Ponencia en el VII Congreso internacional de coloproctología, Bogotá, 18.08.2016. Con énfasis en los estudios recientes en terapia antiangiogénica, y el impacto del lado del primario en el pronóstico (y aspectos predictivos) de la enfermedad metastásica.
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Actualización en el abordaje terapéutico ante un cáncer colorrectal metastásico
1. Actualización en el abordaje terapéutico ante un cáncer
colorrectal metastásico
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia
VII Congreso Internacional de coloproctología
Bogotá, 18.08.2016
2. Page 2
Disclaimer
“Esta presentación ha sido creada por el autor de la charla y es de su
propiedad. La información, conceptos y opiniones aquí expresados son
responsabilidad del autor y no comprometen a Productos Roche S.A., sus
colaboradores o compañías vinculadas.”
7. Advances in the Treatment of Colorectal Cancer[1,2]
2000 2005 2008 2012
Capecitabine
Oxaliplatin
Cetuximab
Irinotecan
5-FU
Panitumumab
Targeted
therapies
Bevacizumab
KRAS
1. National Cancer Institute. Colon cancer treatment (PDQ). 2013.
2. National Cancer Institute. Cancer drug information. 2013.
Regorafenib
10. Median Overall Survival in
First-Line mCRC
BSC
0 6 12 18 24
Median OS (Mos)
~ 4-6 mos
12-14 mos
~ 15-16 mos
19-20 mos
5-FU/LV
FOLFOX4 or CAPEOX
IFL or FOLFIRI
21.5 mosFOLFOX6
Gallagher DJ, et al. Oncology. 2010;78:237-248.
21. 1997: humanization of A4.6.1 produces
bevacizumab
• Recombinant humanized monoclonal anti-VEGF antibody
developed from murine anti-VEGF mAb A4.6.11
• 93% human, 7% murine
• recognizes all major isoforms of
human VEGF, Kd = 8 x 10–10M
• terminal half-life 17–21 days
1. Presta, et al. Cancer Res 1997
22. CRC: Biologic Subsets That Respond
Differently to EGFR-Targeted Agents
BRAF
KRAS
EREG or AREG
PI3K PTEN
EGFR
PIP1
PIP3
Signaling to the nucleus
Low expression of EGFR
ligands → decreased response
to EGFR-targeted agents
PTEN loss of expression →
decreased response to
EGFR-targeted agents
Siena S, et al. J Natl Cancer Inst. 2009;101:1308-1324. Rizzo S, et al. Cancer Treat Rev. 2010;36 Suppl 3:S56-61.
23. CRC: Biologic Subsets That Respond
Differently to EGFR-Targeted Agents
BRAF
KRAS
EREG or AREG
PI3K PTEN
EGFR
PIP1
PIP3
Signaling to the nucleus
Low expression of EGFR
ligands → decreased response
to EGFR-targeted agents
Mutant BRAF → decreased response to
EGFR-targeted agents
PTEN loss of expression →
decreased response to
EGFR-targeted agents
Mutant KRAS → decreased
response to EGFR-targeted
agents
Siena S, et al. J Natl Cancer Inst. 2009;101:1308-1324. Rizzo S, et al. Cancer Treat Rev. 2010;36 Suppl 3:S56-61.
24. 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.
25. 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
26. 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
27. Retrospective US study of real-world costs of
cancer regimens
Cetux = cetuximab; CR = cost ratio; panit = panitumumab; PPPM = per patient per month
Johnston, et al. ASCO GI 2016. Abstract 636
Objective: to compare healthcare costs between mCRC patients treated with either 1L Avastin- or cetuximab-containing regimens,
who continued to a 2L biologic-containing regimen (Avastin, cetuximab, panitumumab, aflibercept or regorafenib)
$845
$1,402
$2,179
$4,279
$0
$1,000
$2,000
$3,000
$4,000
$5,000
PPPMcostsdifferencevs
1LAvastin/2LAvastin
1L Avastin/
2L other‡
(n=221)
1L cetux/
2L other§
(n=71)
1L Avastin/
2L cetux
(n=391)
1L cetux/
2L Avastin
(n=63)
CR=1.04
p=0.2265
CR=1.07
p=0.0101
CR=1.11
p=0.0707
CR=1.21
p=0.0012
Adjustedtotal healthcarecost differences,
with1L/2LAvastin asreference
Mean total cancer regimencosts for the 1L and 2L sequence were lower for patients who received1L Avastin-containing regimens,compared with 1L cetuximab-
containing regimens,due to the higher cost of cetuximab
The majorityof 1L Avastin patients also receivedAvastin in 2L (i.e.TML)
*regorafenib or aflibercept
‡panitumumab, regorafenib or aflibercept
§cetuximab, panitumumab, regorafenib or aflibercept
PPPMcosts
$4,070 $3,465 $3,276 $2,831 $3,570
$2,297 $1,898
$1,097
$1,066 $775 $923
$1,214
$705 $1,074
$6,738 $8,077
$7,886
$7,140
$10,067
$10,380
$12,568
$957
$1,038
$836
$795
$1,285
$1,082
$1,090
$0
$2,000
$4,000
$6,000
$8,000
$10,000
$12,000
$14,000
$16,000
$18,000
1L Avastin/
2L Avastin
n=1,606
Chemotherapy drug
Biologic drug
Chemotherapy administration
Biologic administration
1L Avastin/
2L cetux
n=391
1L Avastin/
2L panit
n=108
1L Avastin/
2L other*
n=113
1L cetux/
2L Avastin
n=63
1L cetux/
2L cetux
n=54
1L cetux/
2L other‡
n=17
$12,862
$13,646
$12,773
$11,690
$16,136
$14,464
$16,629
UnadjustedmeanPPPM cancerregimencosts
28. “Thou shall not use anti-EGFR agents
in mutated RAS CRC patients”
29. mCRC: ESMO Clinical Practice Guidelines
http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Metastatic-Colorectal-Cancer
Group 0
Group 1
Group 2
Group 3
Resectable R0
Convertible
Unlikely
resectable/High
tumor burden
Never resectable
Surgery/ +/- Adj CT
Conversion
CT/Surgery
Active CT + Biologic
Less-toxic CT
Cure
Cure
Long OS
QoL
Criticism: solely based on DISEASE characteristics
30. mCRC: ESMO Clinical Practice Guidelines
http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Metastatic-Colorectal-Cancer
Group 0
Group 1
Group 2
Group 3
Resectable R0
Convertible
Unlikely
resectable/High
tumor burden
Never resectable
Surgery/ +/- Adj CT
Conversion
CT/Surgery
Active CT + Biologic
Less-toxic CT
FOLFOX
FOLFOXIRI-Bev
FOLFIRI-Cet
FOLFOX-Bev
XELOX-Bev
FOLFOX-Cet
FOLFIRI-Cet
FP-Bev
Criticism: solely based on DISEASE characteristics
42. • No increase in serious chemotherapy-associated TEAEs
• Safety profile was consistent with known side effects of Avastin
STEAM: safety
AE = adverse event; CNS = central nervous system; TEAE = treatment-emergent adverse events
Bendell, et al. ASCO GI 2016. Abstract 492
STEAMis thefirststudy tocomparehead-to-headAvastin+ cFOLFOXIRI,
Avastin+ sFOLFOXIRIand Avastin+ FOLFOX
The resultsof STEAMconfirm findings fromTRIBE,withhigh ORR,PFSand resectionrates
TEAE of special interest for Avastin, %
Avastin + cFOLFOXIRI
(n=91)
Avastin + sFOLFOXIRI
(n=90)
Avastin + FOLFOX
(n=90)
Any TEAE of special interest 32 29 24
Grade ≥3 hypertension 20 16 12
Grade ≥3 venous thromboembolic events 5 6 6
Arterial thromboembolic events 2 4 0
Bleeding/haemorrhage (grade ≥3; any grade CNS
bleeding; grade ≥2 haemoptysis)
2 1 4
GI perforation, abscess or fistula 3 1 2
Grade ≥2 non-GI fistula or abscess 1 0 2
Grade ≥3 proteinuria 0 2 0
43. PRODIGE 14-ACCORD 21: resection rates with 1L
bi- or tri-chemotherapy plus Avastin or cetuximab
mCRCwithnon-
resectablehepatic
metastasis
Resection
yes/no
• PRODIGE 14-ACCORD 21 is a phase II, randomised
• Key eligibility criteria: hepatic metastases, not resectable with curative intent for technical (<30% remaining
liver health) or oncological (0.5 and bilateral) reasons, 1-3 lung metastase (<2cm)
• Primary endpoint: resection rate for liver metastases
• Hypothesis: increase rate of resection of hepatic metastasis from 50% with bi-chemotherapy to 70% with tri-
chemotherapy
• 94% patents had 4 cycles of chemotherapy before first evaluation
• SAEs of grade ≥3 were 27% with Avastin and 48% with cetuximab (p<0.001)
R
Bi-chemotherapy
(N=126)
Tri-chemotherapy
(N=130)
FOFIRINOX+
Avastin/cetuximab
R
FOLFIRI+
Avastin/cetuximab
FOLFOX4+
Avastin/cetuximab
Bi-chemotherapy Tri-chemotherapy p value
AEs grade ≥3, % 37.6 41.7 0.503
2-year OS, % (95% CI) 60 (48–70) 73 (62–81)
mOS, months (95% CI) 36 (23.5–40.6) Not reached 0.048
• Ychou, et al. ASCO 2016. Abstract 3512
44. 100
80
60
40
20
0
100
80
60
40
20
0
Per
chemotherapy
PRODIGE 14-ACCORD 21: resection rates with
bi- or tri-chemotherapy plus Avastin or cetuximab
FOLFIRI/FOLFOX +
Avastin/cetuximab
FOLFIRINOX +
Avastin/cetuximab
Avastin +
chemotherapy
PatientswithLMR0/R1
resection(%)
Per targeted therapy
Cetuximab +
chemotherapy
45.2%
56.9%
44.7%
55.6%
p=0.062 p=0.087
PatientswithLMR0/R1
resection(%)PRODIGE14-ACCORD21demonstratesthatcombinationof targetedtherapy(Avastinorcetuximab)withtripletchemotherapy
increases resectionrateforlivermetastasisandOS comparedwithtargetedtherapy+ doubletchemotherapy
Incidence of grade≥3SAEs waslower withAvastinthanwith cetuximab
Ychou, et al. ASCO 2016. Abstract 3512
45. Para pacientes metastásicos
marginalmente resecables
puedo aumentar la tasa de
respuesta (y, potencialmente
el % de resección R0/1) con
tripletas + biológico (ie,
FOLFOXIRI + Bevacizumab o
Cetuximab)
46. La toxicidad se incrementa
sustancialmente con la
tripleta, especialmente si se
combina con biológicos de alta
toxicidad
49. Capecitabine 1000 mg/m2BID
days 1–14, q21d +
Bevacizumab 7.5 mg/kg
day 1, q21d
Previously untreated
mCRC, age 70 years
N = 280
Randomize
1:1
Capecitabine 1000 mg/m2BID
days 1–14, q21d
Stratification factors:
– ECOG PS (0–1 vs 2)
– Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin
AVEX - Study Design
– Geographic region
• Key inclusion criteria
– ECOG PS 0–2
– Prior adjuvant chemotherapy allowed if completed >6 month before inclusion
• Key exclusion criteria
– Prior chemotherapy for mCRC or prior adjuvant anti-VEGF treatment
– Clinically significant cardiovascular disease
– Current or recent use of aspirin (>325 mg/day) or other NSAID
– Use of full-dose anticoagulants or thrombolytic agents
Cunningham D. J Clin Oncol. 2012;30(34): Abstract 337 [Gastrointestinal Cancers Symposium 2013].
Courtesy of: Fotios Loupakis
51. CASSIOPEE: Non interventional study of 1L Avastin
+ chemotherapy in patients ≥75 years with mCRC
• CASSIOPEE is a non-interventional, real world study of patients aged ≥75 years with
mCRC, treated with 1L Avastin + CT in daily practice in France
• Primary endpoints: 12-month PFS rate
• Secondary endpoints: description of patient characteristics, OS, Avastin regimen,
safety and autonomy criteria such as Lawton Instrumental Activities of Daily Living
Scale (IADL 4 items) and Balducci score.
Francois, et al. ASCO 2016. Abstract 3555
Patients aged ≥75 years with
previously untreated mCRC
(n=401)
Avastin + CT
Follow-up
to 24 months
52. CASSIOPEE: Non interventional study of 1L Avastin
+ chemotherapy in patients ≥ 75 years with mCRC
Efficacy population (n=351)
mPFS, months 9.2
12 month PFS rate, % 35.5
mOS, months 18.5
12 month OS rate 69.6
• Interim results: mOS and PFS comparable to randomised studies, and autonomy and
frailty scores unaffected by 1L Avastin + chemotherapy in elderly patients.
• Avastin-related grade ≥3 AEs =7%
• Safety was comparable to the general population
Data showed treatment benefit and acceptable safety of 1L Avastin combined with
chemotherapy in elderly patients
Francois, et al. ASCO 2016. Abstract 3555
53. Primary tumour location: retrospective single-
institution study
Please note the median OS values and K-M curves appear as presented
He, et al. ASCO GI 2016. Abstract 683
Objective: retrospective analysis of the prognostic impact of primary tumour location on survival in Chinese patients with
mCRC
Time (months)
OSestimate
1.0
0.4
0
0.6
0.2
0.8
0 48 60 84 12036 72 96 108
Avastin + chemotherapy (n=78)
Chemotherapy (n=222)
p=0.556
20.219.7
2412
OSestimate
1.0
0.4
0
Time (months)
0.6
0.2
0.8
Avastin + chemotherapy (n=86)
Chemotherapy (n=259)
p=0.021
0 48 60 84 12036 72 96 1082412
26.322.3
OS in patients with right-sided tumours OS in patients with left-sided tumours
OS increase with Avastin was significant in patients with left-sided tumours, but only borderline non-
significant
in patients with right-sided tumours
There was a limited number of patients in this single institution retrospective cohort study
No difference between left- vs right-sided tumours was observed in the chemotherapy-only cohort
The effect of tumour location seem to most pronounced in the WT population treated with biologics
54. No hay razón para NO
ofrecer terapia sistémica
efectiva a pacientes con
cáncer colorrectal
metastásico porque son
ancianos.
56. Mutaciones clínicamente relevantes de la vía MAPK
Aprox. 65% mCRC
Codon 61/146 mKRAS
5%
V600E BRAF
8%
Codon 12/13 mKRAS
48%
mNRAS
6%
Schirripa M, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3613.
57. 57CONFIDENTIAL – for internal use only
Retrospective analysis of two RAS/BRAF WT, mCRC cohorts:
Cohort 1: HER2 tested by IHC / ISH, 14/97 HER2 amplified
Cohort 2: all patients HER2 tested by next generation sequencing (n=37)
HER2 amplification as a negative predictor of efficacy
of anti-EGFR inhibitors
In this retrospective analysis, HER2 amplification was indicated to be a negative predictive
biomarker of efficacy of anti-EGFR inhibitors
Raghav, et al. ASCO 2016. Abstract 3517
Cohort 1: PFS on anti-EGFR tx
Median 2.9 vs 8.1 months
(p<0.001)
Cohort 2: PFS on anti-EGFR tx
Median 2.9 vs 9.3 months
(p<0.001)
Months Months
Percentsurvival
Percentsurvival
HER2 amplified
HER2 non-amplified
HER2 amplified
HER2 non-amplified
58. Primary tumour location
• Incidence: ~40% (increasing)
• Older patients
• Microsatellite instability
• BRAF mutations
• Worse prognosis
Right-sided tumours
• Incidence: ~60%
• Younger patients
• Predominantly WT
• Better prognosis
Left-sided tumours
R L
Iacopetta, et al. Int J Cancer 2002; Brule, et al. ASCO 2013. Abstract 3528;
Missiaglia, et al. ASCO 2013. Abstract 3526
59. CALGB 80405: retrospective analysis of
effect of primary tumour location on OS and PFS
Venook, et al. ASCO 2016. Abstract 3504
• CALGB 80405 (NCT00265850) is a phase III, randomised, open-label study
• Primary endpoint: OS
• Secondary endpoints: PFS, time to treatment failure, DoR
Avastin + FOLFOX/FOLFIRI
Previously untreated
patients with mCRC
(N=1137 KRAS WT)
252 KRAS MT patients
enrolled prior to KRAS
WT protocol amendment
Cetuximab + FOLFOX/FOLFIRI
R
All KRAS Avastin Cetuximab All KRAS All KRAS Avastin Cetuximab
Right Left Right Left Right Left Right Left Right Left Right Left Right Left
OS 19.4 33.3 24.2 31.4 16.7 36.0 23.1 30.3 PFS 8.9 11.7 9.6 11.2 7.8 12.4
HR (95% 1.55
(1.32–1.82)
1.32
(1.05–1.65)
1.87
(1.48–2.32)
1.28
(0.95–1.73)
HR (95% 1.03
(1.11–1.50)
1.06
(0.86–1.31)
1.56
(1.26–1.94)
p value <0.0001 0.01 <0.0001 p value 0.0006 0.55 <0.0001
60. CALGB 80405: OS by primary tumour location
1.0
OSestimate
0.8
0.6
0.4
0.2
0
0 12 24 36 48 60 108
Time (months) Time (months)
1.0
OSestimate
0.8
0.6
0.4
0.2
0
Left
Right
HR=1.55 (1.32–
1.82)
p<0.0001
Left/Avastin
Right/Avastin
72 84 96
Total population By treatment
0 12 24 36 48 60 10872 84 96
19.4 33.3
16.7
24.2 36.0
31.4
This CALGB 80405 retrospective subset analysis was hypothesis generating
and should be interpreted with caution
Primary tumour location is a prognostic factor for poorer outcome in patients with right-sided tumours
irrespective of therapy
More biomarker data are needed to fully understand the predictive value of these data
In previous studies, Avastin has consistently shown efficacy in both right- and left-sided tumours
Cetuximab vs Avastin
HR (95% CI) p value
Left 0.817
(95% CI: 0.69–0.96)
0.018
Righ
t
1.269
(95% CI: 0.98–1.63)
0.065
Venook, et al. ASCO 2016. Abstract 3504
Left/Cetuximab
Right/Cetuximab
61. Relationship between primary tumour
sidedness and prognosis in CRC
• Observational analysis from the SEER database
• Primary endpoints: median OS and 3-year OS
Provides further evidence from a large population that right-sided stage III and IV tumours are associated with
poor survival
Stage III and IV
primary CRC
PD
SEER
analysis
Stage IV (N=64,770) Stage III (N=91,009)
Right Left Rectal Right Left Rectal
mOS (months) 9.5 15.5 15.5 62.5 93.5 85.5
Survival probability
Unadjusted HR (95% CI)
1.32 (1.30– 1.0 1.01 (0.99– 1.35 (1.32– 1.0 1.03 (1.01–
Survival probability
Adjusted HR (95% CI)
1.25 (1.22– 1.0 0.83 (0.81– 1.12 (1.09– 1.0 1.11 (1.08–
Schrag, et al. ASCO 2016. Abstract 3505
62. Association of tumour location and molecular
features with PFS and OS after anti-EGFR therapy
• Retrospective study
• Primary endpoint: PFS
• Secondary endpoint: OS
Right CIMP-High BRAF MT NRAS MT
PFS, HR (95% CI); p value 1.56 (1.01–2.41);
0.040
2.38 (1.47–
3.85); 0.0006
2.14 (1.26–3.65);
0.004
2.12 (1.23–3.65);
0.006
OS, HR (95% CI); p value 1.45 (1.04–2.01);
0.028
1.53 (1.08–
2.16); 0.001
2.46 (1.61–3.74);
<0.0001
NA
KRAS WT mCRC treated
with anti-EGFR therapy
(N=198)
CIMP testing
BRAF, NRAS
and PIK3CA
sequencing
MSI status
• On multivariate analysis, BRAF MT (p=0.001), and NRAS MT (p=0.060) remained significant for OS, but primary
tumour location did not (p=0.121)
• Right-sided CRC and CIMP-high were associated with hypermethylation of EREG and AREG, and distinct expression
patterns of consensus molecular subtypes (CMS) 1 and 3
Lee, et al. ASCO 2016. Abstract 3506
Right-sided tumours were associated with inferior OS and PFS after anti-EGFR therapy
Factors influencing outcome in right-sided tumours were BRAF MT, NRAS MT, molecular subtypes,
and tumour methylation
63. Primary tumour location: combined analysis of
JACCRO CC-05 and -06 studies
Sunakawa, et al. ASCO GI 2016. Abstract 613
Cetuximab + mFOLFOX6
(n=57)
Cetuximab + S-1 + oxaliplatin
(n=67)
Patients with KRAS exon 2 WT mCRC
with EGFR-expressing tumours
JACCRO CC-05
JACCRO CC-06
Objective: to assess the prognostic impact of primary tumour location on clinical outcomes of Japanese patients with
KRAS exon 2 WT mCRC enrolled in the JACCRO CC-05 or -06 trials
PFS in ITT population OS in ITT population
Time (months)
0 6 12 18 24 30 36 42
5.6 11.1
Left-sided tumours (n=90)
Right-sided tumours (n=20)
HR=0.47 (95% CI: 0.28–0.80);
p=0.0041
1.0
PFSestimate
0.8
0.6
0.4
0.2
0
Time (months)
12.6 36.2
Left-sided tumours (n=90)
Right-sided tumours (n=20)
HR=0.28 (95% CI: 0.15–0.52);
p<0.0001
0 6 12 18 24 30 36 42 48
1.0
OSestimate
0.8
0.6
0.4
0.2
0
64. Primary tumour location: combined analysis of
JACCRO CC-05 and -06 studies
Sunakawa, et al. ASCO GI 2016. Abstract 613
PFS in FOLFOX group
Left-sided tumours (n=43)
Right-sided tumours (n=9)
HR=0.15 (95% CI: 0.06–0.37);
p<0.0001
Time (months)
5.7 42.8
0 6 12 18 24 30 36 42 48
1.0
OSestimate
0.8
0.6
0.4
0.2
0
OS in FOLFOX group
Primary tumour location may be a negative predictive factor in patients with mCRC and KRAS WT tumours who
receive
cetuximab + oxaliplatin-based therapy
Left-sided tumours (n=43)
Right-sided tumours (n=9)
HR=0.26 (95% CI: 0.12–0.56); p=0.0002
Time (months)
3.0
11.3
0 6 12 18 24 30 36 42
1.0
PFSestimate
0.8
0.6
0.4
0.2
0
65. 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 (αEGFR) therapy.
Michael Sangmin Lee
66. 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 (αEGFR) therapy.
Michael Sangmin Lee
67. 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 (αEGFR) therapy.
Michael Sangmin Lee
Proc ASCO, 2016, 3505
.
68. 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 (αEGFR) therapy.
Michael Sangmin Lee
69. 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 (αEGFR) therapy.
Michael Sangmin Lee
70. 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 (αEGFR) therapy.
Michael Sangmin Lee
71. 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 (αEGFR) therapy.
Michael Sangmin Lee
72. 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 (αEGFR) therapy.
Michael Sangmin Lee
73. 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 (αEGFR) therapy.
Michael Sangmin Lee
74. Los pacientes con cáncer
de colon metastásico
derechos tienen una
biología compleja que
posiblemente causan
alteraciones a las vías de
señalización intracelular
(mBRAF, MSI, disminución
del AREG, EREG, etc).
La terapia anti-VEGF es igualmente
eficaz, pues es de entorno y no contra
la célula maligna directamente
75. BEV + standard first-
line CT (either
oxaliplatin or
irinotecan-based)
(n=820)
Randomise 1:1
Standard second-line CT (oxaliplatin
or irinotecan-based) until PD
(n=411)
BEV (2.5 mg/kg/wk) +
standard second-line CT (oxaliplatin
or irinotecan-based) until PD
(n=409)
PD
TML18147 study design (phase III)
CT switch:
Oxaliplatin → Irinotecan
Irinotecan → Oxaliplatin
Study conducted in 220 centres in Europe and Saudi Arabia
Primary endpoint • OS from randomisation
Secondary endpoints
included
• PFS
• Best overall response rate
• Safety
Exploratory endpoints • Tumour, plasma and DNA biomarkers
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)
Statistical considerations • Designed to detect 30% (HR 0.77) improvement in median OS
(90% power, 2-sided 5%); 613 events required for analysis
78. • 110 patients with KRAS WT mCRC refractory to 1L Avastin + FOLFIRI were randomised to receive either
cetuximab + irinotecan followed by FOLFOX, or vice versa
• A trend of better PFS (HR=0.83; p=0.35) and OS (HR=0.77;p=0.22) was observed in patients who received 2L FOLFOX
3L cetuximab + irinotecan compared with patients who received 2L cetuximab + irinotecan 3L FOLFOX
Sequence of treatment
3L = third line
• 1. Cascinu, et al. ASCO GI 2016. Abstract 632
• 2. Burge, et al. ASCO GI 2016. Abstract 685
COMETS study: analysis of cetuximab treatment sequence after 1L Avastin-based therapy (Cascinu, et al. Abstract
632)1
Real-world Australian study on impact of 1L Avastin on subsequent anti-EGFR monotherapy (Burge, et al. Abstract
685)2
This study confirms the Avastin TML approach, as the highest effect was seen with the use of 3L anti-EGFRs
Conclusion on 1L treatment cannot be drawn from this study which only assessed 2L or 3L treatments
Prior Avastin treatment did not make tumours more or less sensitive to subsequent anti-EGFR therapy
• 77 patients had received 1L Avastin prior to 2L/3L anti-EGFR monotherapy, according to ACCORD and TRACC
registries
• 1L Avastin treatment did not impact on efficacy of subsequent anti-EGFR monotherapy
– Median PFS 2.7 vs 3.1 months (HR=1.03; p=0.95) in patients who received 1L Avastin vs those who did not
– Median OS 8.9 vs 8.6 months (HR=0.95, p=0.80)
• For Avastin-treated patients, the time since last dose of Avastin to start of anti-EGFR did not impact on PFS or OS
79. Nuevo en mCRC en 2016
El lado importa
Re-examine las opciones biológicas en tumores del lado derecho
Tentativa: algunos tumores resecables pueden entrar en CR con
quimioterapia + bevacizumab
La edad en sí misma no debe ser criterio de exclusión para terapia
sistémica en mCRC