“immer Cetuximab”

26/02/2014
First-line Therapy According to Patient Group
Kontroverse:
“immer Cetuximab”
GROUP 1:
GROUP 2:
GROUP 3:
Patients with
initially non-resectable
metastasis
Patients with
non-resectable
metastases
high tumor load
or tumor-related
symptoms
Patients with definitively
non-resectable
metastases,
asymptomatic and less
aggressive disease
or comorbidity
Resectability
Symptoms Control
Volker Heinemann
Comprehensive Cancer Center
Klinikum Grosshadern, Med Klinik III
LMU München
Intensive therapy
Duration of Survival
and QoL
less intensive therapy ?
Schmoll H-J et al: ESMO Guidelines. Ann Oncol 2012
Relevanz der Erstlinientherapie
Palliative Behandlungslinien des mCRC
Eine systemische Therapie erhalten:
[%] Patienten
[%] Tod
1st line
2nd line
100%
<70%
mCRC
Patienten
mCRC
Patienten
3rd line
<50%
mCRC
Patienten
Eine richtige Entscheidung in der Erstlinientherapie hat den
größten Einfluss auf das Gesamtüberleben
Weniger als 50% der mCRC Patienten erhalten eine
3rd-Line Chemotherapie.
Tumorregister Kolorektales Karzinom I , iOMEDICO März 2012
Effektivität der Erstlinientherapie im Vergleich
mit späteren Therapielinien
Parameter*
Response rate
Progression-free
survival
1st line
2nd line
later lines
38–64%1,2
10–35%5,6
1–13%8,9
8–11 months3,4
4–7 months5,7
2–3 months8,10
Effektivität der Kombinationstherapie auch bei
reduziertem Performance Status
6286 Patienten
*Range of results for targeted treatment arms of key Phase II and III trials
(KRAS wt exon 2 for EGFR inhibitor trials)
Ansprechen in der Erstlinientherapie ist eine kritische Determinante des
Gesamtüberlebens
1. Maughan TS, et al. Lancet 2011;377:2103–2114; 2. Saltz LB, et al. J Clin Oncol 2008;26:2013–2019;
3. Bokemeyer C, et al. Ann Oncol 2011;22:1535–1546; 4. Hurwitz H, et al. New Engl J Med 2004;350:2335–2342;
5. Langer C, et al. ESMO 2008 (Abstract No. 385P); 6. Peeters M, et al. J Clin OncoI 2010;28:4706–4713;
7. Giantonio BJ, et al. J Clin Oncol 2007;25:1539‒1544; 8. Grothey A, et al. Lancet 2013;38:303–312;
9. Karapetis CS, et al. N Engl J Med 2008;359:1757‒1765; 10. Amado RG, et al. J Clin Oncol 2008;26:1626–1634
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Effektivität einer optimalen
2nd-line Chemotherapie
FOLFIRI  FOLFOX
R
primary end point = 15-mo PFS
FOLFOX  FOLFIRI
N = 220
Gesamtüberleben in Phase III Studien
Sequenzielle vs. wenig intensive vs. intensivierte Therapie
Sequential therapy
no antibodies
Non-intensive therapy
plus antibodies
Intensified therapy
plus antibodies
1st-line
FOLFIRI
2nd-line
FOLFOX
Crossover
1st-line
FOLFOX
2nd-line
FOLFIRI
74%
62%
ORR
56%
15%
54%
4%
PFS
8.5 Mo
4.2 Mo
8.0 Mo
2.5 Mo
OS
21.5 mo
Overall survival, months
N = 111
N = 109
20.6 mo
5FU →
FOLFOX/
FOLFIRI
Cape →
Irinotecan
Tournigand C, et al. JCO 2004
Tournigand C, et al. JCO 2004
* KRAS-wt, retrospektive Analyse
5FU →
Irinotecan
5FU +
Bevacizumab
Cape +
Bevacizumab
FOLFOX +
FOLFIRI + FOLFOX + FOLFIRI +
Bevacizumab Cetxuximab Panitumumab Cetuximab
FOLFIRI +
Cetuximab
Seymour et al., Lancet 2007; Koopman et al., Lancet 2007; Cunningham et al., Ann Oncol 2009; Kabbinavar et al., JCO 2005; Price et al., JCO 2011;
Saltz et al., JCO 2008; Van Cutsem et al., JCO 2011; Köhne et al., ASCO 2011; Heinemann et al., ASCO 2013; Heinemann et al., ESMO 2013
1st-line Therapie: Ergebnisse bei unselektierten Patienten
FOLFIRI plus Bevacizumab
Kann man die Ergebnisse der
palliativen Therapie verbessern?
Therapieergebnisse
bei unselektierten Patienten
n
ORR
(%)
PFS
(months)
OS
(months)
Hellenic COG 2012
142
40
10.8
25.3
FNCLCC/ACCORD 2013
73
59
9.0
23.0
TRIBE 2013
256
53
9.7
25.8
( FIRE-3 2013*
295
58
10.3
25.0 )
Study
* Pts with KRAS wt tumors
1. Pectasides D, et al BMC Cancer 2012;12:271–281; 2. Ducreux M, et al. EJC 201;49:1236–1245;
3. Falcone A, et al. ASCO 2013 (Abstract No. 3505);
4. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506
1st-line Therapie: Ergebnisse bei unselektierten Patienten
Maintenance und optimierte Bev-basierte Sequenz
Regimen
PFS
(months)
OS
(months)
MACRO1
CAPOX + Bev
10.4
23.4
CAIRO-32
Chemo + Bev
11.8
19.8 + 4.5 ?
SAKK 41/063
Chemo + Bev
9.5
25.1
TML4
Chemo + Bev
Study
4Ausschlusskriterien:
Effektivität von anti-EGFR moAbs nur bei
KRAS-WT
23.9
- 1st-line PFS < 3 Monate
- Applikation von Bev < 3 Monate
1. Tabernero, et al. ASCO 2010 (Abstract No. 3501); 2. Koopmann M, et al. ASCO 2013 (Abstract No. 3502);
3. Koeberle D, et al. ASCO 2013 (Abstract No. 3503); 4. Bennouna J, et al. Lancet Oncol 2013;14:29–37
Normanno N, et al. Nat Rev Clin Oncol 2009;6:519–527
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26/02/2014
FIRE-3: First head-to-head study of targeted agents
in patients with mCRC
Overall
survival
Cetuximab +
FOLFIRI
R
Bevacizumab +
FOLFIRI
28.7
months
25.0
months
1.0
0.75
OS estimate
Open-label, randomized, multicenter Phase III
Patients with untreated
KRAS wt (exon2) mCRC
N=592
FIRE-3 study results
Bevacizumab + CT (FOLFIRI) (n=295)
∆ = 3.7 months
0.50
HR=0.77
p=0.017
0.25
● Primary endpoint: Overall response rate
● Secondary endpoints: Progression-free survival, overall survival,
time to failure of strategy, depth of response, secondary resection rate,
safety
Cetuximab + CT (FOLFIRI) (n=297)
0.0
12
48
36
24
Months since start of treatment
Overall response rate
(primary endpoint not met)
Progression-free survival
72
Cetuximab + CT
Bevacizumab + CT
62%
58%
0.183
10.0 months
10.3 months
0.547
Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
Gezielte Therapie bei selektierten Patienten
versus ungezielte Therapie
60
p value
Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
Distribution of mutations in mCRC:
A new definition
New
RAS mt
~10%
100%
• Selektion in Richtung höherer
Sensitivität gegenüber einer antiEGFR Therapie
KRAS mt
~40%
• Im Bevacizumab Arm
cross-over zur 2nd-line Therapie mit
Cetuximab bei 41% der Patienten
41%
RAS wt
~50%
• 2/3 der Patiuenten im Bev-arm
erhielten keine anti-EGFR-Therapie
FIRE-3: Greater selection of patients further improves
OS benefit to 7.5 months with cetuximab (RAS wt)
Tested Mutations
Overall
survival
KRAS exon 2 wild-type subset
NRAS
BRAF
EXON 1
EXON 1
EXON 11
EXON 2
12 13
61
wt
4.3%
EXON 2
59 61
3.8%
2%
EXON 15
10%
EXON 4
146
4.9%
EXON 3
12 13
600
0%
EXON 3
EXON 4
16% mutations in
KRAS (exon 3-4)
and NRAS
Bevacizumab + CT (FOLFIRI) (n=171)
∆ = 7.5 months
0.50
HR=0.70
p=0.011
0.25
117 146
0%
Cetuximab + CT (FOLFIRI) (n=171)
33.1
25.6 months
months
0.75
OS estimate
KRAS
1.0
0.0
0
12
48
24
36
Months since start of treatment
60
72
Cetuximab + CT
Bevacizumab + CT
Overall response rate
primary endpoint not met
65.5%
59.6%
p value
0.32
Progression-free survival
10.4 months
10.2 months
0.54
Stintzing S, et al. ECC 2013 (Abstract No. LBA17)
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26/02/2014
FIRE-3: Patients with any RAS mutation
(mutations in KRAS or NRAS exons 2, 3 or 4)
Overall
survival
1.0
20.3
months
Bevacizumab + CT (FOLFIRI) (n=86)
20.6
months
0.75
OS estimate
Cetuximab + CT (FOLFIRI) (n=92)
Ergebnisoptimierung durch
RAS-Testung ?
0.50
= Selektion
HR=1.09
p=0.60
0.25
0.0
0
48
36
24
Months since start of treatment
12
N = 178
60
72
Cetuximab + CT
Bevacizumab + CT
38%
51.2%
0.097
7.5 months
10.1 months
0.085
Overall response rate
Progression-free survival
*Compared with bevacizumab containing regimen
p value
Stintzing S, et al. ECC 2013 (Abstract No. LBA17)
PRIME Study: Overall Survival
Optimierung der Therapieergebnisse
durch Selektion
Improved benefit with patient selection by RAS
Panitumumab + CT (FOLFOX)
alle Patienten
CT (FOLFOX4)
KRAS wt (exon 2)
100%
0.8
RAS wt
0.4
HR=0.83
p=0.03
0.2
50%
0.8
∆ = 4.4 mo
0.6
0.0
0
8
16
20.2 months
months
1.0
OS estimate
OS estimate
.
25.8
23.8
months
19.4
months
1.0
KRAS wt
60%
RAS wt
(KRAS and NRAS wt)
∆ = 5.6 mo
0.6
0.4
HR=0.77
p=0.009
0.2
24
32
40
Months
48
56
0.0
64
0
12
24
48
36
Months
60
72
Douillard J-Y, et al. N Engl J Med 2013;369:1023–1034
FOLFOX + Pan
R
N = 285
WT KRAS exon 2
FIRE-3: OS (KRAS wt exon 2 vs RAS wt)
1.0
60
50
40
30
20
HR* = 0.62 (95% CI, 0.44–0.89)
P = 0.01
10
∆ = 12.4 mo
80
70
50
40
30
20
HR* = 0.63 (95% CI, 0.39–1.02)
P = 0.06
10
0
0
0
4
8
12 16 20 24 28 32 36 40 44
Months
Events
n (%)
Median (95% CI)
months
Panitumumab +
mFOLFOX6 (n = 142)
52 (37)
34.2 (26.6–NR)
Bevacizumab +
mFOLFOX6 (n = 143)
78 (55)
24.3 (21.0–29.2)
Karthaus M, et al. EJC 2013; 49 (suppl 3):abstract 2262 (and poster).
0
4
8
12 16 20 24 28 32 36 40 44
Months
Events
n (%)
Median (95% CI)
months
Panitumumab +
mFOLFOX6 (n = 88)
30 (34)
41.3 (28.8–41.3)
Bevacizumab +
mFOLFOX6 (n = 82)
40 (49)
28.9 (23.9–31.3)
*Stratified Cox proportional hazards model; No formal hypothesis testing
was planned; WT RAS, WT KRAS & NRAS exons 2/3/4;
NR, not reached
∆ = 3.7 months
25.0
months
0.75
60
OS estimate
70
Proportion alive (%)
∆ = 9.9 mo
80
1.0
28.7
months
90
90
RAS* wt
(KRAS and NRAS wt)2
KRAS wt (exon 2)1
WT RAS
100
100
Proportion alive (%)
Prim. Endpoint = PFS
FOLFOX + Bev
HR 0.77
(95% CI: 0.62–0.96)
p=0.017
0.50
∆ = 7.5 months
HR 0.70
(95% CI: 0.53–0.92)
p=0.011
0.50
0.25
0.25
0.0
0
33.1
months
25.6
months
0.75
OS estimate
PEAK study RAS analysis
OS (longer follow-up analysis)
0.0
12
24
36
48
60
Months since start of treatment
─ Cetuximab + FOLFIRI (n=297)
─ Bevacizumab + FOLFIRI (n=295)
*Wild-type at KRAS exon 2, 3 4 and NRAS exon 2, 3, 4
72
0
12
24
36
48
60
72
Months since start of treatment
─ Cetuximab + FOLFIRI (n=171)
─ Bevacizumab + FOLFIRI (n=171)
1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
2. Stintzing S, et al. ECC 2013 (Abstract No. LBA17)
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26/02/2014
First-line Therapy According to Patient Group
GROUP 1:
GROUP 2:
GROUP 3:
Patients with
initially non-resectable
metastasis
Patients with
non-resectable
metastases
high tumor load
or tumor-related
symptoms
Patients with definitively
non-resectable
metastases,
asymptomatic
and less aggressive
disease
Resectability
Symptoms Control
Duration of Survival
and QoL
Intensive therapy according to RAS mutation status
Schmoll H-J & Sargent D. Lancet 2007;370:105–107
TRIBE Study Design
FIRE-3 versus TRIBE
FOLFIRI + Cetuximab vs FOLFOXIRI + Bevacizumab
FOLFIRI+bev
508 mCRC pts
1st line
unresectable
stratified by
 center
 PS 0/1-2
 adjuvant CT
(up to 12 cycles)
5-FU/LV
+Bev
R
PD
FOLFOXIRI+bev
(up to 12 cycles)
INDUCTION
5-FU/LV
+Bev
MAINTENANCE
FIRE-3
TRIBE
FOLFOXIRI
FOLFOXIRI + Bev
Ras-Wildtyp
keine Selektion
n
171
250
ORR (%)
66
65
PFS (mo)
10.4
12.1
OS (mo)
33.1
31.0
- Diarrhoe (%)
11.5
18
- Neutropenie (%)
24.2
49
- Febr. Neutrop (%)
1.7
8
- 60-d-Mortalität (%)
0
3.2
Grad 3-4 Toxizität
Heinemann et al. ASCO 2013
Falcone ASCO 2013
FIRE-3 versus TRIBE
FOLFIRI + Bevacizumab
Zusammenfassung/ Hypothesen
FIRE-3
TRIBE
FOLFIRI + Bev
FOLFIRI + Bev
Ras-Wildtyp
keine Selektion
n
171
254
ORR (%)
60
53
PFS (mo)
10.2
9.7
OS (mo)
25.6
25.8
- Diarrhoe (%)
13.6
11
- Neutropenie (%)
22.8
20
- Febr. Neutrop (%)
1.0
6
- 60-d-Mortalität (%)
1.7
2.3
Grad 3-4 Toxizität
 Die Erstlinientherapie beeinflusst alle weiteren Therapien
 Die Erstlinientherapie ist die effektivste Therapie
 Zweitlinientherapien (und further-lines) können eine
ineffektive Erstlinientherapie nicht kompensieren.
 FIRE-3, PRIME, PEAK (und TRIBE) zeigen: intensive Regime
in der 1st-line ermöglichen ein prolongiertes OS.
Heinemann et al. ASCO 2013
Falcone ASCO 2013
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26/02/2014
Therapie in Abhängigkeit vom
RAS-Mutationsstatus
mCRC
Cetuximab
Panitumumab
sensitiv
Cetuximab
Panitumumab
resistent
RAS-wt
RAS mut
50%
50%
anti-EGFR
Therapie
anti-VEGF
Therapie
FOLFIRI + Cet
FOLFIRI + Bev
FOLFOX + Pan
FOLFOXIRI + Bev bei gutem AZ
6