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Tratamiento del cáncer colorectal metastásico: de las guías
de práctica clínica, pasando por la genómica y la realidad
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia
Cartagena, Colombia
09.07.2014
FULVFULV
CapecCapec
IriIri
BevBev
CetCet
PanPan
Regor.Regor.
SurgerySurgery
Ablative
Rx
Ablative
Rx
OxOx Aflib.Aflib. Ramuc.Ramuc.
FULVFULV BevBevCapecCapec BevBev
FULVFULVCapecCapec
FULVFULV OxOx IriIri
FULVFULV OxOx BevBev CapecCapec OxOx BevBev
FULVFULV OxOx IriIri BevBev FULVFULV OxOx
FULVFULV IriIri BevBev CapecCapec IriIri BevBev
FULVFULV OxOx CetCet CapecCapec OxOx CetCet
FULVFULV IriIri IriIri CetCet
FULVFULV IriIri CetCet CapecCapec IriIri CetCet
CetCet
FULVFULV OxOx PaniPani CapecCapec OxOx PaniPani
FULVFULV IriIri IriIri PaniPani
FULVFULV IriIri PaniPani CapecCapec IriIri PaniPani
PaniPani
FULVFULV OxOx AflibAflib CapecCapec OxOx AflibAflib
FULVFULV IriIri IriIri AflibAflib
FULVFULV IriIri AflibAflib CapecCapec IriIri AflibAflib
“Thou shall not use anti EGFR-agents
in mutated RAS CRC patients”
mCRC: ESMO Clinical Practice
Guidelines
http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Metastatic-Colorectal-Cancer
Group 0Group 0
Group 1Group 1
Group 2Group 2
Group 3Group 3
Resectable R0
Convertible
Unlikely
resectable/High
tumor burden
Never resectable
Surgery/ +/- Adj CTSurgery/ +/- Adj CT
Conversion CT/SurgeryConversion CT/Surgery
Conversion CT/SurgeryConversion CT/Surgery
Less-toxic CTLess-toxic CT
Cure
Cure
Long OS
QoL
Criticism: solely based on DISEASE characteristics
mCRC: ESMO Clinical Practice
Guidelines
http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Metastatic-Colorectal-Cancer
Group 0Group 0
Group 1Group 1
Group 2Group 2
Group 3Group 3
Resectable R0
Convertible
Unlikely
resectable/High
tumor burden
Never resectable
Surgery/ +/- Adj CTSurgery/ +/- Adj CT
Conversion CT/SurgeryConversion CT/Surgery
Conversion CT/SurgeryConversion CT/Surgery
Less-toxic CTLess-toxic CT
FOLFOX
FOLFOXIRI-Bev
FOLFIRI-Cet
FOLFOX-Bev
XELOX-Bev
FOLFOX-Cet
FOLFIRI-Cet
FP-Bev
Criticism: solely based on DISEASE characteristics
Do THESE guidelines, guide?
CAPOX +
Bevacizumab
6 meses
“Continuum of care” in mCRC – “blurring line descriptions”
Cape + Bevacizumab
Hasta progresión
1o
línea
FOLFIRI +
Bevacizumab
Oxaliplatino hasta neuropatía
QT + Bevacizumab
Hasta progresión
2o
línea
Cetuximab +/-
Irinotecán
Regorafenib
Hasta progresión
≥3o
línea (KRAS nativo)
Hasta progresión
CAIRO-3
TML
Cunningham D, et al. N Engl J Med 2004;351:337-45. CORRECT Trial (Van Cutsem 2012)
In the RAS wt, which first-line
agent?
clinicaloptions.com/oncology
Optimizing Treatment of Metastatic Colorectal Cancer
Mutations in KRAS, NRAS, and BRAF
Distribution and Prognostic Significance
BRAF mutation All patients
Any mutation
KRAS mutation
KRAS WT
All WT
Mutation Status
0
6
12
MedianPFS
(Mos)
Arm A Arm B
0
6
12
18
MedianOS
(Mos)
57
340
268
815
367
289
45
366
297
815
362
292
0
10
20
30
40
2-YrOS(%)
Prognostic Effect of Mutational Status
“All WT”
n = 581
(44%)
KRAS MT
n = 565
(43%)
NRAS MT
n = 50 (4%)
BRAF MT
n = 102 (8%)
Total
N = 1316 (81%)
554
11
39
10
2
Population n (%) Arm A Arm B
ITT 1630 815 815
Assessed for mutations 1316 648 668
 KRAS mutation
 NRAS mutation
 BRAF mutation
565 (43)
50 (4)
102 (8)
268
18
57
297
32
45
KRAS WT 729 (55) 367 362
KRAS/NRAS/BRAF WT
“All WT”
581 (44) 289 292
Maughan TS, et al. ASCO 2010. Abstract 3502.
clinicaloptions.com/oncology
Optimizing Treatment of Metastatic Colorectal Cancer
Phase III 80405 Trial: First-line CT + Either
Cetux or Bev in KRAS-WT mCRC
 Primary endpoint: OS
 Secondary endpoints: ORR, PFS, TTF, duration of response
Patients with mCRC
and KRAS WT
(codons 12, 13),
ECOG PS 0/1
(N = 1137)
FOLFOX or FOLFIRI +
Bevacizumab q2w
(n = 559)
ClinicalTrials.gov. NCT00265850. Venook AP, et al. ASCO 2014. LBA3..
FOLFOX or FOLFIRI +
Cetuximab q1w
(N = 578)
A third arm with CT + bevacizumab + cetuximab
was closed to accrual in September 2009
clinicaloptions.com/oncology
Optimizing Treatment of Metastatic Colorectal Cancer
CALGB/SWOG 80405: OS in the ITT
Population
mOS (95% CI), mos
CT + Cetux 29.9 (27.0-32.9)
CT + Bev 29.0 (25.7-31.2)
HR 0.925 (0.78-1.09)
P = 0.34
Venook AP, et al. ASCO 2014. Abstract LBA3.
0
12 24 36 48 60 72
Mos
80
100
60
40
0
OS(%)
20
84
Impact of primary (1º) tumor location on overall survival
(OS) and progression-free survival (PFS) in patients (pts)
with metastatic colorectal cancer (mCRC): Analysis of
CALGB/SWOG 80405 (Alliance). Alan P. Venook.
Proc ASCO, 2016, 3504
.
Impact of primary (1º) tumor location on overall survival
(OS) and progression-free survival (PFS) in patients (pts)
with metastatic colorectal cancer (mCRC): Analysis of
CALGB/SWOG 80405 (Alliance). Alan P. Venook.
Proc ASCO, 2016, 3504
.
Impact of primary (1º) tumor location on overall survival
(OS) and progression-free survival (PFS) in patients (pts)
with metastatic colorectal cancer (mCRC): Analysis of
CALGB/SWOG 80405 (Alliance). Alan P. Venook.
Proc ASCO, 2016, 3504
.
Impact of primary (1º) tumor location on overall survival
(OS) and progression-free survival (PFS) in patients (pts)
with metastatic colorectal cancer (mCRC): Analysis of
CALGB/SWOG 80405 (Alliance). Alan P. Venook.
Proc ASCO, 2016, 3504
.
Impact of primary (1º) tumor location on overall survival
(OS) and progression-free survival (PFS) in patients (pts)
with metastatic colorectal cancer (mCRC): Analysis of
CALGB/SWOG 80405 (Alliance). Alan P. Venook.
Proc ASCO, 2016, 3504
.
Impact of primary (1º) tumor location on overall survival
(OS) and progression-free survival (PFS) in patients (pts)
with metastatic colorectal cancer (mCRC): Analysis of
CALGB/SWOG 80405 (Alliance). Alan P. Venook.
Proc ASCO, 2016, 3504
.
The relationship between primary tumor sidedness and
prognosis in colorectal cancer. Deborah Schrag
Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features with
progression-free survival (PFS) and overall survival (OS) of
metastatic colorectal cancer (mCRC) after anti-epidermal
growth factor receptor ( EGFR) therapy. Michael Sangminα
Lee
Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features with
progression-free survival (PFS) and overall survival (OS) of
metastatic colorectal cancer (mCRC) after anti-epidermal
growth factor receptor ( EGFR) therapy. Michael Sangminα
Lee
Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features with
progression-free survival (PFS) and overall survival (OS) of
metastatic colorectal cancer (mCRC) after anti-epidermal
growth factor receptor ( EGFR) therapy. Michael Sangminα
Lee
Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features with
progression-free survival (PFS) and overall survival (OS) of
metastatic colorectal cancer (mCRC) after anti-epidermal
growth factor receptor ( EGFR) therapy. Michael Sangminα
Lee
Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features with
progression-free survival (PFS) and overall survival (OS) of
metastatic colorectal cancer (mCRC) after anti-epidermal
growth factor receptor ( EGFR) therapy. Michael Sangminα
Lee
Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features with
progression-free survival (PFS) and overall survival (OS) of
metastatic colorectal cancer (mCRC) after anti-epidermal
growth factor receptor ( EGFR) therapy. Michael Sangminα
Lee
Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features with
progression-free survival (PFS) and overall survival (OS) of
metastatic colorectal cancer (mCRC) after anti-epidermal
growth factor receptor ( EGFR) therapy. Michael Sangminα
Lee
Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features with
progression-free survival (PFS) and overall survival (OS) of
metastatic colorectal cancer (mCRC) after anti-epidermal
growth factor receptor ( EGFR) therapy. Michael Sangminα
Lee
Proc ASCO, 2016, 3505
.
Association of primary (1°) site and molecular features with
progression-free survival (PFS) and overall survival (OS) of
metastatic colorectal cancer (mCRC) after anti-epidermal
growth factor receptor ( EGFR) therapy. Michael Sangminα
Lee
Proc ASCO, 2016, 3505
.
Side Matters. Kimmie Ng
Proc ASCO, 2016, Dicussion
.
What should we do with BRAF
mutated mCRC?
Continuum of care
FULVFULV OxOx BevBev
What to do in second line?
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Phase III ML18147 (TML): Continuing
Bevacizumab Beyond Progression
Standard second-line CT
(oxaliplatin or irinotecan based) until PD
(n = 411)
Bevacizumab 2.5 mg/kg/wk +
standard second-line CT (oxaliplatin or
irinotecan-based) until PD
(n = 409)
Progressive mCRC after
BEV + standard first-line
CT (either oxaliplatin or
irinotecan based)
(n = 820)
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.
Stratified by first-line CT (oxaliplatin or irinotecan
based), first-line PFS (≤ 9 vs > 9 mos), time
from last BEV dose (≤ 42 vs > 42 days),
ECOG PS at baseline (0/1 vs 2)
 Primary endpoint: OS
 Secondary endpoints: PFS, ORR, safety
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Continuing Bevacizumab Beyond
Progression (TML): OS, PFS
OS(%)
Mos
CT (n = 410)
BEV + CT (n = 409)
100
80
60
40
20
0
0 6 12 18 24 30 36 42
48
9.8 mos9.8 mos 11.2 mos11.2 mos
Unstratified* HR: 0.81 (95% CI:
0.69-0.94; log-rank P = .0062)
Stratified†
HR: 0.83 (95% CI:
0.71-0.97; log-rank P = .0211)
*Primary analysis method. †
Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS
(≤ 9 mos, > 9 mos), time from last dose of BEV (≤ 42 days, > 42 days), ECOG PS at baseline (0, ≥ 1).
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.
100
80
60
40
20
0
PFS(%) 0 6 12 18 24 30 36 42
Mos
Unstratified* HR: 0.68 (95% CI:
0.59-0.78; log-rank P < .0001)
Stratified†
HR: 0.67 (95% CI: 0.58-
0.78; log-rank P < .0001)
4.1mo4.1mo
5.7 mo5.7 mo
Overall Survival Progression-Free Survival
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Phase III VELOUR Study: FOLFIRI ± ziv-
Aflibercept as Second-line Therapy in mCRC
 Primary endpoint: OS
 Secondary endpoints: PFS, ORR, safety, immunogenicity
 No correlatives
Patients with mCRC
progressing on first-line
oxaliplatin-based
chemotherapy*
(planned N = 1226)
FOLFIRI + ziv-Aflibercept 4 mg/kg q2w
(n = 612)
FOLFIRI + Placebo q2w
(n = 614)
*30% had previous bevacizumab.
Stratified by previous bevacizumab (yes vs no),
ECOG PS (0 vs 1 vs 2)
Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. ClinicalTrials.gov. NCT00561470.
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
FOLFIRI ± ziv-Aflibercept as Second-line
Therapy in mCRC (VELOUR): OS, PFS
Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.
Stratified HR: 0.817 (95.34% CI:
0.713-0.937; log-rank P = .0032)
Placebo/FOLFIRI
Median: 12.06 mos
Aflibercept/FOLFIRI
Median: 13.50 mos
PFS(%)
100
80
60
40
20
0
Mos
0 3 6 9 12 15 18 21 24 27 30
Stratified HR: 0.758 (95% CI: 0.661-
0.869; log-rank P < .0001)
Placebo/FOLFIRI
Median: 4.67 mos
Aflibercept/FOLFIRI
Median: 6.90 mos
Overall Survival Progression-Free Survival
OS(%)
100
80
60
40
20
0
Mos
0 3 6 9 12 15 18 21 24 27 30 33 36 39
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Tabernero J, et al. Eur J Cancer. 2014;50:320-331.
OS(%)
100
80
60
40
20
0
Mos
0 3 6 9 12 15 18 21 24 27 30 33 36 39
HR: 0.862 (95.34% CI: 0.673-1.104)
Placebo/FOLFIRI
Median: 11.7 mos
Aflibercept/FOLFIRI
Median: 12.5 mos
Pts at Risk, n
Placebo
AFL
187
186
170
178
138
150
115
121
81
89
54
59
37
36
22
22
13
13
Previous Bevacizumab
OS(%)
100
80
60
40
20
0
Mos
0 3 6 9 12 15 18 21 24 27 30 33 36 39
HR: 0.788 (95.34% CI: 0.699-0.927)
Placebo/FOLFIRI
Median: 12.4 mos
Aflibercept/FOLFIRI
Median: 13.9 mos
Pts at Risk, n
Placebo
AFL
427
426
403
388
347
348
286
295
205
222
139
157
94
112
65
82
38
62
No Previous Bevacizumab
2nd
-Line FOLFIRI ± ziv-Aflibercept in mCRC
(VELOUR): OS by Prior Bevacizumab
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Phase III RAISE Study: Second-Line
Ramucirumab/FOLFIRI vs FOLFIRI
Patients with CRC
and progression
during or within 6
months of first-line
bevacizumab,
oxaliplatin, and a
fluoropyrimidine
(N = 1072)
Treat until PD or
unacceptable
toxicity
Ramucirumab 8 mg/kg +
FOLFIRI q2w per cycle
(n = 536)
Placebo +
FOLFIRI q2w per cycle
(n = 536)
Stratified by geographic region, KRAS mutation
status, TTP after start of first-line therapy
 Ramucirumab: anti-VEGFR2 antibody
 Primary endpoint: OS
Tabernero J, et al. Lancet Oncol. 2015;16:499-508.
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Ramucirumab +
FOLFIRI
Placebo +
FOLFIRI
Median OS, mo
(95% CI)
13.3
(12.4-14.5)
11.7
(10.8-12.7)
HR (95% CI) 0.844 (0.73-0.976) (stratified)
P Value (log-rank) .0219 (stratified)
Second-Line Ramucirumab/FOLFIRI vs
FOLFIRI (RAISE): Overall Survival
Tabernero J, et al. Lancet Oncol. 2015;16:499-508.
497 345 195 78 34 12 0536 421 269 114 53 422 0
486 329 166 66 22 2 1536 400 228 108 44 210 0
Pts at Risk, n
Placebo +
FOLFIRI
Ram +
FOLFIRI
Ramucirumab + FOLFIRI
Placebo + FOLFIRI
OverallSurvival
0.2
0.4
0.6
0.8
1.0
0
0 6 12 18 24 30 3633 399 15 21 273 42
Mos
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Inhibition of
neoangiogenesis
Inhibition of tumor
microenvironment
signaling
Inhibition of
proliferation
Regorafenib: Oral Multikinase Inhibitor
Targeting Multiple Tumor Pathways
Wilhelm SM, et al. Int J Cancer. 2011;129:245-255. Mross K, et al. Clin Cancer Res. 2012;18:2658-2667. Strumberg D, et
al. Expert Opin Invest Drugs. 2012;21:879-889.
KIT
PDGFR
RET
PDGFR-β
FGFR
VEGFR1-3
TIE2
RegorafenibF
Cl
F
F F
O
O
O
N
H
N
H
N
H
N
Biochemical
Activity
Regorafenib IC50
Mean ±SD nmol/L (n)
VEGFR1 13 ± 0.4 (2)
Murine VEGFR2 4.2 ± 1.6 (10)
Murine VEGFR3 46 ± 10 (4)
TIE2 311 ± 46 (4)
PDGFR-β 22 ± 3 (2)
FGFR1 202 ± 18 (6)
KIT 7 ± 2 (4)
RET 1.5 ± 0.7 (2)
RAF-1 2.5 ± 0.6 (4)
B-RAF 28 ± 10 (6)
B-RAFV600E
19 ± 6 (6)
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Phase III CORRECT: Regorafenib After
Failure of Standard Therapy in mCRC
 Primary endpoint: overall survival
 Prior systemic, anticancer therapies (palliative)
– 1-2 prior lines: 26%
– 3 prior lines: 26%
– ≥ 4 prior lines: 48%
Patients with
progression
after all
available
standard
therapy
(N = 760)
Arm A: Regorafenib 160 mg po qd + BSC
3 wks on, 1 wk off
(n = 505)
Arm B: Placebo + BSC
3 wks on, 1 wk off
(n = 255)
Grothey A, et al. Lancet. 2013;381:303-312.
2:1
clinicaloptions.com/oncology
Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment
Regorafenib After Failure of Standard
Therapy in mCRC (CORRECT): OS, PFS
Primary endpoint met prespecified stopping criteria at second interim analysis
(1-sided P ≤ .009279 at approximately 74% of events required for final analysis)
100
50
25
0
75
Mos From Randomization
OS(%)
HR: 0.77 (95% CI: 0.64-0.94;
P = .0052)
Regorafenib Placebo
Median OS, mo 6.4 5.0
IQR 3.6-11.8 2.8-10.4
Placebo (n = 255)
Regorafenib (n = 505)
Grothey A, et al. Lancet. 2013;381:303-312.
0 2 4 6 8 10 12 14
Regorafenib Placebo
Median PFS, mo 1.9 1.7
IQR 1.6-3.9 1.4-1.9
0 2 4 6 8 10 12
Mos From Randomization
100
50
25
0
75
PFS(%)
Placebo (n = 255)
Regorafenib (n = 505)
HR: 0.49 (95% CI: 0.42-0.58;
P < .0001 )
Overall Survival Progression-Free Survival
Continuum of care
FULVFULV OxOx BevBev
FULVFULV OxOx BevBev
FULVFULV BevBev
FULVFULV IriIri BevBev Regor.Regor.
LL
TML
Continuum of care
FULVFULV OxOx BevBev
FULVFULV OxOx BevBev
FULVFULV BevBev
FULVFULV IriIri BevBev Cetuxi.Cetuxi.
Continuum de tratamiento en mCRC no resecable
KRAS no mutado
Bev+CAPOX x6
Bev+Cap
Bev+CAPOX
FOLFIRI+Bev
Cet+/-Iri
Regorafenib
CAIRO-3 (2013) TML (2012) C0.17 (2008) CORRECT (2012)
Continuum of care
FULVFULV OxOx BevBev
FULVFULV OxOx BevBev
FULVFULV BevBev
FULVFULV IriIri BevBev Regor.Regor.
Capecitabina
Capecitabina
Capecitabina
Aflibercetp
Continuum of care
FULVFULV OxOx BevBev
FULVFULV OxOx BevBev
FULVFULV BevBev
FULVFULV IriIri BevBev Regor.Regor.
Capecitabina
Capecitabina
Capecitabina
Aflibercetp
Continuum of care
FULVFULV OxOx BevBev
FULVFULV OxOx BevBev
FULVFULV BevBev
FULVFULV IriIri BevBev Regor.Regor.
Capecitabina
Capecitabina
Capecitabina
Aflibercetp
Continuum of care
FULVFULV OxOx BevBev
FULVFULV OxOx BevBev
FULVFULV BevBev
FULVFULV IriIri BevBev Regor.Regor.
Capecitabina
Capecitabina
Capecitabina
Cetuxi
Cetuxi
Cetuxim
Continuum of care
KRAS mutated
Bev+CAPOX x6
Bev+Cap
Bev+CAPOX
FOLFIRI+Bev
Regorafenib
What about patient related
issues?
What to do with a patient only able
to tolerate some chemo.
Continuum of care
KRAS wt, un-fit
Bev+Cap
Bev+FOLFOX
FOLFIRI+Bev
Cet+/-Iri
Regorafenib
AVEX (2013)
Continuum of care
KRAS mutated, un-fit
Bev+Cap
Bev+FOLFOX
FOLFIRI+Bev
Regorafenib
Let’s go back to curative intent
Continuum of care
SurgerySurgery FULVFULV OxOx
FULVFULV OxOx IriIri SurgerySurgery
FULVFULV IriIri CetCet
SurgerySurgery
FOLFIRINOX combined to targeted therapy according
RAS status for colorectal cancer patients with liver
metastases initially non-resectable: A phase II randomized
Study—Prodige 14 – accord 21 (METHEP-2), a unicancer
GI trial. Mark Ychou. Proc ASCO, 2016, Abstract 3512
Proc ASCO, 2016, Discussio
.
FOLFIRINOX as induction treatment in rectal cancer
patients with synchronous metastases (RCSM): Results of
the FFCD 1102 phase II trial. JB Bachet. Proc ASCO, 2016,
Abstract 3513
Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussio
.
Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussio
.
Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussio
.
Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussio
.
Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussio
.
Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussio
.
Is More Better?, Steven J Cohen
Proc ASCO, 2016, Discussio
.
Do THESE guidelines, guide?
Maybe, but a more comprehensive
strategy NEEDS to be thought –out
BEFORE therapy initiation.
Conclusions
Clinical presentation
Treatment toolkit
Rules of engagement
What WE desire
Patient preference
Tumor biology
Cost
Patient access
As of today, clinical practice
guidelines for mCRC are but a
repository of treatment options
filled with soft statements aimed
more to convince insurers rather
than to truly guide clinicians.
Tratamiento de cáncer de colon metastásico: de las guías de práctica, genómica a la realidad

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Tratamiento de cáncer de colon metastásico: de las guías de práctica, genómica a la realidad

  • 1. Tratamiento del cáncer colorectal metastásico: de las guías de práctica clínica, pasando por la genómica y la realidad Mauricio Lema Medina MD Clínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia Cartagena, Colombia 09.07.2014
  • 2.
  • 4.
  • 6. FULVFULV OxOx BevBev CapecCapec OxOx BevBev FULVFULV OxOx IriIri BevBev FULVFULV OxOx FULVFULV IriIri BevBev CapecCapec IriIri BevBev
  • 7. FULVFULV OxOx CetCet CapecCapec OxOx CetCet FULVFULV IriIri IriIri CetCet FULVFULV IriIri CetCet CapecCapec IriIri CetCet CetCet
  • 8. FULVFULV OxOx PaniPani CapecCapec OxOx PaniPani FULVFULV IriIri IriIri PaniPani FULVFULV IriIri PaniPani CapecCapec IriIri PaniPani PaniPani
  • 9. FULVFULV OxOx AflibAflib CapecCapec OxOx AflibAflib FULVFULV IriIri IriIri AflibAflib FULVFULV IriIri AflibAflib CapecCapec IriIri AflibAflib
  • 10. “Thou shall not use anti EGFR-agents in mutated RAS CRC patients”
  • 11. mCRC: ESMO Clinical Practice Guidelines http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Metastatic-Colorectal-Cancer Group 0Group 0 Group 1Group 1 Group 2Group 2 Group 3Group 3 Resectable R0 Convertible Unlikely resectable/High tumor burden Never resectable Surgery/ +/- Adj CTSurgery/ +/- Adj CT Conversion CT/SurgeryConversion CT/Surgery Conversion CT/SurgeryConversion CT/Surgery Less-toxic CTLess-toxic CT Cure Cure Long OS QoL Criticism: solely based on DISEASE characteristics
  • 12. mCRC: ESMO Clinical Practice Guidelines http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Metastatic-Colorectal-Cancer Group 0Group 0 Group 1Group 1 Group 2Group 2 Group 3Group 3 Resectable R0 Convertible Unlikely resectable/High tumor burden Never resectable Surgery/ +/- Adj CTSurgery/ +/- Adj CT Conversion CT/SurgeryConversion CT/Surgery Conversion CT/SurgeryConversion CT/Surgery Less-toxic CTLess-toxic CT FOLFOX FOLFOXIRI-Bev FOLFIRI-Cet FOLFOX-Bev XELOX-Bev FOLFOX-Cet FOLFIRI-Cet FP-Bev Criticism: solely based on DISEASE characteristics
  • 14. CAPOX + Bevacizumab 6 meses “Continuum of care” in mCRC – “blurring line descriptions” Cape + Bevacizumab Hasta progresión 1o línea FOLFIRI + Bevacizumab Oxaliplatino hasta neuropatía QT + Bevacizumab Hasta progresión 2o línea Cetuximab +/- Irinotecán Regorafenib Hasta progresión ≥3o línea (KRAS nativo) Hasta progresión CAIRO-3 TML Cunningham D, et al. N Engl J Med 2004;351:337-45. CORRECT Trial (Van Cutsem 2012)
  • 15. In the RAS wt, which first-line agent?
  • 16. clinicaloptions.com/oncology Optimizing Treatment of Metastatic Colorectal Cancer Mutations in KRAS, NRAS, and BRAF Distribution and Prognostic Significance BRAF mutation All patients Any mutation KRAS mutation KRAS WT All WT Mutation Status 0 6 12 MedianPFS (Mos) Arm A Arm B 0 6 12 18 MedianOS (Mos) 57 340 268 815 367 289 45 366 297 815 362 292 0 10 20 30 40 2-YrOS(%) Prognostic Effect of Mutational Status “All WT” n = 581 (44%) KRAS MT n = 565 (43%) NRAS MT n = 50 (4%) BRAF MT n = 102 (8%) Total N = 1316 (81%) 554 11 39 10 2 Population n (%) Arm A Arm B ITT 1630 815 815 Assessed for mutations 1316 648 668  KRAS mutation  NRAS mutation  BRAF mutation 565 (43) 50 (4) 102 (8) 268 18 57 297 32 45 KRAS WT 729 (55) 367 362 KRAS/NRAS/BRAF WT “All WT” 581 (44) 289 292 Maughan TS, et al. ASCO 2010. Abstract 3502.
  • 17. clinicaloptions.com/oncology Optimizing Treatment of Metastatic Colorectal Cancer Phase III 80405 Trial: First-line CT + Either Cetux or Bev in KRAS-WT mCRC  Primary endpoint: OS  Secondary endpoints: ORR, PFS, TTF, duration of response Patients with mCRC and KRAS WT (codons 12, 13), ECOG PS 0/1 (N = 1137) FOLFOX or FOLFIRI + Bevacizumab q2w (n = 559) ClinicalTrials.gov. NCT00265850. Venook AP, et al. ASCO 2014. LBA3.. FOLFOX or FOLFIRI + Cetuximab q1w (N = 578) A third arm with CT + bevacizumab + cetuximab was closed to accrual in September 2009
  • 18. clinicaloptions.com/oncology Optimizing Treatment of Metastatic Colorectal Cancer CALGB/SWOG 80405: OS in the ITT Population mOS (95% CI), mos CT + Cetux 29.9 (27.0-32.9) CT + Bev 29.0 (25.7-31.2) HR 0.925 (0.78-1.09) P = 0.34 Venook AP, et al. ASCO 2014. Abstract LBA3. 0 12 24 36 48 60 72 Mos 80 100 60 40 0 OS(%) 20 84
  • 19. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Alan P. Venook. Proc ASCO, 2016, 3504 .
  • 20. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Alan P. Venook. Proc ASCO, 2016, 3504 .
  • 21. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Alan P. Venook. Proc ASCO, 2016, 3504 .
  • 22. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Alan P. Venook. Proc ASCO, 2016, 3504 .
  • 23. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Alan P. Venook. Proc ASCO, 2016, 3504 .
  • 24. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Alan P. Venook. Proc ASCO, 2016, 3504 .
  • 25. The relationship between primary tumor sidedness and prognosis in colorectal cancer. Deborah Schrag Proc ASCO, 2016, 3505 .
  • 26. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ( EGFR) therapy. Michael Sangminα Lee Proc ASCO, 2016, 3505 .
  • 27. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ( EGFR) therapy. Michael Sangminα Lee Proc ASCO, 2016, 3505 .
  • 28. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ( EGFR) therapy. Michael Sangminα Lee Proc ASCO, 2016, 3505 .
  • 29. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ( EGFR) therapy. Michael Sangminα Lee Proc ASCO, 2016, 3505 .
  • 30. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ( EGFR) therapy. Michael Sangminα Lee Proc ASCO, 2016, 3505 .
  • 31. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ( EGFR) therapy. Michael Sangminα Lee Proc ASCO, 2016, 3505 .
  • 32. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ( EGFR) therapy. Michael Sangminα Lee Proc ASCO, 2016, 3505 .
  • 33. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ( EGFR) therapy. Michael Sangminα Lee Proc ASCO, 2016, 3505 .
  • 34. Association of primary (1°) site and molecular features with progression-free survival (PFS) and overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor ( EGFR) therapy. Michael Sangminα Lee Proc ASCO, 2016, 3505 .
  • 35. Side Matters. Kimmie Ng Proc ASCO, 2016, Dicussion .
  • 36. What should we do with BRAF mutated mCRC?
  • 37. Continuum of care FULVFULV OxOx BevBev What to do in second line?
  • 38. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment Phase III ML18147 (TML): Continuing Bevacizumab Beyond Progression Standard second-line CT (oxaliplatin or irinotecan based) until PD (n = 411) Bevacizumab 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or irinotecan-based) until PD (n = 409) Progressive mCRC after BEV + standard first-line CT (either oxaliplatin or irinotecan based) (n = 820) Bennouna J, et al. Lancet Oncol. 2013;14:29-37. Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS (≤ 9 vs > 9 mos), time from last BEV dose (≤ 42 vs > 42 days), ECOG PS at baseline (0/1 vs 2)  Primary endpoint: OS  Secondary endpoints: PFS, ORR, safety
  • 39. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment Continuing Bevacizumab Beyond Progression (TML): OS, PFS OS(%) Mos CT (n = 410) BEV + CT (n = 409) 100 80 60 40 20 0 0 6 12 18 24 30 36 42 48 9.8 mos9.8 mos 11.2 mos11.2 mos Unstratified* HR: 0.81 (95% CI: 0.69-0.94; log-rank P = .0062) Stratified† HR: 0.83 (95% CI: 0.71-0.97; log-rank P = .0211) *Primary analysis method. † Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS (≤ 9 mos, > 9 mos), time from last dose of BEV (≤ 42 days, > 42 days), ECOG PS at baseline (0, ≥ 1). Bennouna J, et al. Lancet Oncol. 2013;14:29-37. 100 80 60 40 20 0 PFS(%) 0 6 12 18 24 30 36 42 Mos Unstratified* HR: 0.68 (95% CI: 0.59-0.78; log-rank P < .0001) Stratified† HR: 0.67 (95% CI: 0.58- 0.78; log-rank P < .0001) 4.1mo4.1mo 5.7 mo5.7 mo Overall Survival Progression-Free Survival
  • 40. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment Phase III VELOUR Study: FOLFIRI ± ziv- Aflibercept as Second-line Therapy in mCRC  Primary endpoint: OS  Secondary endpoints: PFS, ORR, safety, immunogenicity  No correlatives Patients with mCRC progressing on first-line oxaliplatin-based chemotherapy* (planned N = 1226) FOLFIRI + ziv-Aflibercept 4 mg/kg q2w (n = 612) FOLFIRI + Placebo q2w (n = 614) *30% had previous bevacizumab. Stratified by previous bevacizumab (yes vs no), ECOG PS (0 vs 1 vs 2) Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. ClinicalTrials.gov. NCT00561470.
  • 41. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment FOLFIRI ± ziv-Aflibercept as Second-line Therapy in mCRC (VELOUR): OS, PFS Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. Stratified HR: 0.817 (95.34% CI: 0.713-0.937; log-rank P = .0032) Placebo/FOLFIRI Median: 12.06 mos Aflibercept/FOLFIRI Median: 13.50 mos PFS(%) 100 80 60 40 20 0 Mos 0 3 6 9 12 15 18 21 24 27 30 Stratified HR: 0.758 (95% CI: 0.661- 0.869; log-rank P < .0001) Placebo/FOLFIRI Median: 4.67 mos Aflibercept/FOLFIRI Median: 6.90 mos Overall Survival Progression-Free Survival OS(%) 100 80 60 40 20 0 Mos 0 3 6 9 12 15 18 21 24 27 30 33 36 39
  • 42. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment Tabernero J, et al. Eur J Cancer. 2014;50:320-331. OS(%) 100 80 60 40 20 0 Mos 0 3 6 9 12 15 18 21 24 27 30 33 36 39 HR: 0.862 (95.34% CI: 0.673-1.104) Placebo/FOLFIRI Median: 11.7 mos Aflibercept/FOLFIRI Median: 12.5 mos Pts at Risk, n Placebo AFL 187 186 170 178 138 150 115 121 81 89 54 59 37 36 22 22 13 13 Previous Bevacizumab OS(%) 100 80 60 40 20 0 Mos 0 3 6 9 12 15 18 21 24 27 30 33 36 39 HR: 0.788 (95.34% CI: 0.699-0.927) Placebo/FOLFIRI Median: 12.4 mos Aflibercept/FOLFIRI Median: 13.9 mos Pts at Risk, n Placebo AFL 427 426 403 388 347 348 286 295 205 222 139 157 94 112 65 82 38 62 No Previous Bevacizumab 2nd -Line FOLFIRI ± ziv-Aflibercept in mCRC (VELOUR): OS by Prior Bevacizumab
  • 43. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment Phase III RAISE Study: Second-Line Ramucirumab/FOLFIRI vs FOLFIRI Patients with CRC and progression during or within 6 months of first-line bevacizumab, oxaliplatin, and a fluoropyrimidine (N = 1072) Treat until PD or unacceptable toxicity Ramucirumab 8 mg/kg + FOLFIRI q2w per cycle (n = 536) Placebo + FOLFIRI q2w per cycle (n = 536) Stratified by geographic region, KRAS mutation status, TTP after start of first-line therapy  Ramucirumab: anti-VEGFR2 antibody  Primary endpoint: OS Tabernero J, et al. Lancet Oncol. 2015;16:499-508.
  • 44. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment Ramucirumab + FOLFIRI Placebo + FOLFIRI Median OS, mo (95% CI) 13.3 (12.4-14.5) 11.7 (10.8-12.7) HR (95% CI) 0.844 (0.73-0.976) (stratified) P Value (log-rank) .0219 (stratified) Second-Line Ramucirumab/FOLFIRI vs FOLFIRI (RAISE): Overall Survival Tabernero J, et al. Lancet Oncol. 2015;16:499-508. 497 345 195 78 34 12 0536 421 269 114 53 422 0 486 329 166 66 22 2 1536 400 228 108 44 210 0 Pts at Risk, n Placebo + FOLFIRI Ram + FOLFIRI Ramucirumab + FOLFIRI Placebo + FOLFIRI OverallSurvival 0.2 0.4 0.6 0.8 1.0 0 0 6 12 18 24 30 3633 399 15 21 273 42 Mos
  • 45. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment Inhibition of neoangiogenesis Inhibition of tumor microenvironment signaling Inhibition of proliferation Regorafenib: Oral Multikinase Inhibitor Targeting Multiple Tumor Pathways Wilhelm SM, et al. Int J Cancer. 2011;129:245-255. Mross K, et al. Clin Cancer Res. 2012;18:2658-2667. Strumberg D, et al. Expert Opin Invest Drugs. 2012;21:879-889. KIT PDGFR RET PDGFR-β FGFR VEGFR1-3 TIE2 RegorafenibF Cl F F F O O O N H N H N H N Biochemical Activity Regorafenib IC50 Mean ±SD nmol/L (n) VEGFR1 13 ± 0.4 (2) Murine VEGFR2 4.2 ± 1.6 (10) Murine VEGFR3 46 ± 10 (4) TIE2 311 ± 46 (4) PDGFR-β 22 ± 3 (2) FGFR1 202 ± 18 (6) KIT 7 ± 2 (4) RET 1.5 ± 0.7 (2) RAF-1 2.5 ± 0.6 (4) B-RAF 28 ± 10 (6) B-RAFV600E 19 ± 6 (6)
  • 46. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment Phase III CORRECT: Regorafenib After Failure of Standard Therapy in mCRC  Primary endpoint: overall survival  Prior systemic, anticancer therapies (palliative) – 1-2 prior lines: 26% – 3 prior lines: 26% – ≥ 4 prior lines: 48% Patients with progression after all available standard therapy (N = 760) Arm A: Regorafenib 160 mg po qd + BSC 3 wks on, 1 wk off (n = 505) Arm B: Placebo + BSC 3 wks on, 1 wk off (n = 255) Grothey A, et al. Lancet. 2013;381:303-312. 2:1
  • 47. clinicaloptions.com/oncology Colorectal Cancer: Individualizing Therapy Beyond Second-line Treatment Regorafenib After Failure of Standard Therapy in mCRC (CORRECT): OS, PFS Primary endpoint met prespecified stopping criteria at second interim analysis (1-sided P ≤ .009279 at approximately 74% of events required for final analysis) 100 50 25 0 75 Mos From Randomization OS(%) HR: 0.77 (95% CI: 0.64-0.94; P = .0052) Regorafenib Placebo Median OS, mo 6.4 5.0 IQR 3.6-11.8 2.8-10.4 Placebo (n = 255) Regorafenib (n = 505) Grothey A, et al. Lancet. 2013;381:303-312. 0 2 4 6 8 10 12 14 Regorafenib Placebo Median PFS, mo 1.9 1.7 IQR 1.6-3.9 1.4-1.9 0 2 4 6 8 10 12 Mos From Randomization 100 50 25 0 75 PFS(%) Placebo (n = 255) Regorafenib (n = 505) HR: 0.49 (95% CI: 0.42-0.58; P < .0001 ) Overall Survival Progression-Free Survival
  • 48. Continuum of care FULVFULV OxOx BevBev FULVFULV OxOx BevBev FULVFULV BevBev FULVFULV IriIri BevBev Regor.Regor. LL TML
  • 49. Continuum of care FULVFULV OxOx BevBev FULVFULV OxOx BevBev FULVFULV BevBev FULVFULV IriIri BevBev Cetuxi.Cetuxi.
  • 50. Continuum de tratamiento en mCRC no resecable KRAS no mutado Bev+CAPOX x6 Bev+Cap Bev+CAPOX FOLFIRI+Bev Cet+/-Iri Regorafenib CAIRO-3 (2013) TML (2012) C0.17 (2008) CORRECT (2012)
  • 51. Continuum of care FULVFULV OxOx BevBev FULVFULV OxOx BevBev FULVFULV BevBev FULVFULV IriIri BevBev Regor.Regor. Capecitabina Capecitabina Capecitabina Aflibercetp
  • 52. Continuum of care FULVFULV OxOx BevBev FULVFULV OxOx BevBev FULVFULV BevBev FULVFULV IriIri BevBev Regor.Regor. Capecitabina Capecitabina Capecitabina Aflibercetp
  • 53. Continuum of care FULVFULV OxOx BevBev FULVFULV OxOx BevBev FULVFULV BevBev FULVFULV IriIri BevBev Regor.Regor. Capecitabina Capecitabina Capecitabina Aflibercetp
  • 54. Continuum of care FULVFULV OxOx BevBev FULVFULV OxOx BevBev FULVFULV BevBev FULVFULV IriIri BevBev Regor.Regor. Capecitabina Capecitabina Capecitabina Cetuxi Cetuxi Cetuxim
  • 55. Continuum of care KRAS mutated Bev+CAPOX x6 Bev+Cap Bev+CAPOX FOLFIRI+Bev Regorafenib
  • 56. What about patient related issues? What to do with a patient only able to tolerate some chemo.
  • 57. Continuum of care KRAS wt, un-fit Bev+Cap Bev+FOLFOX FOLFIRI+Bev Cet+/-Iri Regorafenib AVEX (2013)
  • 58. Continuum of care KRAS mutated, un-fit Bev+Cap Bev+FOLFOX FOLFIRI+Bev Regorafenib
  • 59. Let’s go back to curative intent
  • 60. Continuum of care SurgerySurgery FULVFULV OxOx FULVFULV OxOx IriIri SurgerySurgery FULVFULV IriIri CetCet SurgerySurgery
  • 61. FOLFIRINOX combined to targeted therapy according RAS status for colorectal cancer patients with liver metastases initially non-resectable: A phase II randomized Study—Prodige 14 – accord 21 (METHEP-2), a unicancer GI trial. Mark Ychou. Proc ASCO, 2016, Abstract 3512 Proc ASCO, 2016, Discussio . FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases (RCSM): Results of the FFCD 1102 phase II trial. JB Bachet. Proc ASCO, 2016, Abstract 3513
  • 62. Is More Better?, Steven J Cohen Proc ASCO, 2016, Discussio .
  • 63. Is More Better?, Steven J Cohen Proc ASCO, 2016, Discussio .
  • 64. Is More Better?, Steven J Cohen Proc ASCO, 2016, Discussio .
  • 65. Is More Better?, Steven J Cohen Proc ASCO, 2016, Discussio .
  • 66. Is More Better?, Steven J Cohen Proc ASCO, 2016, Discussio .
  • 67. Is More Better?, Steven J Cohen Proc ASCO, 2016, Discussio .
  • 68. Is More Better?, Steven J Cohen Proc ASCO, 2016, Discussio .
  • 69. Do THESE guidelines, guide? Maybe, but a more comprehensive strategy NEEDS to be thought –out BEFORE therapy initiation.
  • 70. Conclusions Clinical presentation Treatment toolkit Rules of engagement What WE desire Patient preference Tumor biology Cost Patient access
  • 71. As of today, clinical practice guidelines for mCRC are but a repository of treatment options filled with soft statements aimed more to convince insurers rather than to truly guide clinicians.

Notas del editor

  1. ITT, intention to treat; MT, mutation; OS, overall survival; PFS, progression-free survival; WT, wild-type
  2. Bev, bevacizumab; Cetux, cetuximab; CT, computed tomography; FOLFIRI; fluorouracil, leucovorin, irinotecan; FOLFOX; fluorouracil, leucovorin, oxaliplatin; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; q1w, every week; q2w, every 2 weeks; TTF, time to treatment failure; WT, wild type.
  3. 5-FU, 5-fluorouracil; BEV, bevacizumab; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; mCRC, metastatic colorectal cancer; OS, overall survival; PD, progressive disease; PFS, progression-free survival. Let’s take a look at the data that’s really come forward for helping us manage patients with metastatic colorectal cancer. And in particular we’re going to focus on second line and beyond because there are a lot of new choices, a lot of new trials, new medicines that have come forward in this setting, and we want to give everybody a context of how to manage it. And really, there are a lot of choices for these patients. So let’s make sure we have good clarity on this.   Now the first of these studies that really came forward into the second line with biologics is known as the TML study, and the idea behind this was that if you were on bevacizumab in first line, could you continue it on through the second line and still demonstrate benefit?
  4. CT, chemotherapy; BEV, bevacizumab; ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; OS, overall survival; PFS, progression-free survival; PS, performance score; TML, treatment with multiple lines. And in a randomized clinical trial where half got the bevacizumab on through to second line, the other half did not, we showed a survival advantage for those patients—not a very big one, a 1.4‑month improvement in survival, but it’s been an important positive impact for patients through lines of therapy. So this really established anti‑VEGF therapy through lines of therapy, using bevacizumab. It also showed a progression‑free survival advantage in those patients.
  5. ECOG, Eastern Cooperative Oncology Group; FOLFIRI, fluorouracil/leucovorin/irinotecan; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; q2w, once every 2 weeks; PFS, progression-free survival; PS, performance status. In a very similar design, the VELOUR study randomized patients in second line to FOLFIRI plus or minus ziv‑aflibercept. Very similar design to the TML. Some patients had had prior bevacizumab in this clinical trial, but it was not a requirement of this clinical trial.
  6. FOLFIRI, fluorouracil/leucovorin/irinotecan; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival. And just like the TML study, a 1.4‑month improvement in overall survival and improvement in progression‑free survival.
  7. AFL, aflibercept; FOLFIRI, fluorouracil/leucovorin/irinotecan; mCRC, metastatic colorectal cancer; OS, overall survival When we look at the subset of patients who had had prior bevacizumab, we also see an improvement in outcome there, in both PFS and OS. So even if you’d had a VEGF inhibitor in the first line, this switching to a second VEGF inhibitor was still a positive impact and, of course, supported its approval in the United States and around the world for second-line treatment in combination with FOLFIRI.
  8. CRC, colorectal cancer; FOLFIRI, fluorouracil/leucovorin/irinotecan; OS, overall survival; PD, progressive disease; TTP, time to progression. Enrollment of at least 1050 patients with 756 events for 85% power; Hazard ratio of 0.8; Median overall survival of 10 months in the control arm vs 12.5 months with ramucirumab with a 2-sided α level of 0.05. And then comes along the third of these clinical trials and the third of these medicines, a medicine called ramucirumab. Also a monoclonal antibody, but it binds again to the receptor and not to the ligand, so slightly different mechanism of action, but exactly the same design again. Second‑line metastatic colon, FOLFIRI plus or minus ramucirumab in these patients.
  9. FOLFIRI, fluorouracil/leucovorin/irinotecan; OS, overall survival; Ram, ramucirumab. Yet again we see a one and a half or so month improvement in overall survival in those patients, and again the majority of these folks had had prior VEGF therapy as well.
  10. Now I want to kind of end our discussion about the third line and beyond treatments, and a drug that we’ve had for a while now: regorafenib. You know this medicine. It’s a multitargeted tyrosine kinase inhibitor, hits a lot of different targets within cancer cells. We’re not really sure of the true mechanism of action for this drug.
  11. BSC, best supportive care; mCRC, metastatic colorectal cancer; po, orally; qd, daily. It has some VEGF activity and others, but it was tried in a randomized clinical trial known as the CORRECT study, 2:1 randomization against placebo, done around the world. And of course, this really sets a new stage for us, for the treatment of metastatic colon; this trial accrued very quickly. It showed us that there are a lot of these patients out there who’ve tried all their standard medicines and are now looking for new treatment options.
  12. IQR, interquartile range; OS, overall survival; PFS, progression-free survival. And it accrued, as I said, quickly, and it demonstrated an improvement in overall survival. Again, 1.4 months’ improvement and was enough to justify its approval both here in the United States and around the world. So it is a drug that has value, it controls our cancer in patients, and we should utilize it more.