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SAGLB.AFL.17.03.0196a (06/17)SAGLB.AFL.17.03.0196a (06/17)
SAGLB.AFL.17.03.0196a (06/17)
The role of maintenance treatment– and what to do after 1st line ?
Instituto CUF de Oncologia
Lisboa, Portugal
Asklepios Tumorzentrum Hamburg
AK Altona , Abt. Onkologie, Hämatologie und Palliativmedizin
ATZ: Organisationsfelder
„Disease
Track /
Programs“
per Tumorentität
Klinische
„Core
Facilities“
unabhängig von
Tumorentität
QM /
Zertifizierung /
Register
Fortbildung /
Veranstaltung
Studien /
Wissenschaft
Marketing / PR
Klinischer Bereichadministrativer
Bereich
Ergänzende
klinische
Angebote
unabhängig von
Tumorentität
SAGLB.AFL.17.03.0196a (06/17)SAGLB.AFL.17.03.0196a (06/17)
• Participate on Advisory Board with:
Roche, Merck Serono, Amgen, Bayer, Servier, Sanofi, BTG, Lilly
• Speaker and Chairman for educational events with:
Boston Scientific, BTG, Roche, Merck Serono, Bayer, Lilly, Servier, Sanofi
• Investigator and researcher in data generating activities supported and sponsored by
Roche, Mologen, AstraZeneca, Bayer
Disclosures Dirk Arnold, 2014-2019
SAGLB.AFL.17.03.0196a (06/17)
• Diagnostic work-up and biomarkers
• Choice of treatment in 1st line
• Integration of local and ablative treatments
• The principle of „continuum of care“ in mCRC
Ways to improve OS in metastatic CRC
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
SAGLB.AFL.17.03.0196a (06/17)
Induction
Best systemictreatment
Best maintenance
De-escalation ?
pause ?
other compound?
Best ablation
resection
„ablation toolbox“
severalmanifeststions,
„palliative“
Oligometastastaticdisease
„ablative“
post induction
where ?response?
Metastatic CRC: Main principles in 1st line
Arnold et al, Clin Colorect Cancer 2017
SAGLB.AFL.17.03.0196a (06/17)
OPTIMOX'Studies'
OPTIMOX/1'N=620'
FOLFOX'4'un: l'TF'
FOLFOX'7' FOLFOX'7'
sLV5FU2'
OPTIMOX/2'N=202'
mFOLFOX'7' mFOLFOX'7'
sLV5FU2'
mFOLFOX'7' mFOLFOX'7'
Chemo'free'interval'
Chibaudel'et'al.,'J'Clin'Oncol'2009'
Tournigand'et'al,'J'Clin'Oncol'2006'
„First generation maintenance trials“
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
SAGLB.AFL.17.03.0196a (06/17)Chibaudel et al., J Clin Oncol 2009
HR 0.88; p=0.42
Median 19.5 vs. 23.8 mos
(=4.3 mos. shorter OS)
„First generation maintenance trials“: OPTIMOX-2
No treatment („CFI“) vs. FP after 3 mos. combination CT
SAGLB.AFL.17.03.0196a (06/17)
“Deescalation maintenance”: Trials
1. Koopman, et al. ; 2. Arnold, et al. ASCO 2014 ; 3. Koeberle, et al. ASCO 2013
SAKK 41/063
Previously
untreated mCRC
(n=852*/452)
FP +
oxaliplatin +
Bev
(24 weeks)
With CR/PR/SD
BevN=156
FP + BevN=158
No therapyN=158
R PD
AIO 02072
Previously
untreated mCRC
n=558
XELOX + Bev
(18 weeks, x6)
With CR/PR/SD
Cape + BevN=278
No therapyN=279
R PD
CAIRO31
Primary endpoint: superiority in PFS2 (maintenance and reinduction treatment)
Primary endpoint: non-inferiority in TFS (maintenance and reinduction treatment)
Bev + CT
(16-24 weeks)
Previously
untreated mCRC
(n=262
R
BevN=131
No therapyN=131
PD
PD
Primary endpoint: non-inferiority in TTP (from randomisation)
XELOX + Bev
XELOX + Bev
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De-escalation maintenance: „Time to failure of strategy“ (TFS)
AIO: Arnold, et al. ASCO 2014; Hegewisch-Becker et al., Lancet Oncol 2015 DCCG: Koopman, et al., ASCO 2014; Simkens et al., Lancet 2015
HR nihil vs. FP/Bev: 0.76; p<0.04 HR nihil vs. FP/Bev: 0.67;
p<0.0001
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HR nihil vs. FP/Bev: 0.49; p<0.0001 HR nihil vs. FP/Bev: 0.43;
p<0.0001
AIO: Arnold, et al. ASCO 2014; Hegewisch-Becker et al., Lancet Oncol 2015 DCCG: Koopman, et al., ASCO 2014; Simkens et al., Lancet 2015
De-escalation maintenance: „Time to first progression (PFS)
SAGLB.AFL.17.03.0196a (06/17)
HR nihil vs. FP/Bev: exploratory, n.s. HR nihil vs. FP/Bev: 0.83; p=0.06
Median OS: 18.1 vs. 21.6 mos
(+3.5 mos.)
AIO: Arnold, et al. ASCO 2014; Hegewisch-Becker et al., Lancet Oncol 2015 DCCG: Koopman, et al., ASCO 2014; Simkens et al., Lancet 2015
De-escalation maintenance: Overall survival (OS)
SAGLB.AFL.17.03.0196a (06/17)
Arnold et al., ASCO 2016 (oral presentation)Stein and Arnold, Clin Colorectal Cancer 2017
Maintenance or observation after induction?
PFS
OS
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ESMO Guideline: Maintenance treatment
• Patients receiving FOLFOX or CAPOX as induction therapy should be allocated to maintenance therapy after 6–8 cycles.
• Patients receiving FOLFIRI as induction should continue for (at least) as long as tumour shrinkage continues.
• Optimal maintenance treatment after a bevacizumab-containing induction is a combination of a fluoropyrimidine plus bevacizumab. Bevacizumab monotherapy as maintenance is not recommended.
• Individualisation and discussion with the patient is essential.
Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
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Apricio et al., J Clin Oncol 2018
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Goey et al., ESMO 2016; poster discussion session
Clinical factors influencing outcome in
metastatic colorectal cancer patients treated with fluoropyrimidine and
bevacizumab (FP+Bev) maintenance treatment vs observation:
a pooled analysis of the phase 3 CAIRO3 and AIO 0207 trials
Kaitlyn Goey ● Sjoerd Elias ● Axel Hinke ● Martijn van Oijen ● Kees Punt ● Susanna Hegewisch-Becker ● Dirk Arnold ● Miriam Koopman
April 29, 2016
SAGLB.AFL.17.03.0196a (06/17)Goey, Arnold et al., Br J Cancer 2017
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RAS & BRAF wild-type RAS or BRAF mutant
Hegewisch-Becker et al., Lancet Oncol 2015
Who benefits from active maintenance?
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Reinacher-Schick, Arnold et al., Ann Oncol 2018
Figure 1A) PFS left vs. right sided mCRCs in randomized
patients.
B) PFS by maintenance arm in randomized
patients with right sided tumors.
C) PFS by mainenance arm in randomized
patients with left sided tumors.
FU=Fluoropyrimidine, Bev=Bevacizumab
A B
C
Does sidedness pedict benefit?
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Erhaltungstherapie.
40,0.
50,0.
60,0.
70,0.
80,0.
Woche.0. Woche.06. Woche.12. Woche.18. Woche.24.
FP/Bev. 57,2. 58,5. 54,1. 56,6. 56,3.
Bev. 54,3. 58,3. 58,3. 58. 55,4.
Ø.Tx. 55,1. 58,3. 58,5. 58,7. 57.
GH
S/Q
oL(s
core
( FP/Bev vs Bev: p= 0,439 FP/Bev vs Ø Tx: p= 0,486
Bev vs Ø Tx: p= 0,927
T-Test 2-sided
Koopman et al, GI Caancer Symposium 2014; Quidde et al., DGHO 2014 (presentation)
[TITLE]
Presented By Miriam Koopman, MD, PhD at 2014 Gastrointestinal Cancers Symposium
AIO 0207
CAIRO-3
100% 98% 97% 97% 95%N=427
N=491
Quality of life whilst maintenance
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Erhaltungstherapie.
0.
10.
20.
30.
40.
Abnahme der QHS/QoL Zunahme der QHS/QoL
0.
10.
20.
30.
40.
FP/Bev.
Bev.
Ø.Tx.
Patientenanzahl in %
(Mittelwert1) Patientenanzahl in %
(Mittelwert1)
1 Mittelwert über die einzelnen Messzeiträume
(Woche 6-12. 6-18, 6-24)
@ wk 24:
% of patients
with at least 10 IP
„overall HRQoL“
improvement
@ wk 24:
% of patients
with at least 10 IP
„overall HRQoL“
deterioration
AIO 0207: Quality of life analyses
Quidde et al., Ann Oncol 2016
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TRIBE2: a phase III, randomized strategy study by GONO
in the 1st- and 2nd-line treatment of unresectable
metastatic colorectal cancer (mCRC) patients (pts)
C.Cremolini, C.Antoniotti, S. Lonardi, D. Rossini, F. Pietrantonio, S.S. Cordio, S. Murgioni, F.
Marmorino, E. Maiello, A. Passardi, G. Masi, E. Tamburini, D. Santini, R. Grande, A.
Zaniboni, C. Granetto, F. Loupakis, L. Delliponti, L. Boni, A. Falcone
on behalf of the GONO Investigators
2018 ESMO Congress
Munich, 19 – 23 October 2018
SAGLB.AFL.17.03.0196a (06/17)
R
1:1
FOLFOX +
bev*
FOLFOXIRI
+ bev*
PD15FU/bev
5FU/bev
Progression Free Survival 2
FOLFIRI +
bev* PD25FU/bev
PD1FOLFOXIRI
+ bev* 5FU/bevPD2
Arm A
Arm B
* Up to 8 cycles
Intensive or sequential treatment?Tribe-2 trial
SAGLB.AFL.17.03.0196a (06/17)
Median follow up =
22.8 mos
Arm A
N = 340
Arm B
N = 339
Events, N (%) 235 (69%) 188 (55%)
Median PFS2, mos 16.2 18.9
HR = 0.69 [95% CI: 0.57-0.83] p<0.001
Intensive or sequential treatment?Tribe-2 trial, PFS 2 (= sequence)
SAGLB.AFL.17.03.0196a (06/17)
Median follow up =
22.8 mos
FOLFOX + bev
N = 340
FOLFOXIRI + bev
N = 339
Events, N (%) 288 (85%) 261 (77%)
Median PFS, mos 9.9 12.0
HR = 0.73 [95% CI: 0.62-0.87] p<0.001
Intensive or sequential treatment?Tribe-2 trial, PFS1 (= „1st line“)
SAGLB.AFL.17.03.0196a (06/17)
R
1:1
FOLFOX +
bev*
FOLFOXIRI
+ bev*
PD15FU/bev
5FU/bev
Progression Free Survival 2
FOLFIRI +
bev* PD25FU/bev
PD1FOLFOXIRI
+ bev* 5FU/bevPD2
Arm A
Arm B
* Up to 8 cycles
Intensive or sequential treatment?Tribe-2 trial
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Aranda et al., Eur J Cancer 2018
Maintenance following FOLFOX/Cet´mab: The TTD MACRO2 trial
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Maintenance following FOLFOX/Cet´mab: The TTD MACRO2 trial
Aranda et al., Eur J Cancer 2018
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VALENTINO Trial: EGFR maintenance
Pietrantonio et al., ASCO 2018
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HR = 1.55; 95% CI: 1.09-2.20; P = 0.011
Median PFS 10.2 vs. 13.0 months
VALENTINO Trial: EGFR maintenance
Pietrantonio et al., ASCO 2018
SAGLB.AFL.17.03.0196a (06/17)
HR = 1.55; 95% CI: 1.09-2.20; P = 0.011
Median PFS 10.2 vs. 13.0 months
VALENTINO Trial: EGFR maintenance
Same
treat-
ment
here!
Pietrantonio et al., ASCO 2018
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German AIO: PanaMa Trial
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Marusyk et al., Science 2013
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Re-challenge of EGFR Inhibitors?
Goldberg et al ESMO Open 2018
→ Time interval?
→ Detection?
SAGLB.AFL.17.03.0196a (06/17)
0
100
200
300
400
500
600
700
800
900C
EA (
ng/
ml)
CEA
Response by RECIST (CT scan)
Tumor burden (CT-scan)
1 32 4 5 6 7
cycles of chemotherapy
Evaluation of response to treatment in mCRC
Montagut, Siravegna & Bardelli . Ann Oncol 2015
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0
10
20
30
40
50
60
0
100
200
300
400
500
600
700
800
900
Mu
tate
d a
llele
s (%
)
CEA
(n
g/m
l)
CEA
ctDNA mutation in plasma
Molecular response by liquid
biopsy
Blood draws (ctDNA)
Tumor burden
1 32 4 5 6 7
Response by RECIST (CT scan)
cycles of chemotherapy
Evaluation of response to treatment in mCRC
Montagut, Siravegna & Bardelli . Ann Oncol 2015
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Nachweis der „erneuten Wildtypsituation“
Rossini et al., ASCO 2018
→ ORR 22%
→ DCR 54%
ctDNA for RAS/BRAF
mutations
(ddPCR+NGS)
The „again or still wildtype“ situation
SAGLB.AFL.17.03.0196a (06/17)
Wirksamkeit in Abhängigkeit des ctDNA Mutationstatus
→ Mutations in ctDNA in 48% (12/25)
→ Confirmed response only in ctDNA RAS WT (before re-induction)
The „again or still wildtype“ situation
Rossini et al., ASCO 2018
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CRICKET trial: Phase 2 single-arm study of re-challenge with cetuximab + irinotecan as 3rd-line
therapy in RAS and BRAF WT pts with acquired resistance to 1st-line cetuximab- and irinotecan-
containing therapy
CRICKET trial: Re-challenge with anti-EGFRs
Cremolini C, et al. JAMA Oncol 2019; 5:343-350
ctDNA, circulating tumor DNA
SAGLB.AFL.17.03.0196a (06/17)
Induction
chemotherapy+ antibody
„best maintenance“
De-escalation ?
pause ?
other compound?
„best ablation“
resection
„ablation toolbox“
severalmanifeststions,
„palliative“
Oligometastastaticdisease
„ablative“
post induction
where ?response?
Contemporary mCRC algorithm
SAGLB.AFL.17.03.0196a (06/17)
Induction
chemotherapy+ antibody
„best maintenance“
De-escalation ?
pause ?
other compound?
„best ablation“
resection
„ablation toolbox“
severalmanifeststions,
„palliative“
Oligometastastaticdisease
„ablative“
post induction
where ?response?
Contemporary mCRC algorithm
SAGLB.AFL.17.03.0196a (06/17)
New compounds in maintenanceBev vs. Bev/Erlotinib following combination CT/Bev induction
PFS maintenance: HR 0.81; p=0.059
Median: 4.9 vs. 5.4 mos.
OS from maintenance: HR 0.79;
p=0.036
Median: 22.1 vs. 24.9 mos.
Tournigand et al., Lancet Oncol 2015
esmo.org
FLUOROPYRIMIDINE (FP) AND BEVACIZUMAB ±
ATEZOLIZUMAB AS FIRST-LINE TREATMENT FOR
BRAFWT METASTATIC COLORECTAL CANCER:
FINDINGS FROM THE MODUL TRIAL OF BIOMARKER-
DRIVEN MAINTENANCE
Grothey A,1 Tabernero J,2 Arnold D,3 de Gramont A,4 Ducreux M,5 O’Dwyer PJ,6
Van Cutsem E,7 Bosanac I,8 Srock S,8 Mancao C,8 Gilberg F,8 Winter J,8 Schmoll H-J9
1West Cancer Center, Germantown, TN, USA; 2Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology
(VHIO), Barcelona, Spain; 3Asklepios Clinic Altona, Hamburg, Germany; 4Franco-British Institute, Levallois-Perret,
France; 5Gustave Roussy, Villejuif, Université Paris Saclay, France; 6Abramson Cancer Center, University of
Pennsylvania, Philadelphia, PA, USA; 7University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium; 8F.
Hoffmann-La Roche Ltd, Basel, Switzerland; 9Martin-Luther-University, Halle, Germany
SAGLB.AFL.17.03.0196a (06/17)
MODUL: overall study design
Cohort 1BRAFmut
Cohort 2BRAFwt
R
R
5-FU/LV + cetuximab + vemurafenib
FP + bevacizumab + atezolizumab
FP + bevacizumab
FP + bevacizumab
Induction treatmenta,b Biomarker-driven maintenance treatment
Cohort 3HER2+
FP + bevacizumab
Capecitabine + trastuzumab + pertuzumab
R
Cobimetinib + atezolizumab
FP + bevacizumab
Cohort 4HER2– BRAFwt
R
TREATMENT
UNTIL
PD
Follow-up
Primary objective: Progression-free survival (PFS; RECIST v1.1) measured from randomization in each maintenance treatment cohort
Secondary objectives: Overall survival (OS); overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR);
duration of response (DoR); change in ECOG performance status; safety
FOLFOX +
bevacizumab
8 cycles (16w)
or
FOLFOX +
bevacizumab
6 cycles (12w)
then
5-FU/LV +
bevacizumab
2 cycles (4w)
CR
PR
SD
Grothey et al., ESMO 2018
SAGLB.AFL.17.03.0196a (06/17)
Cohort 1BRAFmut
Cohort 2BRAFwt
R
R
5-FU/LV + cetuximab + vemurafenib
FP + bevacizumab + atezolizumab
FP + bevacizumab
FP + bevacizumab
Induction treatmenta,b Biomarker-driven maintenance treatment
Cohort 3HER2+
FP + bevacizumab
Capecitabine + trastuzumab + pertuzumab
R
Cobimetinib + atezolizumab
FP + bevacizumab
Cohort 4HER2– BRAFwt
R
TREATMENT
UNTIL
PD
Follow-up
Primary objective: Progression-free survival (PFS; RECIST v1.1) measured from randomization in each maintenance treatment cohort
Secondary objectives: Overall survival (OS); overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR);
duration of response (DoR); change in ECOG performance status; safety
FOLFOX +
bevacizumab
8 cycles (16w)
or
FOLFOX +
bevacizumab
6 cycles (12w)
then
5-FU/LV +
bevacizumab
2 cycles (4w)
CR
PR
SD
MODUL: overall study design
Grothey et al., ESMO 2018
SAGLB.AFL.17.03.0196a (06/17)
OSPFS
FP + bev + atezo FP + bev
Median PFS, months 7.20 7.39
Stratified HR (95% CI) 0.96 (0.77–1.20)
p=0.727
FP + bev + atezo FP + bev
Median OS, months 22.05 21.91
Stratified HR (95% CI) 0.86 (0.66–1.13)
p=0.283
No. at risk
FP+bev+atezo
FP+bev
Time (months)
0 3 6 9 12 15 18 21
1.00
0.75
0.50
0.25
0.00
297 224 147 103 70 49 29 15
148 109 74 55 29 21 17 6
24 27 30
6 1 0
3 1 0
FP + bev + atezo
FP + bev
Surv
ival pro
babili
ty
297 293 275 244 214 189 164 104
148 142 130 120 108 94 79 49
70 28 8
30 14 5
0
0
Time (months)
0 3 6 9 12 15 18 21
1.00
0.75
0.50
0.25
0.00
24 27 30 33
FP + bev + atezo
FP + bev
No. at risk
FP+bev+atezo
FP+bev
Surv
ival pro
babili
ty
Primary analysis of PFS: 1L BRAFwt
Median follow-up 18.7 months
Grothey et al., ESMO 2018
SAGLB.AFL.17.03.0196a (06/17)
Immunotherapy as „switch maintenance“
N= > 580; primary endpoint: OSPI: Dirk Arnold, DE & David Cunningham, UK
SAGLB.AFL.17.03.0196a (06/17)
Treatment goals change with “line” of therapy
adapted from Stintzing S. F1000 Prime Reports 2014;6:108
Line of systemic treatment Realistic treatment goal
Adjuvant‘Cure’
Reduce risk of recurrence
1st lineDeepest tumor response
Long duration of low/no tumor burden
2nd lineDurable disease control
Tumor response if needed
3rd lineDurable disease control
Maintenance of QoL and PS
Subsequent linesDisease control
and maintenance of QoL; palliation
OSandQoL
Arnold D . Clin Colorect Cancer 2016
SAGLB.AFL.17.03.0196a (06/17)
1st-line 2nd- and further-line
Treatment goal
Disease-related factors
Patient-related factors Disease-related factors
Biomarkers Patient-related factors
Anticipated toxicity Treatment goal
Biomarkers
Factors That Impact on Treatment Decisions
Arnold, WCGC 2016 (oral presentation)
SAGLB.AFL.17.03.0196a (06/17)
1st-line 2nd- and further-line
Treatment goal
Disease-related factors
Patient-related factors Disease-related factors
Biomarkers Patient-related factors
Anticipated toxicity Treatment goal
Biomarkers
Factors That Impact on Treatment Decisions
Arnold, WCGC 2016 (oral presentation)
SAGLB.AFL.17.03.0196a (06/17)
1st-line 2nd- and further-line
Treatment goal
Disease-related factors
Patient-related factors Disease-related factors
Biomarkers Patient-related factors
Anticipated toxicity Treatment goal
Biomarkers
Pretreatment
Information from pretreatment(including reported toxicity)
Factors That Impact on Treatment Decisions
Arnold, WCGC 2016 (oral presentation)
SAGLB.AFL.17.03.0196a (06/17)
Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014
ESMO 2014 Guidelines: Sequences
SAGLB.AFL.17.03.0196a (06/17)
Chemo (B)
Other (anti-EGFR)
Chemo (A)
Anti-VEGF
R
R
Chemo (A) Chemo (B)R
Anti-VEGF R
VEGF resistance occurs – but when?
Arnold et al., Clin Colorectal Cancer 2014
SAGLB.AFL.17.03.0196a (06/17)
2L chemo alone or plus continued Bevacizumab after progression with chemo plus Bevacizumab
TML study: Results
Arnold et al., J Clin Oncol Suppl. 2012Benounna, Arnold et al., Lancet Oncol 2013
SAGLB.AFL.17.03.0196a (06/17)Benounna, Sastre, Arnold et al. Lancet Oncol. 2013;14:29-37; Masi et al. Ann Oncol. 2015;26:724-30.
Bevacizumab Beyond Progression: 2 different trials, Overall Survival
TML, Int´l phase IIIBEBYP, Italian phase II
adjusted HR 0.77, p=0.043 (strat. log-rank)
Stratified HR 0.83; p=0.0211 (log-rank)
SAGLB.AFL.17.03.0196a (06/17)
TML trial: Subgroup analyses
Vieitez de Prado, Borg, Arnold et al., ESMO 2012Benounna, Arnold et al., Lancet Oncol 2013
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Antiangiogenic treatment in mCRC
Arnold & Tabernero, J Oncopathol 2013
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Antiangiogenic Treatment Options in mCRC
• When VEGF-A levels are reducedor activation of VEGFR-2 is reduced by an antagonist, there is evidence to suggest PlGF and VEGF-B ligands serve as an alternative angiogenic and/or metastatic pathway
• Targeting a broader set ofpro-angiogenic growth factors could help in overcoming antiangiogenic resistance (e.g., PlGF and VEGF-B)
‒ But, this hypothesis has yet to be confirmed in clinical studies
VEGFR-2
P
P
P
P
VEGF-BVEGF-APIGF
LymphangiogenicFactors
VEGF-DVEGF-C
RegorafenibSmall molecule MKI
Bevacizumab(Anti-VEGF-A
MAb)
Aflibercept(Fusion protein/
VEGF Trap)
Brave et al. Angiogenesis. 2010;13:337–347. Cao et al. Sci Signal. 2009
RamucirumabAnti-VEGFR-2 MAb
SAGLB.AFL.17.03.0196a (06/17)
Phase III VELOUR: 2nd line FOLFIRI +/- Aflibercept
Van Cutsem et al., J Clin Oncol 2012
PFS: HR 0.76, p<0.001med. 4.7 vs. 6.9 mos.
OS: HR 0.82, p<0.0032med. 12.06 vs. 13.5 mos.
SAGLB.AFL.17.03.0196a (06/17)
VELOUR trial: Stratified subgroups
Overall survival
Progression free survival
Van Cutsem et al., J Clin Oncol 2012
SAGLB.AFL.17.03.0196a (06/17)
Overall survival
Progression free survival
VELOUR trial: Stratified subgroups
Van Cutsem et al., J Clin Oncol 2012
SAGLB.AFL.17.03.0196a (06/17)
Phase III RAISE: 2nd line FOLFIRI +/- Ramucirumab
Tabernero et al., Lancet Oncol 2015
SAGLB.AFL.17.03.0196a (06/17)
E3200 TML VELOUR RAISE
Bev + FOLFOX4 (n=286)
FOLFOX
(n=291)Bev + CT(n=410)
CT
(n=409)
Aflib + FOLFIRI
(n=612)
Plac + FOLFIRI
(n=614)
Ramu + FOLFIRI
(n=536)
Plac + FOLFIRI
(n=536)
Bev before? none all 30% all
mOS, months 12.9 10.8 11.2 9.8 13.5 12.1 13.3 11.7
HR=0.75p=0.0011
HR=0.81
p=0.0062
HR=0.82p=0.0032
HR=0.84p=0.022
mPFS, months
7.3 4.7 5.7 4.1 6.9 4.7 5.7 4.4
HR=0.61p<0.0001
HR=0.68p<0.0001
HR=0.76p=0.00007
HR=0.79
p=0.0005ORR, %
22.7 8.6 5.4 3.9 19.8 11.1 13.4 12.5
p<0.0001 ns p=0.0001 ns
1. Langer, et al. ESMO 2008; 2 . Peeters, et al. JCO 2010; 3. Van Cutsem, et al. WCGC 20114. Giantonio, et al. J Clin Oncol 2007; 5. Roche data on file Plac = placebo
Giantonio, et al. J Clin Oncol 2007; Benounna, Arnold et al, Lancet Oncol 2013; Van Cutsem, et al. J Clin Oncol 2012 ; Tabernero et al., Lancet Oncol 2015
2nd line with anti-VEGF combinations
SAGLB.AFL.17.03.0196a (06/17)Van Cutsem, Cervantes, Nordlinger & Arnold; Ann Oncol 2014
Treatment sequences: Strategies
SAGLB.AFL.17.03.0196a (06/17)
Case #1: 57y/o lawyer, ECOG PS 0, motivated
• C. transversum cancer, diagnosed and resected (19 mos. ago)
• Synchronous liver mets and retroperitoneal mets
• intraoperatively localized peritoneal carcinomatosis
1st line FOLFOX/Bevacizumab for 5 months → PR
FP/Bevacizumab maintenance for 8 more months
at progression 2 months re-induction of oxaliplatin→ neuropathy and increasing CEA
• RAS wild-type, BRAF wild-type
• What now?
SAGLB.AFL.17.03.0196a (06/17)
4
PRODIGE 18 STUDY DESIGN
Primary endpoint • PFS rate at 4 months (a CT-scan was performed every
6 weeks)
Secondary endpoints • Objective Response Rate (RECIST 1.1)
• Overall survival (OS)
• PFS
• OS from the start of first-line therapy
• Safety (adverse events using the NCIC-CTCAE)
• Quality of life
Stratification factors
• Type of first-line chemo. irinotecan vs oxaliplatin
• first-line PFS : ● 9 vs > 9 months
Patients with wtKRAS exon 2
mCRC progressing after Bev
plus chemotherapy doublet
(fluoropyrimidine + oxaliplatine
or irinotecan)
(n = 133)
R 1:1
Arm A
mFOLFOX6 or FOLFIRI
+ bevacizumab
Arm B
mFOLFOX6 or FOLFIRI
+ cetuximab
PD
with a chemotherapy
crossover from the
first-line to second-line
mFOLFOX6
Oxaliplatin: 85 mg/m², d1
Folinic acid: 400 mg/m², d1
5-FU bolus: 400 mg/m², d1
5-FU IV 46H: 2400 mg/m²
d1-d14
FOLFIRI
Irinotecan: 180 mg/m², d1
Folinic acid: 400 mg/m², d1
5-FU bolus: 400 mg/m², d1
5-FU IV 46 h: 2400 mg/m²
d1-d14
+ Bevacizumab: 5mg/kg, d1
or
+ Cetuximab: 500mg/m², d1
d1-d14
PD
SAGLB.AFL.17.03.0196a (06/17)
9
MEDIAN PFS AND MEDIAN OS (WTKRAS EXON 2)
Cet (Arm B, n=67)
Median PFS 5.6 months
(95 % CI : 4.2 – 6.5)
Bev (Arm A, n=65)
Median PFS 7.1 months
(95% CI: 5.7 - 8.2)
HR 0.710 (95% CI: 0.495–1.018)
p=0.0622
Cet (Arm B, n=67)
Median OS 10.4 months
(95 % CI : 7.0 – 16.2)
Bev (Arm A, n=65)
Median OS 15.8 months
(95% CI: 9.5 – 22.3)
HR 0.688 (95 CI: 0.456 – 1.038)
p=0.0750
Overall SurvivalProgression-Free Survival
Median follow-up was 37.4 months (95%CI: 25.1–39.6 months)
SAGLB.AFL.17.03.0196a (06/17)
11
Cet (Arm B, n=37)
Median PFS 5.7 months
(95 % CI : 4.1 – 7.1)
Bev (Arm A, n=36)
Median PFS 8.2 months
(95% CI: 6.6 - 8.6)
HR 0.665 (95% CI: 0.407 – 1.087)
p=0.1035
Cet (Arm B, n=37)
Median OS 12.6 months
(95 % CI : 6.8 – 22.5)
Bev (Arm A, n=36)
Median OS 21.1 months
(95% CI: 12.3 – 35.1)
HR 0.758 (95 CI: 0.416 – 1.383)
p=0.3669
MEDIAN PFS AND MEDIAN OS (WTKRAS, NRAS EXONS 2,3,4, WTBRAF)
Overall SurvivalProgression-Free Survival
Median follow-up was 29.2 months (CI95%: 19.7 – 41.4 months)
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KRAS wild-type; N=182
Hecht et al., Clin Colorectal Cancer 2015
2nd line, after FOLFOX/bev:FOLFIRI with bev or with p´mab? SPIRITT trial
ORR: 32% FOLFIRI/p´mab vs. 19% FOLFIRI/bev
bev→ egfr bev→ egfr
bev→ bev sequencebev→ bev sequence
SAGLB.AFL.17.03.0196a (06/17)
SPRITT trial, KRAS wild-type; N=182
SPIRITT trial, Hecht et al., Clin Colorectal Cancer 2015
bev→ bev sequence bev→ bev sequence
PRODIGE trial, KRAS wild-type; N=130
Prodige trial, Hiret et al., ASCO 2016
bev→ egfr bev→ egfr
After 1st line bev combo:2nd line/bev versus 2nd line/egfr
SAGLB.AFL.17.03.0196a (06/17)
Second-Line Treatment Options for wt KRAS/NRAS mCRC: Randomized Trials of Anti-EGFR Agents
Peeters et al. Clin Cancer Res. 2015;21:5469-79; Hecht et al. Clin Colorectal Cancer. 2015;14:72-80; Hiret S, et al. J Clin Oncol. 2016;34 (suppl; abstr 3514).
Trial TreatmentNo. Pts
ORR, %Median PFS,
moMedian OS,
mo
181 (RAS WT
subgp)1
FOLFIRIPanitumumab + FOLFIRI
294303
1041
6.7 (p=.023)
4.914.5 (p=.366)
12.5
SPIRITT (KRAS WT)2
Panitumumab + FOLFIRIBevacizumab + FOLFIRI
9191
3219
7.7 (p=0.97)
9.218.0 (p=0.75)
21.4
PRODIGE-18 (KRAS WT)3
Cetuximab + chemo* Bevacizumab + chemo*
6565
3225
5.7 (p=0.07)
7.511.4 (p=0.07)
19.3
*mFOLFOX6 or FOLFIRI
SAGLB.AFL.17.03.0196a (06/17)
Chemo (B)
Other (anti-EGFR)
Chemo (A)
Anti-VEGF
R
R
Chemo (A) Chemo (B)R
Anti-VEGF R
VEGF Resistance Occurs – But When?
?Arnold et al., Clin Colorectal Cancer 2014
SAGLB.AFL.17.03.0196a (06/17)
Potential biomarkers of Bevacizumab resistance and progression in mCRC
• Single arms trials showed an increase of PlGF at bevacizumab progression1,2
• An increase in serum VEGF-A level during or before disease progression has been documented2
• These increases may contribute to bevacizumab treatment resistance
1. Kopetz S et al. J Clin Oncol. 2010;28:453-9; 2. Hayashi H et al. Oncotarget. 2014;5:2588-94
0
10
20
30
40
PIG
F (
pg
/mL
)V
EG
F-A
(p
g/m
L) 200
150
100
50
00 1 2 3 4 5 6
Time (months)
VE
GF
-A (
pg
/mL
) 200
150
100
50
00 1 2 3 4 5 6
Time (months)
Responders(N=16)
Nonresponders(N=9)
P < .01*
P < .001*
P < .001*
0
10
20
30
40
50
0 1 2 4 6
PIGF† † † †
SAGLB.AFL.17.03.0196a (06/17)
PlGF expression correlates with progression and survival status
S-C Wei et al. Gut. 2005;54:666-672; Escudero-Esparza A et al. Cancer Genomics & Proteomics. 2009;6:239-246.
UICC-TNM classification stage I, n=14; stage
II, n=27; stage III, n=22; stage IV, n=11 PlGF, placental growth factor; TNM, tumor node metastasis; VEGF, vascular endothelial growth factor
Distribution of Ratios Between
Pretreatment Expression Levels
of PlGF in Tumor and Non-tumor
Tissues (UICC-TNM)
Survival Curves of Patients in
Relation To Pretreatment PlGF
Expression Levels in Tumors
Pretreatment Levels of
PLGF-1 Transcript in CRC vs
Normal Tissue
SAGLB.AFL.17.03.0196a (06/17)
High VEGF level (≥115 pg/mL, TR population)
Results according to VEGF-D levelsResults
Figure 1. Kaplan-Meier graph of overall survival by treatment arm with stratification
factors as covariates, high VEGF-D expression levels (≥115 pg/mL), TR population.
Results
Figure 2. Kaplan-Meier graph of overall survival by treatment arm with stratification
factors as covariates, low VEGF-D expression levels (<115 pg/mL), TR population.
Low VEGF level (<115 pg/mL, TR population)
Tabernero J et al., Ann Oncol 2018
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Chemo
Biological
Assessment of CAF every 2 weeks and RECIST every 8 weeks
Bevacizumab Aflibercept
CHEMO A CHEMO B
PD
Conventional switch of
Chemo and Biological
at timepoint of PD
1st-line 2nd-line
PD
Chemo A/B = FP + Ox/IriN=60
PERMAD Trial: Determination of Markers for (Early) Angiogenic Switch
PI: Seufferlein, D and Arnold, PT; NCT02331927; https://clinicaltrials.gov/ct2/show/NCT02331927 accessed June 21, 2017.
SAGLB.AFL.17.03.0196a (06/17)
Chemo A/B = FP + Ox/Iri
PERMAD Trial: Randomized Part
Bevacizumab Aflibercept
CHEMO A CHEMO B
Bevacizumab Aflibercept
CHEMO A CHEMO B
R
Patients with marker change
and at least SD (RECIST)
Chemo
Chemo
Biological
Biological
Conventional switch
of chemo and
biological at timepoint
of PD
Marker-driven early
switch of biological
and conventional
switch of chemo at
timepoint of PD
1st-line 2nd-line
PD
n=120 n=60
PI: Seufferlein, D and Arnold, PT; NCT02331927; https://clinicaltrials.gov/ct2/show/NCT02331927 accessed June 21, 2017.
A
B
SAGLB.AFL.17.03.0196a (06/17)
Treatment goals change with “line” of therapy
adapted from Stintzing S. F1000 Prime Reports 2014;6:108
Line of systemic treatment Realistic treatment goal
Adjuvant‘Cure’
Reduce risk of recurrence
1st lineDeepest tumor response
Long duration of low/no tumor burden
2nd lineDurable disease control
Tumor response if needed
3rd lineDurable disease control
Maintenance of QoL and PS
Subsequent linesDisease control
and maintenance of QoL; palliation
OSandQoL
Arnold D . Clin Colorect Cancer 2016
SAGLB.AFL.17.03.0196a (06/17)
Evidence-based treatment beyond 2nd line
Many patients are candidates for further treatment: After 2+ lines of treatment
a significant number of patients with mCRC are able and willing to receive more treatments
n=4877 patients with mCRC who received chemotherapy between Jan 2004 and March 2011 inoncology practices subscribing to a US-wide chemotherapy order entry system2
1L
2L
3L
Chibaudel et al. Ther Adv Med Oncol 2012; Abrams et al. J Natl Cancer Inst 2014; ; Salvatore L et al. Expert Rev Anticancer Ther 2015
SAGLB.AFL.17.03.0196a (06/17)
“Snapshot” of 3rd and 4th line treatment for mCRC
• A significant number of patients progressing beyond the 2nd line are still fit for further therapy.
• Italian study assessed oncologists’ clinical practice in the management of Italian mCRC patients,with a focus on the 3rd, 4th, and later lines of therapy.
3L treatment ECOG PS (%) patients 4L treatment ECOG PS (%) patients
ECOG 0
43%
ECOG 1
43%
ECOG 0
52%
ECOG 2
14%
ECOG 1
26%
ECOG 2
19%
ECOG 3
3%
Heiman F et al. Value in Health. 2015
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Van Cutsem E, Cervantes A, …...Arnold D ESMO Consensus; Ann Oncol 2016Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
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Grothey et al., WCGC 2015 (oral presentation)
Overall'survival'(OS)'
CORRECT&
CONCUR&
Grothey&A,&Van&Cutsem&E,&et#al.#Lancet#2013;381:303–312;&Li&J,&et#al.#Lancet#Oncol#2015;16:619–629.#
Regorafenib vs. placebo: Two phase III trials
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83
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Tipiracil substantially increases bioavailability of trifluridine
Mean trifluridine plasma concentrations time profile after single dose of
trifluridine/tipiracil (35 mg/m2) or trifluridine alone
EMA Assessment Report for Lonsurf, http://www.ema.europa.eu/ema/(date last accessed 24 August, 2016)
Trifluridine/tipiracil dosing achieved:• 37-fold greater trifluridine AUC concentration• 22-fold greater trifluridine Cmax
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85
SAGLB.AFL.17.03.0196a (06/17)
86
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87
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88
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Cytotoxicity of trifluridine/tipiracil
1. Emura T, et al. Int J Oncol 2004;25:571–8
2. Emura T, et al. Int J Mol Med 2004;13:545–9
Rate
of
tum
ou
r g
row
th in
hib
itio
n
(%)
0
20
40
60
80
1005FU-sensitive xenograft 5FU-resistant xenograft
Dose
(mg/kg/day)
Control
Trifluridine/tipiracil 75
Trifluridine/tipiracil 100
Trifluridine/tipiracil 150
5-FU iv 15
5-FU continuous
infusion 20
UFT 17.5
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Trifluridine/tipiracil efficacy in mCRC (RECOURSE)
Mayer RJ, et al. N Engl J Med 2015;372:1909–19
TFD/TPI
(N=534)
Placebo
(N=266)
Median
OS, mo*7.1 5.3
Stratified log-rank test:
p<0.001; HR 0.68
95% CI 0.58–0.81
Alive at
12 mo, %
27 18
Overall survival Progression-free survival
0 2 4 6 8 10 1612 14
47.3%
20.8%
No. at Risk:
Placebo
534TFD/TPI
Months from randomization
266 51 10 2 2 1 0
238 121 30 18 5 2
2
66
1
4
Pro
gre
ss
ion
-fre
e
dis
trib
uti
on
fu
nc
tio
n (
%)
0
50
100
CT scans were performed
every 8 weeks from month 2
TFD/TPI
(N=534)
Placebo
(N=266)
Median
PFS, mo*2.0 1.7
Stratified log-rank test:
p<0.001; HR 0.48
95% CI 0.41–0.57
Ove
rall
su
rviv
al
dis
trib
uti
on
fu
nc
tio
n (
%)
Time from randomization (months)
0 3 6 9 12 15 18
266 198 107 47 24
534 459 294 137 64 23 7
9 3
TFD/TPI
No. at risk:
Placebo
0
50
100
SAGLB.AFL.17.03.0196a (06/17)
Trifluridine/tipiracil effectively prolongs time to deterioration (ECOG PS ≥2) (RECOURSE)
Trifluridine/tipiracil
No. at risk:
Placebo
EC
OG
perf
orm
an
ce s
tatu
s <
2 (
%)
Months from randomization0 3 6 9 12 15 18
266 134 57 21 11
534 352 188 84 28 7 03 1
100
0
50
5.7
4.0
Longer median time to
worsening ECOG PS
from 0–1 to ≥2
(5.7 vs. 4.0)
84% of patients
maintain ECOG PS2
Mayer RJ, et al. N Engl J Med 2015;372:1909–19
SAGLB.AFL.17.03.0196a (06/17)
Trifluridine/tipiracil – haematological AEs (RECOURSE)
Most common AEs*
Trifluridine/tipiracil
(N=533)
Placebo
(N=265)
Grade ≥3 Grade ≥3
Haematological
Neutropenia, % 38 0
Leukopenia, % 21 0
Anaemia, % 18 3
Thrombocytopenia, % 5 <1
Non-haematological
Nausea,% 2 1
Vomiting,% 2 <1
Decreased appetite,% 4 5
Fatigue,% 4 6
Diarrhoea,% 3 <1
Abdominal pain,% 2 4
Fever,% 1 <1
Asthenia,% 3 3
Mayer RJ, et al. N Engl J Med 2015;372:1909–19
SAGLB.AFL.17.03.0196a (06/17)
PRECONNECT (phase 3b EAP): Progression-free survival
Falcone A, et al. ESMO WCGC 2018
Efficacy based on investigator
assessment
• Median PFS: 2.8 months (95% CI
2.7–3.3), range (0.1–11.1);
• ORR: 2.4% (95% CI 1.2–4.2).
• DCR: 36.8% (95% CI 32.4–41.4).
• At cut-off, 40 deaths were
reported in this population
100
80
60
40
20
0
Eve
nt-
fre
e (
%)
Time from start of treatment (months)
0 2 4 6 8 10 12
462 295 130 62 23 5 0N
Patients at risk
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84% of patients are ECOG PS 0–1 at the end of FTD/TPI treatment
Eve
nt-
free
(%
)
Time from start of treatment (months)
0 2 4 6 8 10 120
50
100
60
70
80
90
40
30
20
10
Time to first ECOG PS deterioration to PS ≥2
Median Range: 8.7 (0.2–11.0) months
Falcone A, et al. ESMO WCGC 2018
PRECONNECT (phase 3b EAP): Time to deterioration of PS
SAGLB.AFL.17.03.0196a (06/17)
.Vogel et al. Cancer Treat Rev. 2017
Treatment arms nMedian OS,
monthsHR in OS
(95% CI), P valueMedian PFS,
monthsHR in PFS
(95% CI), P value
RECOURSEMayer, 2015
• Trifluridine/tipiracil• Placebo
800 7.1 vs 5.3*0.68 (0.58–0.81),
P <.0012.0 vs 1.7
0.48 (0.41–0.57),P <.001
CONCURLi, 2015
• Regorafenib• Placebo
204 8.8 vs 6.3*0.55 (0.40–0.77),
P = .000163.2 vs 1.7
0.31 (0.22–0.44),P <.0001
ASPECCTPrice, 2014
• Panitumumab• Cetuximab
1010 10.4 vs 10.0 0.97 (0.84–1.11) - 1.00 (0.88–1.14)
CORRECTGrothey, 2013
• Regorafenib• Placebo
760 6.4 vs 5.0*0.77 (0.64–0.94),
P = .00521.9 vs 1.7
0.49 (0.42–0.58),P <.0001
CO17Jonker, 2007
• Cetuximab + BSC• BSC
572 6.1 vs 4.6*0.77 (0.64–0.92),
P = .005-
0.68 (0.57–0.80),P <.001
Van Cutsem,2007
• Panitumumab + BSC• BSC
463 - 1.00 (0.82–1.22) 8.0 vs 7.3* 0.54 (0.44–0.66)
SAGLB.AFL.17.03.0196a (06/17)
Van Cutsem E, Cervantes A, …...Arnold D ESMO Consensus; Ann Oncol 2016
What to do after 1st line discontinuation?
SAGLB.AFL.17.03.0196a (06/17)
Retreatment = Reintroduction or Rechallengewith a previously used regimen
Reintroduction1
No progression of CRC while on therapy
Treatment was either of a set duration (eg, adjuvant) or was stopped for a planned break (eg, to reduce or manage AEs)
Rechallenge2
Reintroduction, after an intervening treatment, of the same therapy to which tumor has already proved to be resistant
The disease is challenged with the same regimen/agent in later-line treatment
1. Maindrault G, et al. Ann Oncol. 2004;15:1210-1214; 2. Tonini G, et al. J Exp Clin Cancer Res. 2013;32:92.
=/
G.SM.ON.09.2014.1007
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Arnold et al., Ann Oncol 2018 (online ahead of print)
SAGLB.AFL.17.03.0196a (06/17)
Arnold et al., Ann Oncol 2018
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Arnold et al., Ann Oncol 2018
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Möhler et al., Eur J Cancer 2016
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Sequences of „lines“ in 1L MCRC
Standard
ablative
ideal
0 10 20 30 40
Induction
post Induction
2nd line
post 2nd line
3rd line
Re-Induction
4th line2
bsctoday
Biologicmaintenance
or ablation
Biologicmaintenance
or ablation
SAGLB.AFL.17.03.0196a (06/17)
Dirk Arnold
Asklepios Tumorzentrum Hamburg, AK Altona, Hamburg, DE
Instituto CUF de Oncologia, Lisboa, PT
Statine
vor und während der Systemtherapie wirken protektiv!
Seicean et al., JACC 2012.
Statine
vor und während der Systemtherapie wirken protektiv!
Seicean et al., JACC 2012.
SAGLB.AFL.17.03.0196a (06/17)
Van Cutsem E, Cervantes A, …...Arnold D ESMO Consensus; Ann Oncol 2016
What to do after 1st line discontinuation?