Kras Mutasyonu Olmayan(KRAS wild tip ) Kolorektal Kanserli

Kras Mutasyonu Olmayan (KRAS wild tip )
Kolorektal Kanserli Olgularda
Sistemik Tedavi Seçenekleri
Dr Hande Turna
İstanbul Üniversitesi
Cerrahpaşa Tıp Fakültesi
Medikal Onkoloji Bilim Dalı
Metastatik Kolorektal Kanser Tedavisinde
Tarihsel Gelişim
KOLOREKTAL KANSER
Ras ‘wild type’ olmak
veya olmamak ?
Vogelgram (Vogelstein ve ark 1988)
EGFR ve Ras Proteini
K-Ras
K-ras
Influence of Epidermal Growth Factor Receptor Expression and Rash on Rates of Response.
Cunningham D et al. N Engl J Med 2004;351:337-345.
Kras mutasyonları -Andreyev HJ, RASCAL study.
J Natl Cancer Inst. 90:675-684 1998
1.2 MİLYON
KOLOREKTAL
KANSERLİ OLGU
~%60 KRAS wt
http://globocan.iarc.fr/ (accessed on 16/02/2012);
Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019; Bokemeyer C, et al. Ann Oncol 2011;22:1535–1546
Kolorektal Kanserde Belirteçler
Andreyev H J Natl Cancer Inst. 90:675-684 1998
Kras Mutasyonu
Prognostik
faktör?
Prediktif
faktör?
Ras
Mutasyonu
KRAS and BRAF Mutations in Advanced Colorectal Cancer Are Associated With
Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan:
Results From the MRC FOCUS TrialJ Clin Oncol 27:2009 :5931-5937
Richman SD,FOCUS trial. J Clin Oncol. 27:5931-5937 2009
K-ras prognostik bir faktör mü?
• PETACC3 (1321 olgu) Roth AD, J Clin Oncol.
28:466-474 2010
• CALGB 89803 (508 olgu) (Ogino S, Clin Cancer
Res. 15:7322-7329 2009
K-ras exon2 mutasyonları bağımsız bir
prognostik faktör değil
Prediktif Faktör ?
Kras Wt
Cevap Oranı
Ek yarar +
CT* + bev#
CT*
Cetuximab
+ CT*
Cetuximab +
CT KRAS mt
Cetuximab + CT*
KRAS ts
CRYSTAL:CETUXIMAB + FOLFIRI kombinasyonu RR, PFS ve OS’yi
istatistiki anlamlı olarak arttırır(KRAS wt)
PFS
OS
1.0
1.0
20.0 23.5
0.8
PFS estimate
stimate
0.8
0.6
0.4
HR=0.796
p=0.0093
0.2
0.6
0.4
0.2
0.0
8.4 9.9
CETUXIMAB +
FOLFIRI (n=350)
FOLFIRI (n=316)
HR=0.696
p=0.0012
0.0
6
12
18
24 30 36
Zaman (ay)
RR
Ölüm riskinde
% 20
42
48
0
54
70
Response rate (%)
0
4
p<0.001
60
57
50
40
30
8
12
Zaman (ay)
16
20
Progresyon riskinde
% 30
40
20
Yanıt Oranında
% 17
10
0
FOLFIRI
(n=350)
Cetuximab + FOLFIRI
(n=316)
Van Cutsem E, et al. ASCO 2010 (Abstract no. 3570); Van Cutsem E, et al. J Clin Oncol 2011;29:2011–2019
OPUS:CETUXIMAB + FOLFOX4 kombinasyonu RR ve PFS’i istatistiki
anlamlı olarak arttırır(KRAS wt)
OS
PFS
1.0
1.0
18.5 22.8
PFS estimate
0.6
0.4
HR=0.855
p=0.3854
0.2
0.0
0
6
0.6
12
18
24
Zaman (ay)
30
36
CETUXIMAB +
FOLFOX4 (n=82)
FOLFOX4 (n=97)
0.4
HR=0.567
p=0.0064
0.0
RR
Ölüm riskinde
% 15
0.8
0.2
0
4
8
12
Zaman (ay)
16
20
70
Response rate (%)
OS estimate
0.8
7.2 8.3
60
p=0.0027
57
50
Progresyon
riskinde % 43
40
30
34
20
10
0
FOLFOX4 Cetuximab + FOLFOX4
(n=97)
(n=82)
Yanıt Oranında
% 23
Bokemeyer C, et al. Ann Oncol 2011;22:1535–1546; Bokemeyer C, et al. ASCO GI 2010 (Abstract No. 428)
Metastatik Kolorektal Kanserde
Anti-EGFR Tedaviler
.Addition of cetuximab to oxaliplatin-based first-line
combination chemotherapy for treatment of advanced
colorectal cancer: results of the randomised phase 3 MRC COIN
Lancet. 2011 Jun 18;377(9783):2103-14.
PRIME:Panitumumab+ FOLFOX4 kombinasyon sonuçları
(KRAS wt
)
Panitumumab + FOLFOX4 (n=325)
FOLFOX4 (n=331)
1
1.0
0.8
8.6 ay
10.0 s
19.4 months
23.8 months
0.6
0.6
OS
Probability of PFS
0.8
0.4
0.4
0.2
0.2
0
0.0
0
2
4
6
8
10 12 14
Months
16
18
20
22
HR=0.80 (p5% CI: 0.67–0.95)
p=0.009
0
4
8
12
16
20
24
28
32
36
Months
HR=0.83 (95% CI: 0.70–0.98)
p=0.03
Douillard J-Y, et al. ASCO 2013
PRIME
Panitumumab + CT (FOLFOX)
CT (FOLFOX4)
KRAS wt (exon 2)
1.0
19.4
ay
23.8
ay
0.8
Δ = 4.4 ay
0.6
0.4
HR=0.83
p=0.03
0.2
8
16
Δ = 5.6 ay
0.6
0.4
HR=0.77
p=0.009
0.2
0.0
0
25.8
20.2 ay
ay
1.0
OS estimate
OS estimate
0.8
RAS wt
(KRAS and NRAS wt)
24
32
40
Months
48
56
64
0.0
0
12
24
36
Months
48
60
Douillard J-Y, et al. N Engl J Med 2013;369:1023–1034
72
Anti EGFR Tedavilerin Kras wild tip Kolorektal
Kanserin Birinci Basamak Tedavisinde Etkinliği
Trial
CRYSTAL[1]
OPUS[2]
PRIME[3-5]
COIN[6]
Comparative Regimens
Median PFS, Mos
Median OS, Mos
FOLFIRI/Cetux vs FOLFIRI
9.9 vs 8.4
23.5 vs 20.0
FOLFOX4/Cetux vs FOLFOX4
8.3 vs 7.2
22.8 vs 18.5
FOLFOX4/Pmab vs FOLFOX4
9.6 vs 8.0
23.8 vs 19.4
FOLFOX4/Pmab vs FOLFOX4
(KRAS/NRAS WT)
10.1 vs 7.9
26.0 vs 20.2
FOLFOX/XELOX/Cetux vs
FOLFOX/XELOX
8.6 vs 8.6
17.0 vs 17.9
1. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019. 2. Bokemeyer C, et al. Ann Oncol. 2010;22:15351546. 3. Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705. 4. Douillard JY, et al. ASCO 2013. Abstract
3620. 5. Douillard JY, et al. N Engl J Med. 2013;369:1023-1034. 6. Maughan TS, et al. Lancet.
2011;377:2103-2114.
Randomize Çalışmalar
FIRE-31
Patients with untreated
KRAS wt mCRC
N=592
Cetuximab + FOLFIRI
R
Bev + FOLFIRI
CALGB 804052,3
Cetuximab +
FOLFOX/FOLFIRI
Patients with untreated
KRAS wt mCRC
N~1200
(after trial modification)
R
Bev + FOLFOX/FOLFIRI
Bev + cetuximab +
FOLFOX/FOLFIRI*
*Arm closed to accrual as of 09/10/2009
PEAK4,5
Patients with untreated
KRAS wt mCRC
N=285
Pani + mFOLFOX6
R
Bev + mFOLFOX6
1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506);
2. Naughton MJ, et al. ASCO 2013 (Abstract No. 3611); 3. NCT00265850;
4. Schwartzberg LS, et al. ASCO GI 2013 (Abstract No. 446); 5. Schwartzberg LS, et
al. ASCO 2013 (Abstract No. 3631)
FIRE-3
Randomize,açık etiketli,çok merkezli Faz III
KRAS wt (exon2)
metastatik olgular
N=592
Cetuximab +
FOLFIRI
R
Bevacizumab + FOLFIRI
● Primer sonlanım noktası: Genel cevap oranı
● İkincil sonlanım noktası: Progresyonsuz sağkalım, genel sağkalım, cevap
derinliği, ikincil rezeksiyon oranı, güvenlik
Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
FIRE-3: OS
RAS* wt
(KRAS and NRAS wt)2
KRAS wt (exon 2)1
1.0
Δ = 3.7 ay
25.0 ay
0.75
HR 0.77
(95% CI: 0.62–0.96)
p=0.017
0.50
25.6
ay
Δ = 7.5 ay
HR 0.70
(95% CI: 0.53–0.92)
p=0.011
0.50
0.25
0.25
0.0
0
33.1
ay
0.75
GSK
GSK
1.0
28.7
ay
0.0
12
24
36
48
60
Aylar
72
0
12
24
36
48
60
Aylar
─ Cetuximab + FOLFIRI (n=297)
─ Cetuximab + FOLFIRI (n=171)
─ Bevacizumab + FOLFIRI (n=295)
─ Bevacizumab + FOLFIRI (n=171)
*Wild-type at KRAS exon 2, 3 4 and NRAS exon 2, 3, 4
72
1. Heinemann V, et al. ASCO 2013 (Abstract No. LBA3506)
2. Stintzing S, et al. ECC 2013 (Abstract No. LBA17)
PEAK Çalışması: Faz 2 ;Panitumumab / Bevacizumab
Panitumumab + mFOLFOX6
(deney kolu)
KRAS wt mCRC
n=285
R
Bevacizumab + mFOLFOX6
(karşılaştırılan kol)
● Primer sonlanım noktası
● Progression-free survival (PFS)
● Sekonder sonlanım noktası
● Genel sağkalım (OS), Objektif yanıt (OR), Cevap süresi (DoR), time to
progression (TTP), time to response (TTR) and rezeksiyon oranı
Schwartzberg LS et al., ASCO GI 2013 (abstract 446)
FOLFOX + Pan
PEAK
R
N = 285
WT KRAS exon 2
100
90
90
Δ = 9.9 ay
70
60
60
50
50
40
40
30
30
HR* = 0.62 (95% CI, 0.44–0.89)
P = 0.01
10
0
Δ = 12.4 ay
80
70
20
FOLFOX + Bev
WT RAS
100
80
Prim. Endpoint = PFS
20
HR* = 0.63 (95% CI, 0.39–1.02)
P = 0.06
10
0
0
4
8
12 16 20 24 28 32 36 40 44
Months
n (%)
Medyan (95%
CI) ay
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
n (%)
Medyan (95%
CI) ay
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
Anti EGFR: Tedavi sekansını belirlerken
biyomarker durumu ile ilişkisi
HRc
(95% CI)
Descriptive
p-value
10.1
(9.0–12.7)
0.66
(0.46–0.95)
0.03
41.3
(28.8–41.3)
28.9
(23.9–31.3)
0.63
(0.39–1.02)
0.06
24
27
ORR†, % (95% CI)
58 (37–78)
56 (35–75)
Median PFS†, mo
(95% CI)
7.8
(6.5–9.8)
8.9
(7.3–12.0)
1.39
(0.73–2.64)
0.32
NR
(13.0–NR)
21.6
(13.9–25.4)
0.72
(0.28–1.83)
0.50
Pani +
mFOLFOX6
Bev +
mFOLFOX6
88
82
ORR†, % (95% CI)
64 (53–74)
60 (49–71)
Median PFS‡, mo
(95% CI)
13.0
(10.9–15.1)
Median OS‡, mo
(95% CI)
WT RASa, n
WT KRAS-2/MT RASb, n
Median OS, mo
(95% CI)
aWT
KRAS (exons 2, 3, 4) and NRAS (exons 2, 3, 4)
KRAS (exon 2) and mutant KRAS (exons 3 or 4) or mutant NRAS (exons 2, 3, 4)
cStratified Cox proportional hazards model
†Data cutoff date: 30 May 2012; ‡Data cutoff date: 3 January 2013
bWT
Schwartzberg LS, et al. ASCO 2013 (Abstract No. 3631)
Phase III 80405 Trial
Patients with mCRC
and KRAS WT,
ECOG PS 0/1
(N = 2900)
• Primary endpoint: OS
• Secondary endpoints:
ORR, PFS, TTF, duration
of response
ClinicalTrials.gov. NCT00265850.
FOLFOX or FOLFIRI +
Bevacizumab q2w
FOLFOX or FOLFIRI +
Cetuximab q1w
A third arm with CT + bevacizumab +
cetuximab was closed to accrual in
September 2009
Metastatik Kolorektal Kanserde Belirteçler
• KRAS G13D[1]
– Prognostik ve prediktif değeri üzerinde veri net değil
– Büyük randomize çalışmalarda anti-EGFR tedavi yararı
• BRAF[2,3]
– Kötü prognostik faktör
– Prediktif değeri?
• Pan RAS analizi[4,5]
– ~ 10% of KRAS 12/13 WT tumörlerde diğer RAS mutasyonları var
• KRAS exons 3, 4
• NRAS exons 2,3,4
– Anti-EGFR tedavi yararı yok
1. Peeters M, et al. J Clin Oncol. 2013; 31:759-765. 2. Richman SD, et al. J Clin Oncol. 2009;27:5931-5937. 3. Van Custem E, et al. J Clin
Oncol. 2011;29:2011-2019 4. Peeters M, et al. Clin Cancer Res. 2013;19:1902-1912. 5. Douillard JY, et al. N Engl J Med.
2013;369:1023-1034.
ESMO consensus 2012 strongly recommends the testing of all patients for
KRAS status before clinical decision making to guide treatment decisions as the
only valid biomarker to drive therapeutic choice
KRAS wt
KRAS mt
1
FOLFIRI/FOLFOX + Erbitux
FOLFOX + pani
FOLFIRI/XELIRI + bev
FOLFOX/XELOX + bev
FOLFOXIRI
FOLFOX/XELOX or FOLFIRI/XELIRI
IRIS
+++
+++
++(+)
++(+)
++(+)
+
+
FOLFOX/XELOX + bev
FOLFOXIRI
FOLFIRI/XELIRI + bev
FOLFOX/XELOX
FOLFIRI/XELIRI IRIS
+++
++(+)
++(+)
+
+
2
FOLFIRI + Erbitux/pani
FOLFOX/XELOX + bev
FOLFIRI/XELIRI + bev
FOLFOXIRI
FOLFOX + Erbitux
FOLFOX/XELOX or FOLFIRI/XELIRI
IRIS
+++
+++
++(+)
+(+)
+(+)
+
+
FOLFOX/XELOX + bev
FOLFOXIRI/XELIRI + bev
FOLFOX/XELOX
FOLFIRI/XELIRI
FOLFOXIRI
IRIS
+++
++(+)
++
++
++
+
3
5-FU/capecitabine +/- bev
FOLFIRI/XELIRI or XELOX/FOLFOX
IRIS
Erbitux/pani (mono)
Watchful waiting/triplets (+/−bev/Erb/pani)
+++
++
+
(+)
+*
5-FU/capecitabine +/- bev
XELOX/FOLFOX
FOLFIRI/XELIRI
IRIS
Watchful waiting/triplets +/−bev
+++
++
++
+
+*
* Selected patients
Schmoll H-J, et al. Ann Oncol 2012;23:2479–2516
NCCN 2014 Version3