Actualización en el abordaje terapéutico ante un cáncer colorrectal metastásico
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Transcript of Actualización en el abordaje terapéutico ante un cáncer colorrectal metastásico
Actualización en el abordaje terapéutico ante un cáncer colorrectal metastásico
Mauricio Lema Medina MDClínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia
VII Congreso Internacional de coloproctologíaBogotá, 18.08.2016
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.”
Mauricio Lema: Conflicto de interés
Roche
@onconerd
FULV
Capec
Iri
Bev
Cet
Pan
TKI
Surgery
Ablative Rx
OxOther anti
VEGF
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
Access to Chemotherapy Improves Survival
Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.
22
20
18
16
14
12
Med
ian
OS
(Mos
)
0 20 40 60 80Patients With 3 Drugs (%)
LV5FU2Bolus 5-FU/LV
Infusional 5-FU/LV+ irinotecanInfusional 5-FU/LV+ oxaliplatinBolus 5-FU/LV+ irinotecanIrinotecan+ oxaliplatin
First-line therapy
0102030405060708090
100
0 1 2Years
% A
live
IFL (med 15.0 mo)FOLFOX4 (med 19.5 mo)IROX (med 17.4 mo)
FOLFOX4 vs IFL (P=.0001; HR=0.66) IROX vs IFL (P=.04)
N9741: Overall Survival
Goldberg et al. J Clin Oncol. 2004;22:23.
Median Overall Survival in First-Line mCRC
BSC
0 6 12 18 24Median 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.
Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol 2003;200:183-194.
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
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.
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.
Mutations in KRAS, NRAS, and BRAF Distribution and Prognostic Significance
BRAF mutation All patientsAny mutationKRAS mutation
KRAS WTAll WT
Mutation Status
0
6
12
Med
ian
PFS
(Mos
)
Arm A Arm B
0
6
12
18
Med
ian
OS
(Mos
)
57 340
268
815
367
289
45 366
297
815
362
2920
10
20
30
40
2-Yr
OS
(%)
Prognostic Effect of Mutational Status
“All WT”n = 581 (44%)
KRAS MTn = 565 (43%)
NRAS MTn = 50 (4%)
BRAF MTn = 102 (8%)
TotalN = 1316 (81%)
554
1139
102
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)
2681857
2973245
KRAS WT 729 (55) 367 362
KRAS/NRAS/BRAF WT“All WT”
581 (44) 289 292
Maughan TS, et al. ASCO 2010. Abstract 3502.
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
CALGB/SWOG 80405: OS in the ITT Population
mOS (95% CI), mosCT + 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.
012 24 36 48 60 72
Mos
80
100
60
40
0
OS
(%)
20
84
Retrospective US study of real-world costs of cancer regimens
Cetux = cetuximab; CR = cost ratio; panit = panitumumab; PPPM = per patient per monthJohnston, 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)
$0
$1,000
$2,000
$3,000
$4,000
$5,000
$845
$1,402
$2,179
$4,279
PPPM
cos
ts d
iffer
ence
vs
1L A
vasti
n/2L
Ava
stin
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=1.04p=0.2265
CR=1.07p=0.0101
CR=1.11p=0.0707
CR=1.21p=0.0012
Adjusted total healthcare cost differences,
with 1L/2L Avastin as reference
Mean total cancer regimen costs for the 1L and 2L sequence were lower for patients who received 1L Avastin-containing regimens, compared with 1L cetuximab-containing regimens,
due to the higher cost of cetuximab
The majority of 1L Avastin patients also received Avastin in 2L (i.e. TML)
*regorafenib or aflibercept ‡panitumumab, regorafenib or aflibercept§cetuximab, panitumumab, regorafenib or aflibercept
PPPM
cost
s
$0
$2,000
$4,000
$6,000
$8,000
$10,000
$12,000
$14,000
$16,000
$18,000
$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
1L Avastin/2L Avastinn=1,606
Chemotherapy drugBiologic drugChemotherapy administrationBiologic administration
1L Avastin/2L cetuxn=391
1L Avastin/2L panitn=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
Unadjusted mean PPPM cancer regimen costs
“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 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
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-BevFOLFIRI-Cet
FOLFOX-BevXELOX-BevFOLFOX-CetFOLFIRI-Cet
FP-Bev
Criticism: solely based on DISEASE characteristics
Grupos 0 y 1
Quirúrgicos
OS after resection in liver metastasis
Adam R, Oncologist, 2012
OS after resection in liver metastasis
Adam R, Oncologist, 2012
Avastin(n=205)
NED, % (95% CI) Patients without detectable metastatic disease (n=194) 47 (40–55)
No detectable metastases after surgery 85 (76–91)
No detectable metastases after complete response 4 (1–11)
mPFS, months (95% CI) 11.5 (10.4–12.4)
36-month OS rate, % (95% CI) 52 (44–59)
PICASSO: prospective, non-interventional cohort study
Malka, et al. ASCO 2016. Abstract 3554
Untreated mCRC with potentially resectable
liver and/or lung metastases(N=218)
• Primary endpoint: Patients without detectable metastatic disease • Secondary endpoints: PFS, relapse-free survival after surgery, OS, safety, criteria to define patients
unresectability
Avastin + chemotherapy
Primary endpoint
OS for the total efficacy population was not reached
35CONFIDENTIAL – for internal use only
PICASSO: final efficacy results
Use of 1L Avastin + chemotherapy was effective in mCRC patients with potentially resectable
lung/liver metastases
Secondary resection rate of 47% resulted in a high 3-year OS rate (52%)
Without detectable metastatic disease (n=92)
With detectable metastatic disease (102)
mPFS, months (95% CI) 15.7 (12.9–18.9) 8.7 (7.8–10.4)
36-month PFS, % (95% CI) 21 (1330) 3 (19)
1.0
OS
estim
ate
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 42
Time (months)
OS(total population)
24 3027 36 3933
Time (months)
1.0
PFS
estim
ate
0.8
0.6
0.4
0.2
0
PFS (with or without detectable metastases)
No detectable metastatic disease
Detectable metastatic disease
0 3 6 9 12 15 18 21 4224 3027 36 3933
mOS not reached
Malka, et al. ASCO 2016. Abstract 3554
OS after resection in liver metastasis, after preoperative chemotherapy
Adam R, Oncologist, 2012
FOLFIRI+bev (up to 12 cycles)
5FU/LV +Bev
508 mCRC pts 1st line unresectablestratified by center PS 0/1-2 adjuvant CT
R PD
FOLFOXIRI+bev 5FU/LV +Bev (up to 12
cycles)
TRIBE Study Design
INDUCTIONMAINTENANCE
Primary Endpoint: PFSSecondary Endpoints:
Response rate, secondary R0-resection rate, safety profile, biomarkers evaluation
Falcone A, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3505
Courtesy of: Fotios Loupakis
FOLFIRI + bevFOLFOXIRI + bev
-Fre
e Su
rviv
al P
roba
bilit
y
Median follow-up: 32.3 mos
FOLFIRI + bev: N = 256 / Progressed = 226 FOLFOXIRI + bev: N = 252 / Progressed = 213
FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.1 mos
Unstratified HR: 0.77 [0.64-0.93] P = .006
Prog
ress
ion Stratified HR: 0.75 [0.62-
0.90] P = .003
Follow-Up Time, Months
Primary Endpoint: PFS
Falcone A, et al. J Clin Oncol. 2013;31(Suppl):Abstract 3505
Courtesy of: Fotios Loupakis
Secondary Endpoint: Response Rate
Falcone A, et al. J Clin Oncol. 2013;31(Suppl):Abstract 3505
FOLFIRI + bev
N = 256Best Response, %
FOLFOXIRI + bev
N = 252 P
Complete Response 3% 5%
Partial Response 50% 60%
Response Rate 53% 65% .006
Stable Disease 32% 25%
Progressive Disease 11% 6%
Not Assessed 4% 4%
Courtesy of: Fotios Loupakis
• STEAM is a phase II, randomised, open-label, US-based study
• Primary endpoints: – Investigator-assessed ORR during 1L therapy for Avastin + concurrent FOLFOXIRI vs Avastin + FOLFOX– PFS during 1L therapy (PFS1) for Avastin + FOLFOXIRI regimens (concurrent and sequential) vs
Avastin + FOLFOX
STEAM: preliminary efficacy results
1L = first line; 2L = second line; 5-FU = 5-fluorouracil; CI = confidence interval; FP = fluoropyrimidine; LV = leucovorin; ORR = overall response rate; PD1 = progression on 1L therapy; PD2 = progression on 2L therapy
Bendell, et al. ASCO GI 2016. Abstract 492
Treatment-naïve patients
with mCRC(N=280)
R
Avastin + concurrent FOLFOXIRI
(n=93)Avastin + sequential FOLFOXIRI
(n=92) Avastin + FOLFOX
(n=95)
Avastin + 5-FU/LV
or
Avastin + capecitabine
PD1
PD2
Avastin + FP-based
chemotherapy (investigator’
s choice)
Induction Maintenance
2L
Avastin + cFOLFOXIRI
(n=93)Avastin +
sFOLFOXIRI (n=92)
Pooled Avastin + FOLFOXIRI(n=185)
Avastin + FOLFOX(n=95)
ORR, % 60.2 62.0 61.1 47.4Odds ratio vs Avastin + FOLFOX (90% CI); p value
1.7 (1.05–2.77); p=0.075
1.8(1.12–2.97); p=0.040
1.8(1.16–2.68); 0.025
STEAM: interim PFS and liver resection rates
*Stratified HR vs Avastin + FOLFOXAvastin + cFOLFOXIRI: HR=0.672 (90% CI: 0.489–0.922)Avastin + sFOLFOXIRI: HR=0.738 (90% CI: 0.537–1.012)HR = hazard ratio; ITT = intent-to-treat
Bendell, et al. ASCO GI 2016. Abstract 492
Interim PFS (ITT population)
Interim PFS (pooled Avastin + FOLFOXIRI vs Avastin +
FOLFOX)
PFS
est
imat
e
1.0
0.4
0
Time (months)0
0.6
0.2
0.8
11.49.3
Pooled Avastin + FOLFOXIRI (n=185)Avastin + FOLFOX (n=95)HR=0.704 (90% CI: 0.537–0.923)
3 9 12 18 276 15 21 24Time (months)
PFS
est
imat
e
1.0
0.4
0
0.6
0.2
0.8
0 9 12 18 276 15 21 24
Avastin + cFOLFOXIRI (n=93)*Avastin + sFOLFOXIRI (n=92)*Avastin + FOLFOX (n=95)
10.79.3
3
11.7
Avastin + cFOLFOXIRI
(n=93)
Avastin + sFOLFOXIRI
(n=92)
Pooled Avastin + FOLFOXIRI(n=185)
Avastin + FOLFOX(n=95)
Liver resection rates, % 15.1 9.8 12.4 7.4R0 resection rates, % 15.1 8.7 11.9 6.3
• 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 eventsBendell, et al. ASCO GI 2016. Abstract 492
STEAM is the first study to compare head-to-head Avastin + cFOLFOXIRI, Avastin + sFOLFOXIRI and Avastin + FOLFOX
The results of STEAM confirm findings from TRIBE, with high ORR, PFS and resection rates
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
PRODIGE 14-ACCORD 21: resection rates with 1Lbi- or tri-chemotherapy plus Avastin or cetuximab
mCRC with non-
resectable hepatic
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/cetuxi
mab
R
FOLFIRI + Avastin/cetuxi
mabFOLFOX4 +
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
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
Patie
nts w
ith L
M R
0/R1
re
secti
on (%
)
Per targeted therapy
Cetuximab + chemotherapy
45.2%
56.9%
44.7%55.6%
p=0.062 p=0.087
Patie
nts w
ith L
M R
0/R1
re
secti
on (%
)PRODIGE 14-ACCORD 21 demonstrates that combination of targeted therapy (Avastin or cetuximab) with triplet chemotherapy increases resection rate for
liver metastasis and OS compared with targeted therapy + doublet chemotherapy
Incidence of grade ≥3 SAEs was lower with Avastin than with cetuximab
Ychou, et al. ASCO 2016. Abstract 3512
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)
La toxicidad se incrementa sustancialmente con la tripleta, especialmente si se combina con biológicos de alta toxicidad
Grupo 3
No resecables
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
1.0 Cape + BEV (n = 140) Cape (n = 140) 0.8
HR=0.53 (95% CI: 0.41–0.69) 0.6 P<.00
1 0.4
0.2
5.1 mo 9.1 mo 0.0
Progression-Free Survival PF
S Es
timat
e
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Time, Months
Cunningham D. J Clin Oncol. 2012;30(34): Abstract 337 [Gastrointestinal Cancers Symposium 2013]. Courtesy of: Fotios Loupakis
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
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
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)
OS e
stim
ate
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
OS e
stim
ate
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 108241226.322.3
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 tumoursThere was a limited number of patients in this single institution retrospective cohort studyNo difference between left- vs right-sided tumours was observed in the chemotherapy-only
cohortThe effect of tumour location seem to most pronounced in the WT population treated with
biologics
No hay razón para NO ofrecer terapia sistémica efectiva a pacientes con cáncer colorrectal metastásico porque son ancianos.
Grupo 2
Alta carga tumoral, no resecables
55
Mutaciones clínicamente relevantes de la vía MAPKAprox. 65% mCRC
Codon 61/146 mKRAS5%
V600E BRAF
8%
Codon 12/13 mKRAS48%
mNRAS6%
Schirripa M, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3613.
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 txMedian 2.9 vs 8.1 months(p<0.001)
Cohort 2: PFS on anti-EGFR txMedian 2.9 vs 9.3 months(p<0.001)
Months Months
Perc
ent s
urvi
val
Perc
ent s
urvi
val
HER2 amplifiedHER2 non-amplified
HER2 amplifiedHER2 non-amplified
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
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/FOLFIRIPreviously 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 WT Avastin
Cetuximab
All KRAS MT
All KRAS WT Avastin
Cetuximab
Right Left
Right Left
Right Left
Right Left
Right Left
Right Left
Right Left
OS (months)
19.4
33.3
24.2
31.4
16.7
36.0
23.1
30.3
PFS (months)
8.9 11.7
9.6 11.2
7.8 12.4
HR (95% CI)
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% CI)
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
CALGB 80405: OS by primary tumour location
1.0
OS e
stim
ate
0.8
0.6
0.4
0.2
00 12 24 36 48 60 108
Time (months) Time (months)
1.0
OS e
stim
ate
0.8
0.6
0.4
0.2
0
LeftRightHR=1.55 (1.32–1.82)p<0.0001
Left/AvastinRight/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 generatingand 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 dataIn previous studies, Avastin has consistently shown efficacy in both right- and left-sided
tumours
Cetuximab vs Avastin
HR (95% CI)p
valueLeft 0.817
(95% CI: 0.69–0.96)
0.018
Right
1.269 (95% CI: 0.98–
1.63)
0.065
Venook, et al. ASCO 2016. Abstract 3504
Left/CetuximabRight/Cetuximab
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 PDSEER
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 85.5Survival probability Unadjusted HR (95% CI)
1.32 (1.30–1.35)
1.0 1.01 (0.99–1.03)
1.35 (1.32–1.38)
1.0 1.03 (1.01–1.06)
Survival probabilityAdjusted HR (95% CI)
1.25 (1.22–1.27)
1.0 0.83 (0.81–0.85)
1.12 (1.09–1.15)
1.0 1.11 (1.08–1.14)
Schrag, et al. ASCO 2016. Abstract 3505
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 MTPFS, HR (95% CI); p value 1.56 (1.01–
2.41); 0.0402.38 (1.47–
3.85); 0.00062.14 (1.26–3.65);
0.0042.12 (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 sequencingMSI 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
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
PFS
estim
ate
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
OS e
stim
ate
0.8
0.6
0.4
0.2
0
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 4248
1.0
OS e
stim
ate
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 3642
1.0
PFS
estim
ate
0.8
0.6
0.4
0.2
0
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
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
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.
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
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
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
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
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
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
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
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 → IrinotecanIrinotecan → 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
Overall survival (ITT population)O
S es
timat
e
Time (months)
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42 48
No. at riskCT 410 293 162 51 24 7 3 2 0BEV + CT 409 328 188 64 29 13 4 1 0
CT (n=410)BEV + CT (n=409)
9.8 11.2
Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)p=0.0062 (log-rank test)
Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)p=0.0211 (log-rank test)
aPrimary analysis method. bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG PS at baseline (0, ≥1)
Progression-free survival (ITT population)PF
S es
timat
e
Time (months)
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42
No. at riskCT 410 119 20 6 4 0 0 0BEV + CT 409 189 45 12 5 2 2 0
CT (n=410)BEV + CT (n=409)
4.1 5.7
Unstratifieda HR: 0.68 (95% CI: 0.59–0.78) p<0.0001 (log-rank test)
Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)p<0.0001 (log-rank test)
aPrimary analysis method. bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG PS at baseline (0, ≥1)
• 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 6322. 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
Nuevo en mCRC en 2016
El lado importaRe-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
@Onconerd