disease).
  • BRAF , TTR and tumor site predict for survival
    after relapse in patients with stage II and III
    CRC.

27
Future Biologics
28
(No Transcript)
29
Hedgehog Inhibitors
  • (Abstr 3530) Safety Analysis of a randomized
    phase II trial of hedgehog pathway inhibitor
    GDC-0449 (vesmodegib) versus placebo with FOLFOX
    or FOLFIRI and bevacizumab in patients with
    previously untreated metastatic colorectal cancer
    (mCRC)
  • Authors Bendell, Hart, Firdaus, Gore, Hermann,
    Mackey, Graham, Zerivitz, Low, Berlin

30
Hedgehog
Overexpression
Mutation
Celium Cell Membrane
SMO
Mutation
GDC-0449
Gli
Activated Gli
Inactive SMO
Pathway Mechanism Unknown
Mutation
Nuclear Membrane
Hedgehog Gene Targets GLI1, BCL2, SNAIL, etc
Proliferation and survival
Stem Cell Maintenance
Angiogenesis
31
FOLFOX/ or FOLFIRI/B GDC-0449
  • Results some concerning signals in tox data
  • More deaths in the GDC-0449 arm (4 vs 0)
  • Two sudden deaths two pneumonias (unusual cause
    of death for colorectal patients?)
  • All deaths occurred before the median PFS for 1st
    line CRC (days 91, 95, 155, 231)
  • Slightly less exposure to conventional chemo and
    biologics in experimental arms
  • No PK interactions (preliminary)
  • Added toxicities consistent with phase I trial1

1Von Hoff, NEJM 2009
32
Perifosine
  • (abstr 3531) Final results of a randomized phase
    II study of perifosine in combination with
    capecitabine (P-CAP) versus placebo plus
    capecitabine (CAP) in patients with second- or
    third-line metastatic colorectal cancer (mCRC)
  • Authors Richards, Nemunaitis, Vukelja,
    Hagenstad, Campos, Letzer, Hermann, Sportelli,
    Gardner, Bendell

33
Perifosine
O
N
  • What is perifosine?
  • Oral alkylphospholipid
  • Related to miltefosine (FDA approved for breast
    CA cutaneous mets, and leishmaniasis), which has
    significant GI side effects
  • Mechanism of action is complex/unclear.
    Interacts with cell membrane and inhibits AKT
    (indirectly?). Also inhibits NF-?B facilitates
    degradation of mTOR pathway members activates
    JNK (apoptotic) pathway.
  • Phase I studies
  • Phase I (daily dosing, 3 on, 1 off) in solid
    tumors (Eur J Ca 2002)
  • n22, diarrhea and vomiting dose-limiting, MTD
    200 mg/day
  • ½ life 105 hr 11 CRC patients, no responses
  • Phase I (weekly dosing) in solid tumors (Eur J
    Ca 2010)
  • n36, diarrhea/vomiting, RP2D 600 mg/wk
  • linear PK, ½-life 80 120 hr range, no responses

P
O
O
O
34
Capecitabine /- perifosine
  • Small trial (n38 interim analysis, no power
    calculation provided but primary endpoint TTP)
  • Toxicity profile as expected perifosine appeared
    to add fatigue, diarrhea, nausea, anemia. Also
    surprising rate of g3/4 HFS (30) in combo arm
  • Improvement in
  • Response rate (4 pts v 1 pt, n35 total), most gt1
    yr
  • (Only one response was in 5-FU refractory)
  • Time to progression (28 v. 11 weeks, HR0.28)
  • Overall survival (17.7 v 10.9 mos, HR0.41)

35
Results capecitabine /- perifosine
Richards, ASCO 2010
36
Signaling Pathway Target PI3K
PIP2
p85
PI3K
p110
Growth Factor Receptor
PI3K inhibitors (XL147, GDC-0941, PX-866,
SF1126, BEZ235)
AKT inhibitors (perifosine?, MK-2206 GSK2141795,
SR13668, XL418, GSK690693)
AKT
Blocking the Pathway
mTOR
mTOR inhibitors (sirolimus, temsirolimus,
everolimus, AP23573, AZD8055, OSI-027, palomid
529)
37
Combining Biologics ?
38
Double-Targeting EGFR
EGFR
Compensatory overexpression of EGFR?
Tyrosine Kinase Inhibitor
Monoclonal Antibody
Endocytosis of EGFR
EGFR
39
Dual Targeting
  • EGFR VEGFR ( mAB) ? No Go
  • VEGF mTOR ? early signals
  • EGFR VGFRR ( TKI) ? Too toxic
  • Etc

40
Conclusions
  • Revealing the many molecules and pathways that go
    awry in tumor cells has and will allow us to
    develop precise strategies to attack cancer
  • Thousands of new drugs are being studied for
    cancer therapy
  • We are moving to an era of predictive testing
    (enrichment strategies) and thus away from trial
    and error.
  • Kras mutational status and effectiveness of EGFR
    inhibitors
  • The example of Panitumumab and Cetuximab
  • Global gene expression profile as a tool to
    select targets
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