Transcript Document 7216924

Colon cancer:
Combining molecular diagnostics and the
art of medicine in the long term
management of advanced colon cancer
J. Randolph Hecht, MD
Professor of Clinical Medicine
Director, UCLA GI Oncology Program
David Geffen School of Medicine at UCLA
Median Overall Survival in
First-Line MCRC: The Golden Age
BSC
~4-6 mo
12-14 mo
5-FU/LV
~ 15-16 mo
IFL or FOLFIRI
FOLFOX4 or CAPEOX
19-20 mo
IFL + bevacizumab
20.3 mo
FOLFOX6
21.5 mo
?24 mo
FOLFIRI + bevacizumab
0
BSC = best supportive care.
*FOLFOX6 followed by FOLFIRI.
6
12
18
Median OS (mo)
24
BSC
5-FU
IFL
FOLFOX/IRI
BSC
5-FU
IFL
FOLFOX/IRI
Modern Chemotherapy for Unresectable
Metastatic Disease: 50 Years of Work
• Infusional 5-FU is better than bolus (? Capecitabine)
• Irinotecan and Oxaliplatin: ? Equivalent
• 3 drug hypothesis (Grothey)
• Almost all the improvement in mCRC survival is
due to better cytotoxic therapies, not biologic
therapies
1st Line Metastatic Colorectal
Cancer
• Irinotecan
• IFL > 5-FU
• Oxaliplatin
• FOLFOX > 5-FU
• FOLFOX > IFL
• FOLFOX = FOLFIRI
Treatment: Chemotherapy
• 1st line therapy: CPT-11+5FU/LV (Saltz)
– Median survival 14.8 vs. 12.6 mo.
– Similar to Douillard, Lancet 2000
NEJM, 2000
1st Line Metastatic Colorectal
Cancer
• Irinotecan
• IFL > 5-FU
• Oxaliplatin
• FOLFOX > 5-FU
• FOLFOX > IFL
• FOLFOX = FOLFIRI
N9741: Overall Survival
100
IFL (med 15.0 mo)
FOLFOX4 (med 19.5 mo)
IROX (med 17.4 mo)
90
80
% Alive
70
60
50
40
30
FOLFOX4 vs IFL (P=.0001; HR=0.66)
IROX vs IFL (P=.04)
20
10
0
0
1
Years
Goldberg et al. J Clin Oncol. 2004;22:23.
2
1st Line Metastatic Colorectal
Cancer
• Irinotecan
• IFL > 5-FU
• Oxaliplatin
• FOLFOX > 5-FU
• FOLFOX > IFL
• FOLFOX = FOLFIRI
FOLFOX vs. FOLFIRI
in First-Line Metastatic CRC:
Overall Survival
FOLFOX n = 172, 34% RR
FOLFIRI n = 164, 31% RR
P = 0.60
Copyright © American Society of Clinical Oncology
Colucci, G. et al., J Clin Oncol; 23:4866-4875 2005.
Access to Chemotherapy
Improves Survival
Grothey J Clin Oncol 2005;23:9441–9442
Capecitabine
•
•
•
•
Converted to systemic 5-FU
Single agent trials comparable to 5-FU
CapeOx = FOLFOX (Cassidy)
? CapeIRI
– Some trials with excessive toxicity
– ? Reduced efficacy BICC-C (Fuchs)
Modern Synthesis of
Chemotherapy for mCRC 2012
• Combination chemotherapy if possible
• “Continuum of Care”
• Chose for toxicity, not efficacy
• 2nd Line Chemotherapy
Whatever they didn’t get 1st line
Molecular Markers
• Colorectal cancers are
molecularly heterogeneous
– MSI, KRAS, CIMP
– We already do this in other
cancers
– Cytotoxics have targets
too!
– And yet we treat them all
the same!
– Still no validated markers
for efficacy or toxicity
(sorry Response Genetics!)
Eng at al. BMC Cancer 2010
Advanced Disease:
“Standard” Biological Therapies
• Angiogenesis inhibitors
– Cancers need new vasculature to grow beyond a certain size
(Folkman)
– Multiple angiogenic factors
– Hypoxia
• Epidermal growth factor receptor (EGFR)
antagonists
– Member of HER (ErbB) family of tyrosine kinases
– Multiple ligands:
TGF-a, EGF, amphiregulin, betacellulin, HB-EGF, and epiregulin
– Undergoes hetero and homodimerization
– Activation of multiple downstream pathways including Ras,
ERK1/2, PI3K/AKT, and STAT pathways
– Leads to proliferation, survival, angiogenesis, and metastasis
The VEGF and VEGF-Receptor Family
Ligand
isoforms
PlGF
VEGF-B
VEGF-A VEGF-E VEGF-C VEGF-D
VEGFR-1s
VEGF-A 165
Extracellular
Intracellular
Receptor
isoforms
VEGFR-1
(Flt-1)
VEGFR-2
NRP-1
(KDR)
Angiogenesis
VEGFR-3
(Flt-4)
Lymph angiogenesis
tumor metastases
• VEGF regulates angiogenesis via interaction with
receptor tyrosine kinases
– VEGFR-2/KDR and VEGFR-1/Flt-1
Agents Targeting the Vascular
Endothelial Growth Factor (VEGF)
Pathway
Anti-VEGF
antibodies
VEGF
Soluble
VEGF
receptors
(bevacizumab)
(aflibercept)
Anti-VEGFR
antibodies
(IMC-1121b)
P
P
P
P
VEGFR-1
P
P
P
P
VEGFR-2
Endothelial cell
Small-molecule
VEGFR inhibitors
(regorafenib, PTK787,
sunitinib)
First-Line Irinotecan/5-FU/LV + Bevacizumab
IFL/bevacizumab
15.6 20.3
Progression-free Survival (%)
Percent Surviving
1.0
0.8
0.6
(n = 402)
0.4
0.2
(n = 411)
0.0
IFL/placebo
100
6.2 10.6
80
60
40
20
0
0
10
20
30
40
0
Duration of Survival (months)
HR = 0.66, P <.001
10
20
30
Progression-Free Survival (months)
HR = 0.54, P <.001
Hurwitz H et al. N Engl J Med. 2004;350:2335-2342.
How was this information processed
by the oncology community?
• FOLFOX/bevacizumab became the standard
of care
– FOLFOX > IFL
– IFL+bev > IFL
– Ergo, FOLFOX+bev must be > FOLFOX alone,
right?
• What was the FOLFOX/ bevacizumab data?
– Giantonio E3200 second line
– TREE phase II trials
– NO16966
PFS chemotherapy + bevacizumab
superiority: primary objective met
1.0
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)
p = 0.0023
PFS estimate
0.8
0.6
0.4
0.2
8.0
9.4
0
0
5
10
15
20
Months
FOLFOX+placebo/XELOX+placebo
FOLFOX+bevacizumab/XELOX+bevacizumab
N=701; 547 events
N=699; 513 events
25
Second Line Bevacizumab:
E3200
• Stratification factors:
– ECOG PS: 0 vs 1, 2
– Prior XRT
Previously treated
metastatic CRC
FOLFOX4 +
Bevacizumab
(10 mg/kg, q 2 weeks)
PD
FOLFOX4
PD
Bevacizumab
(10mg/kg, q 2 wks)
PD
Giantonio PASCO 2005
E3200: Overall Survival
P r o b a b i l i t y
1.0
0.9
HR = 0.76
0.8
A vs B: p = 0.0018
0.7
B vs C: p = 0.95
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
OS (months)
A:FOLFOX4 + bevacizumab
B:FOLFOX4
C:bevacizumab
Giantonio BJ, et al. ASCO 2005
TOTAL
DEAD
ALIVE
MEDIAN
289
290
243
246
257
216
43
33
27
12.9
10.8
10.2
Bevacizumab Beyond
Progression
• Bevacizumab Approved
• “in combination with intravenous 5-fluorouracil–
based chemotherapy, is indicated for first- OR
second-line treatment of patients with
metastatic carcinoma of the colon or rectum.”
(PI)
• What is the data supporting second-line
bevacizumab in bevacizumab failures?
• BRITE Registry: Nonrandomized!
• ML 18147/AIO Trial FOLFIRI +bev > FOLFIRI OS PR 1/26/12
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
• Where has it been?
26
EFC10262: VELOUR
Phase III Trial 2nd Line FOLFIRI +/VEGF-TRAP (Aflibercept)
N=1226
600 pts
mCRC after
failure of an
oxaliplatin
based regimen
R
Stratification factors:
Prior bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)
PI: Allegra
Aflibercept 4 mg/kg
IV
+ FOLFIRI q 2 weeks
1:1
600 pts
Placebo + FOLFIRI
q 2 weeks
30% of patients had prior BEV
VELOUR: Results
Van Cutsem, et al. WCGC 2011
VELOUR Discussion
• 30% had received bev, reportedly similar
results
• How does this compare to bev 2nd line?
• What about EGFR Ab in KRAS WT:
SPIRITT?
• Does bev treatment change the tumor?
Regorafenib: What A
Difference a F Makes!
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
• Statistically positive but is it clinically significant?
Overall survival (primary
endpoint)
1.00
Survival distribution function
Median
95% CI
Regorafenib
Placebo
6.4 mos
5.0 mos
5.9–7.3
4.4–5.8
Hazard ratio: 0.77 (95% CI: 0.64–0.94)
1-sided p-value: 0.0052
0.75
0.50
0.25
Placebo N=255
Regorafenib N=505
0
0
50
100
150
200
250
300
350
400
450
Days from randomization
Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final analysis)
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 (RipTAG Paez-Ribes, 2009 and sunitinib conditioning Ebos, 2009)
– Differences between PFS and OS with PTK/ZK (Hecht ECCO 2007)
Yarden & Sliwkowski Nat Rev Mol Cell Biol 2001
BOND Trial: Randomized Phase II Study With
Cetuximab and Irinotecan
% RR for
cetuximab
alone (n)
% RR for
cetuximab +
irinotecan (n)
P-value
All patients
11 (111)
23 (218)
0.007
Irinotecanoxaliplatin
failure
11 (44)
24 (80)
0.09
Irinotecan
refractory
15 (69)
26 (132
0.07
Cetuximab PI. February 2004
What About Earlier in Treatment?
• 1st Line
– High RR in phase II trials
– CRYSTAL: FOLFIRI +/- cetuximab
• 2nd Line
– EPIC: irinotecan +/- cetuximab PFS not OS
• But
– Clearly, only some helped
– Significant toxicities, particularly with long-term use in most
Why Do We Try to Predict
Response?
• Modestly effective drugs that help a
subset
• Toxicity
• Expense
Predictors of Response
Predictors of Response
• NSCLC Cancer
EGFR mutation, K-ras wt correlate with response
• CRC
Mutations rare
EGFR staining not helpful (Hecht, 2010)
EGFR copy # (Moroni, 2005)
Ligands: amphiregulin, epiregulin (Ford 2007)
K-ras (Lievre, 2006; DiFiore 2007)
Ligand
Extracellular
EGFR
PTEN
PI3K
Akt
Ras
Raf
Intracellular
MEK
MAPK
Cell survival
DNA
Proliferation
Cell motility
Metastasis
Angiogenesis
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
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pmab + BSC
BSC alone
Events/N (%)
115/124 (93)
114/119 (96)
Median
in Wks
Mean
in Wks
12.3
7.3
19.0
9.3
HR: 0.45 (95% CI: 0.34–0.59)
Stratified log rank test: P < .0001
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52
Weeks
Amado et al., JCO 2008.
Patients With Mutant KRAS
1.0
Proportion With PFS
Proportion With PFS
Patients With Wild-Type KRAS
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Pmab + BSC
BSC alone
Events/N (%)
76/84 (90)
95/100 (95)
Median
in Wks
Mean
in Wks
7.4
7.3
9.9
10.2
HR: 0.99 (95% CI: 0.73–1.36)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52
Weeks
EGFR Abs Earlier in Treatment in
the Era of KRAS
• CRYSTAL positive, but others (COIN,
NORDIC VII) negative
• Second line trials (EPIC, 181) negative for OS
• SPIRITT: FOLFIRI+bev vs FOLFIRI+Pmab
2012
• Role in second line remains unclear
Other Biomarkers For AntiEGFR Abs?
BRAF
KRAS G13D
BRAF Background
• BRAF is a serine/threonine kinase downstream of
KRAS
• V600E mutation is found in 5-10% of CRCs
• Mutation mutually exclusive with KRAS mut
• Correlatated with poor prognosis
– Ogino, Gut, 2009
– Tol, NEJM, 2009 (letter)
• Retrospective studies correlated with lack of
response
– Di Nicolantonio, JCO, 2008
Does BRAF Mutation Identify Nonresponders?
Ligand
Extracellular
EGFR
PTEN
PI3K
Akt
Ras
Raf
Intracellular
MEK
MAPK
Cell survival
DNA
Proliferation
Cell motility
Metastasis
Angiogenesis
Clinical efficacy in KRAS wild-type tumors by
BRAF mutation status: CRYSTAL
KRAS wt/BRAF wt
(n=566)
FOLFIRI
Median OS mo
[95% CI]
HR [95% CI]
p-valuea
Median PFS mo
[95% CI]
HR [95% CI]
p-valuea
OR rate (%)
[95% CI]
p-valueb
aStratified
KRAS wt/BRAF mt
(n=59)
FOLFIRI
(n= 289)
Cetuximab
+FOLFIRI
(n= 277)
(n=33)
Cetuximab
+FOLFIRI
(n=26)
21.6
25.1
10.3
14.1
[20.0–24.9]
[22.5–28.7]
[8.4–14.9]
[8.5–18.5]
0.830 [0.687–1.004]
0.0549
0.908 [0.507–1.624]
0.7440
8.8
10.9
5.6
8.0
[7.6–9.4]
[9.4–11.8]
[3.5–8.1]
[3.6–9.1]
0.679 [0.533–0.864]
0.0016
0.934 [0.425–2.056]
0.8656
42.6
61.0
15.2
19.2
[36.8–48.5]
[55.0–66.8]
[5.1–31.9]
[6.6–39.4]
<0.0001
0.9136
log-rank test; bCochran-Mantel-Haenszel test
CI, confidence interval; OR, best overall response; OS, overall survival;
PFS, progression-free survival; mo, months; mt, mutant; wt, wild-type
Van Cutsem GI ASCO 2010
KRAS G13D mutations: Effect on outcome in pts with mCRC
treated with First Line Chemotherapy +/- cetuximab
Tejpar et al . Abs 3511 ASCO 2011.
Once Again Larger Numbers Needed:
Peeters GI ASCO 2012
• Analysis of PRIME, 181, 408 data sets: 2606 pts!
• 40-45% KRAS codon 12 or 13 mutations
• No allele prognostic for PFS or OS
• G13D worse prognosis in PRIME
• Would not treat G13D pts with an anti-EGFR Ab
What is the treatment of mCRC in 2012?
• 1st Line
– FP/Ox +bevacizumab (timing of reintroduction?)
– FOLFIRI+ bevacizumab
• 2nd Line
– If FP/OX+bevacizumab 1st line
• FOLFIRI+bevacizumab
• ? FOLFIRI+aflibercept
• (FP)+IRI+panitumumab or cetuximab (KRAS WT)
– IF FOLFIRI+bevacizumab 1st line
• FP/Ox+bevacizumab
• (FP)+IRI+panitumumab or cetuximab (KRAS WT)
• 3rd Line (KRAS WT)
– Whatever wasn’t used
• Salvage
– ? Regorafenib