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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)
Disclosures
Advisory role
• Bayer, Boehringer, BTG, Lilly, Merck Serono, Roche, Sanofi, Servier
Honoraria for speeches
• Bayer, BTG, Lilly, Roche, Sanofi, Servier
Trial and research support
• Roche, Sanofi
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)
33
EVALUATION OF RESPONSE
SIDEDNESS + GENOTYPE
mFOLFOXIRI +
panitumumab
mFOLFOXIRI +
panitumumab
FOLFOXIRIFOLFOXIRI
left right
ORR (%)
10
20
30
40
50
60
70
80
90
100
90,6
68,0
60,0
37,5
OR 4.518
(1.29-15.71)
P=0.0210
OR 2.500
(0.37-16.88)
P=0.6372
mFOLFOXIRI +
panitumumab
mFOLFOXIRI +
panitumumab
FOLFOXIRIFOLFOXIRI
super wild-type
ORR (%)
BRAF mutation
10
20
30
40
50
60
70
80
90
100
86,0
64,7
71,4
22,2
OR 3.364
(0.90-12.54)
P=0.0806
OR 8.750
(0.9-84.80)P=0.1262
N=60 N=16N=78 N=18
Phase II VOLFI trial: FOLFOXIRI +/- Panitumumab
Geissler et al., ESMO 2017
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
SAGLB.AFL.17.03.0196a (06/17)
Van Cutsem E, Cervantes A, …...Arnold D ESMO Consensus; Ann Oncol 2016Van Cutsem E, Cervantes A, …...Arnold D. ESMO Consensus; Ann Oncol 2016
SAGLB.AFL.17.03.0196a (06/17)
No tx. Bev FP/Bev
Median TFS
Median PFS1
Re-induction
No re-induction
45% 43% 21%
Re-induction rates and PFS1/TFS
2
4
6
months
Presented by: Dirk Arnold, M.D., on behalf of the AIO CRC study group
SAGLB.AFL.17.03.0196a (06/17)
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
SAGLB.AFL.17.03.0196a (06/17)
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 2016
Maintenance or observation after induction?
PFS
OS
SAGLB.AFL.17.03.0196a (06/17)
Apricio et al., J Clin Oncol 2018
SAGLB.AFL.17.03.0196a (06/17)
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
SAGLB.AFL.17.03.0196a (06/17)
RAS & BRAF wild-type RAS or BRAF mutant
Hegewisch-Becker et al., Lancet Oncol 2015
Who benefits from active maintenance?
SAGLB.AFL.17.03.0196a (06/17)
Following FOLFOX/C´mab Continuation vs. C´mab only
Garcia Alfonso et al., ESMO 2014
SAGLB.AFL.17.03.0196a (06/17)
MEDIZINISCHE KLINIK UND POLIKLINIK III
DIREKTOR PROF. DR. W. HIDDEMANN
KLINIKUM DER UNIVERSITÄT MÜNCHEN®
FIRE-4 (AIO KRK-0114) DESIGN
19.05.181
R1
anti-
EGFR-free
therapyFOLFIRICetuximab
mCRCRAS-wild-
type
(FOLF)-IRICetuximab
R2
N= 450 N= 230
FOLFIRICetuximab
5-FU/CapeBevacizumab
1st
progression
2nd
progression
switch after
8-12 cycles
Induction 2nd-lineMaintenance Re-induction
physician‘schoice
(no anti EGFRsubstances)
Entry 1 Entry 2
Primary Endpoint: OS3 after randomisation R2Secondary Endpoint: PFS in 1st-line
SAGLB.AFL.17.03.0196a (06/17)
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
SAGLB.AFL.17.03.0196a (06/17)
The price to pay? Toxicity
Hegewisch-Becker et al., Lancet Oncol 2015; Simkens et al., Lancet 2015
SAGLB.AFL.17.03.0196a (06/17)
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
SAGLB.AFL.17.03.0196a (06/17)
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
SAGLB.AFL.17.03.0196a (06/17)
Mannsmann UR ASCO GI 2013, abstract no. 427
∆ OS
No tumor shrinkage
PFS
PFS
∆ PFS
Tumor shrinkage
Lethal tumor load
Baseline tumor load
Time under treatment
SAGLB.AFL.17.03.0196a (06/17)
Time
Cel
lco
un
t
Goldie-Coldman Hypothesis:
less therapy-resistant clones with a smaller number of cells
- Goldie JH et al., Cancer Res. 1984
- Withers HR et al., Sem Radiat Oncol 2006
Norton-Simon Hypothesis: kinetic resistance - poorer response to chemotherapy in small residualsNorton L et al., Cancer Treat Rep 1986, Oncologist 2005
Chemotherapy
Metastasis 1
Metastasis 2Primary
Subclone
Gerlinger et al., New Engl J Med 2012
SAGLB.AFL.17.03.0196a (06/17)
Marusyk et al., Science 2013
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
SAGLB.AFL.17.03.0196a (06/17)
UK FOCUS-4 trial
Lawler et al., The Oncologist 2015
SAGLB.AFL.17.03.0196a (06/17)
Cobimetinib + Atezolizumab + Bevacizumab
5-FU/LV + Cetuximab + Vemurafenib
Induction Treatment
Phase
Investigator’s
choice:
FOLFOX
+ bevacizumab
for 8 cycles
(16 weeks)
or
FOLFOX
+ bevacizumab
for 6 cycles
(12 weeks)
followed by
2 cycles
(4 weeks)
5-FU/LV
+ bevacizumab
Early
PD a
CR PR
SD
PD, evaluation of resectability, pt
refusal or ineligible for any cohort
Biomarker-driven Maintenance Treatment Phase Post-treatment
Follow-up Phase
BRAFmut
FP = fluoropyrimidine (5-FU or capecitabine)
a. Patients who progress early and who are not BRAFmut will enter the Post-treatment Follow-up Phase with initiation of 2nd-line treatment per Investigator discretion
T R E
A T
ME N
T U
N T I
L P D
Bev+ Atezo + Chemo of
choice
Cohort 1 BRAFmut R
5-FU/LV + Cetuximab + Vemurafenib
FP + Bevacizumab
«MSI Stable»
«MSI High» FP + Bevacizymab + Atezolizumab Testing Hierarchy:
a) Her2 -> BRAF -> MSI
b) Her2 ->MSI -> BRAF
Cohort 2
“No
Biomarker”
BRAFWT”
R
FP + Bevacizumab + Atezolizumab
FP + Bevacizumab
«Stratified for MSI »
Bev+ Atezo + Chemo of
choice
Cohort 3 Her2-pos
R
(FP) + Transtuzumab + Pertuzumab
FP + Bevacizumab «Stratified for IHC? »
Cohort 4 “No
Biomarker”
2
Where we might be in 1year from now MODUL Trial: New arms under discussion
FU plus anti EGFR plus anti V600E
FP plus Bevacizumab plus antiPD1
FP plus „double“ antiHER2
Beva plus antiPD1 plus antiMEK
modified from: Arnold et al., WCGC 2015
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)
Schmoll,(...,(Arnold,...,(Cervantes;(Ann(Oncol(2012(
(
Schmoll et al. Ann Oncol. 2012;23:2479-516.
ESMO Consensus 2012: Sequences
FOLFOX FOLFIRI vs. FOLFIRI FOLFOX
Tournigand et al. J Clin Oncol. 2004:
Median OS 20.6 months
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
SAGLB.AFL.17.03.0196a (06/17)
Antiangiogenic treatment in mCRC
Arnold & Tabernero, J Oncopathol 2013
SAGLB.AFL.17.03.0196a (06/17)
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
SAGLB.AFL.17.03.0196a (06/17)
Overall survival
Progression free survival
VELOUR trial: Stratified subgroups
SAGLB.AFL.17.03.0196a (06/17)
Phase III RAISE: 2nd line FOLFIRI +/- Ramucirumab
Tabernero et al., GI Cancer Symposium 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)
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)
SAGLB.AFL.17.03.0196a (06/17)
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)
After 15 months 1st line: Now continued stabilisation with FOLFIRI + Aflibercept
07/2016 04/2017 09/2017
Case #1: 57y/o lawyer, ECOG PS 0, motivated
SAGLB.AFL.17.03.0196a (06/17)
Case #1: 57y/o lawyer, ECOG PS 0, motivated
• C. transversum cancer with synchronous liver mets and intraoperatively localized peritoneal carcinomatosis
• 16 mos. FP/(oxaliplatin)/bev strategy
• 14 mos. FOLFIRI/aflibercept strategy
• Now progressing
RAS wild-type, BRAF wild-type
• 4 mos. irinotecan/cetuximab PD
• 2 mos. TAS102 PD
• Re-introduction of oxaliplatin?
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)
VEGF-A, VEGF-B, and PlGF are all involved in multiple pathways of angiogenic response
PlGF
VEGF-B
ENDOTHELIAL CELL
Survival, Migration, Proliferation
VEGF-A
MACROPHAGE
• Recruitment and activation
• Release of angiogenic factors
TUMOR CELL
• Proliferationand migration
• Chemoprotection
STROMAL CELLPERICYTE, SMC
• Migration
• Proliferation
DENDRITIC CELL
• Suppression of antigen recognition
VEGF-A
BM PROGENITORS LEUKEMIC CELL
Proliferation, Migration, Survival
sVEGFR-1
Fischer. Nat Rev Cancer. 2008;8:942–956.
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)
● Plasma and tumor tissue collection was mandatory.
● Analyses were performed to assess the correlations of the baseline individual marker levels with clinical outcomes.
● Plasma samples were collected from whole blood prior to cycle 1. VEGF-C, VEGF-D*, soluble VEGFR-1 (sVEGFR-1), sVEGFR-2, and sVEGFR-3 were assessed by exploratory, individual, proprietary Eli Lilly and Company-developed dual-monoclonal sandwich immunoassays (Version 1 for each).
● Archived tumor samples were submitted to the central laboratory for VEGFR-2 immunohistochemistry assay.
RAISE Study (2nd line, FOLFIRI +/- Ramucirumab)
Tabernero J et al., Proc. ESMO 2017
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., Proc. ESMO 2017
SAGLB.AFL.17.03.0196a (06/17)Tabernero et al. ASCO 2017 (poster 592)
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)
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)
RegorafenibTAS 102 combo?CIT plus anti-VEGF?
Anti-VEGF
Other
Chemo (B)
Other (anti-EGFR)
Chemo (A)
Anti-VEGF
R
R
Chemo (A) Chemo (B)R
VEGF Resistance Occurs – But When?
Arnold et al., Clin Colorectal Cancer 2014
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
SAGLB.AFL.17.03.0196a (06/17)
Regorafenib (BAY 73-4506): an oral multikinase inhibitor 1,2,3
1. Wilhelm SM, et al. Int J Cancer. 2011;1219(1):245-255. 2. 2. Mross K, et al. Clin Cancer Research 2012;18(9):2658-2667.3. 3Strumberg D, et al. Expert Opin Investig Drugs. 2012;21(6):879-889.
Inhibition of
roliferation
Inhibition of
angiogenesis
Inhibition pf signalling
In tumor –
microenvironment
SAGLB.AFL.17.03.0196a (06/17)
CORRECT Trial: Regorafenib or Placebo after failure of standard therapy
Pat. mit
vorbehandeltem
mCRC
(n=760)*
R 2:1
Placebo + BSC
(n=255)
Regorafenib + BSC
(n=505)
Preceding treatment MUST have been contained Fluoropyrimidine, Oxaliplatin, Irinotecan, Bevacizumab,and (in KRAS wt) Cetuximab or Panitumumab
SAGLB.AFL.17.03.0196a (06/17)
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
SAGLB.AFL.17.03.0196a (06/17)
74
SAGLB.AFL.17.03.0196a (06/17)
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
SAGLB.AFL.17.03.0196a (06/17)
76
SAGLB.AFL.17.03.0196a (06/17)
77
SAGLB.AFL.17.03.0196a (06/17)
78
SAGLB.AFL.17.03.0196a (06/17)
79
SAGLB.AFL.17.03.0196a (06/17)
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
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)
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
SAGLB.AFL.17.03.0196a (06/17)
Arnold et al., Ann Oncol 2018 (online ahead of print)
SAGLB.AFL.17.03.0196a (06/17)
Arnold et al., Ann Oncol 2018 (online ahead of print)
SAGLB.AFL.17.03.0196a (06/17)
Arnold et al., Ann Oncol 2018 (online ahead of print)
SAGLB.AFL.17.03.0196a (06/17)
Arnold et al., Ann Oncol 2018 (online ahead of print)
SAGLB.AFL.17.03.0196a (06/17)
Not all approaches are successful in refractory mCRC: Nintedanib Phase III LUME trial
Van Cutsem et al., ESMO 2016
PFS: 2.60 vs 1.41 mo
HR 0.57, P<0.0001
Investigator assessment
SAGLB.AFL.17.03.0196a (06/17)
Xu, et al., Chin J Cancer. 2017
PFS OS
Median PFS: 2.8 vs 1.5 months in famitinib vs placebo
(HR, 0.60, P = .004)
Median OS: 7.4 vs 7.2 months in famitinib vs placebo
(P = .657)
• Famitinib is a multikinase receptor inhibitor
• Famitinib vs placebo in patients with mCRC who have previously received at least 2 lines of standard chemotherapy
Not all approaches are successful in refractory mCRC: Famitinib rand. phase II trial
SAGLB.AFL.17.03.0196a (06/17)
Möhler et al., Eur J Cancer 2016
SAGLB.AFL.17.03.0196a (06/17)
Clinical activity and safety of cobimetinib and
atezolizumab in colorectal cancer
Johanna Bendell,1 Tae Won Kim,2 Boon Cher Goh,3 Jeffrey Wallin,4 Do-Youn Oh,5 Sae-Won Han,5 Carrie Lee,6 Matthew D. Hellmann,7 Jayesh Desai,8 Jeremy Lewin,9 Benjamin J. Solomon,10 Laura Q.
Chow,11 Wilson H. Miller Jr,12 Justin Gainor,13 Keith Flaherty,13 Jeffrey Infante,1 Meghna Das Thakur,4
Paul Foster,4 Edward Cha,4 Yung-Jue Bang5
1Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; 2Asan Medical Center, Seoul, South Korea; 3Cancer
Science Institute of Singapore, National University of Singapore, Singapore; 4Genentech, Inc., South San Francisco, CA; 5Seoul
National University Hospital, Seoul, South Korea; 6UNC Lineberger Comprehensive Cancer Center, University of North Carolina –
Chapel Hill, North Carolina; 7Memorial Sloan Kettering Cancer Center, New York, NY; 8Royal Melbourne Hospital, University of
Melbourne, Melbourne, VIC, Australia; 9Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; 10Peter
MacCallum Cancer Center, Melbourne, VIC, Australia; 11University of Washington, Seattle, WA; 12Segal Cancer Center and Jewish
General Hospital, McGill University, Montreal, QC, Canada; 13Massachusetts General Hospital, Boston, MA
Bendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 2016
SAGLB.AFL.17.03.0196a (06/17)
SAGLB.AFL.17.03.0196a (06/17)
MediaRelease
F. Hoffmann-La Roche Ltd 4070 Basel
Switzerland
Group Communications
Roche Group Media Relations
Tel. +41 61 688 88 88
www.roche.com
1/5
Basel,10thMay2018
ROCHEPROVIDESUPDATEONPHASEIIISTUDYOFTECENTRIQ®(ATEZOLIZUMAB)AND
COTELLIC®(COBIMETINIB)INPEOPLEWITHHEAVILYPRE-TREATEDLOCALLYADVANCED
ORMETASTATICCOLORECTALCANCER
Roche(SIX:RO,ROG;OTCQX:RHHBY)todayannouncedthatthePhaseIIIIMblaze370study
evaluatingthecombinationofTECENTRIQ®(atezolizumab)andCOTELLIC®(cobimetinib)didnot
meetitsprimaryendpointofoverallsurvival(OS)comparedtoregorafenib.Thestudyevaluatedthe
combinationinpeoplewithdifficult-to-treat,locallyadvancedormetastaticcolorectalcancer(CRC)
whosediseaseprogressedorwhowereintoleranttoatleasttwosystemicchemotherapyregimens.
Morethan95%ofpatientsinIMblaze370havemicrosatellitestable(MSS)tumoursandbasedonthe
availabledata,checkpointinhibitorsasmonotherapyhavenotdemonstratedclinicallymeaningful
efficacyinMSSmCRC.TheresultsfromIMblaze370wereconsistentwiththispriormonotherapy
experience,showingthattreatmentwithTECENTRIQalonedidnotprovideameaningfulclinical
benefitcomparedtoregorafenibinthispatientpopulation.
SafetyforthecombinationofTECENTRIQandCOTELLICappearedtobeconsistentwiththeknown
safetyprofilesoftheindividualmedicines,andnonewsafetysignalswereidentifiedwiththe
combination.TheresultsfromIMblaze370willbefurtherexaminedandpresentedatanupcoming
medicalmeeting.
“Whiletheseresultsarenotwhatwehopedfor,weremaincommittedtoapplyingourdeep
experiencetodevelopmedicinesthatwillimproveoutcomesforpeoplelivingwithgastrointestinal
cancers,”saidSandraHorning,M.D.,ChiefMedicalOfficerandHeadofGlobalProductDevelopment.
“Inparticular,wehaveanumberofstudiesevaluatingmedicinesincolorectalcancerthatcouldplay
animportantroleinthetreatmentofpeoplewiththisdiseaseinthefuture.”
RochehasanextensiveclinicaltrialdevelopmentprogramforTECENTRIQ,withmorethan50studies
ongoing,includingmultiplePhaseIIIstudiesacrosslung,kidney,skin,breast,colorectal,prostate,
MediaRelease
F. Hoffmann-La Roche Ltd 4070 Basel
Switzerland
Group Communications
Roche Group Media Relations
Tel. +41 61 688 88 88
www.roche.com
1/5
Basel,10thMay2018
ROCHEPROVIDESUPDATEONPHASEIIISTUDYOFTECENTRIQ®(ATEZOLIZUMAB)AND
COTELLIC®(COBIMETINIB)INPEOPLEWITHHEAVILYPRE-TREATEDLOCALLYADVANCED
ORMETASTATICCOLORECTALCANCER
Roche(SIX:RO,ROG;OTCQX:RHHBY)todayannouncedthatthePhaseIIIIMblaze370study
evaluatingthecombinationofTECENTRIQ®(atezolizumab)andCOTELLIC®(cobimetinib)didnot
meetitsprimaryendpointofoverallsurvival(OS)comparedtoregorafenib.Thestudyevaluatedthe
combinationinpeoplewithdifficult-to-treat,locallyadvancedormetastaticcolorectalcancer(CRC)
whosediseaseprogressedorwhowereintoleranttoatleasttwosystemicchemotherapyregimens.
Morethan95%ofpatientsinIMblaze370havemicrosatellitestable(MSS)tumoursandbasedonthe
availabledata,checkpointinhibitorsasmonotherapyhavenotdemonstratedclinicallymeaningful
efficacyinMSSmCRC.TheresultsfromIMblaze370wereconsistentwiththispriormonotherapy
experience,showingthattreatmentwithTECENTRIQalonedidnotprovideameaningfulclinical
benefitcomparedtoregorafenibinthispatientpopulation.
SafetyforthecombinationofTECENTRIQandCOTELLICappearedtobeconsistentwiththeknown
safetyprofilesoftheindividualmedicines,andnonewsafetysignalswereidentifiedwiththe
combination.TheresultsfromIMblaze370willbefurtherexaminedandpresentedatanupcoming
medicalmeeting.
“Whiletheseresultsarenotwhatwehopedfor,weremaincommittedtoapplyingourdeep
experiencetodevelopmedicinesthatwillimproveoutcomesforpeoplelivingwithgastrointestinal
cancers,”saidSandraHorning,M.D.,ChiefMedicalOfficerandHeadofGlobalProductDevelopment.
“Inparticular,wehaveanumberofstudiesevaluatingmedicinesincolorectalcancerthatcouldplay
animportantroleinthetreatmentofpeoplewiththisdiseaseinthefuture.”
RochehasanextensiveclinicaltrialdevelopmentprogramforTECENTRIQ,withmorethan50studies
ongoing,includingmultiplePhaseIIIstudiesacrosslung,kidney,skin,breast,colorectal,prostate,
SAGLB.AFL.17.03.0196a (06/17)
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.
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