Upload
meghan-cameron
View
216
Download
0
Embed Size (px)
DESCRIPTION
A controversial starting point… Patient harbouring K-ras mutated tumors: Easy patient! Difficult patient! ?
Citation preview
Riccardo Giampieri Scuola di Specializzazione Oncologia
Università Politecnica delle Marche Ancona
How to manage patients with mutated KRAS tumors
•Hot-spot point mutations within codons 12 or 13 of the KRAS gene constitutively active KRAS protein
•Constitutively active KRAS protein cancer cell growth and survival through the RAF-MEK-ERK and PI3K-AKT pathways independently from EGFR signaling
K-ras mutation
A controversial starting point…
Patient harbouring K-ras mutated tumors:
Easy patient! Difficult patient!
?
Why easy patient?
- We know what DO NOT give to this patient
- We know what CAN be given to this patient
- Treatment sequence is almost always set without difficulties
What DO NOT give: preclinical data
- Anti-EGFR monoclonal antibodies + DiFi colon cancer cell lines + k-ras mutation or not
Benvenuti et al. Cancer Res 2007
Moroni Lancet Oncol 2005 n=31
Lièvre Clin Cancer Res 2006 n=30
Di Fiore Br J Cancer 2007 n=59
Frattini Br J Cancer 2007 n=27
Benvenuti Cancer Res 2007 n=48
Khambata-Ford J Clin Oncol 2007 n=80
De Roock ASCO Proc 2007 n=37
Finocchiaro ASCO Proc 2007 n=81
Response rate:analysis of 8 studies available in PubMed or from ASCO Proceedings:
Responders (n=82)
wt (93.0%)
RAS mutated (7.0%)
wt (56.1%)
RAS mutated (43.9%)
Non-Responders (n=312)
p = 0.000000635 (Fisher’s exact test)
Pre-treated patients and response rate differencies
FOLFOX FOLFOX+Cetuximab 168 pts 169 ptsRR (%) 36 46 p=0.06
Kras status PFS (mo.) RR (%) C+Ffox Ffox C+Ffox Ffox
Wt 7.7 7.1 61 37
Mutated 5.5 8.6 33 49
Bokemeyer C, ASCO 2008
First line: OPUS trial (randomized phase II)
Bokemeyer C. ASCO 2008, J Clin Oncol 2009; 27(5)
OPUS trial k-ras mutant population: response rates
FOLFOX N=47
ERBITUX + FOLFOX
N=52
CR 4.3% 0%
PR 44.7% 32.7%
SD 36.2% 51.9%
PD 10.6% 13.5%
NE 4.3% 1.9%
RR 48.9% 32.7%
95% CI (exact)
[34.1%, 63.9%]
[20.3%, 47.1%]
ERBITUX + FOLFOXFOLFOX
49
33
p=0.106Odds Ratio = 0.507(95% CI: 0.223 –1.150)
0
10
20
30
40
50
60
Res
pons
e ra
te (%
)
No benefit for Erbitux
p = 0.106
Stratification by: – Region– ECOG PS
FOLFIRI
Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2
as 46-h continuous infusion) + LV (every 2 weeks)
Cetuximab + FOLFIRI
Cetuximab (IV 400 mg/m2 on day 1,then 250 mg/m2 weekly)
+ irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2
as 46-h continuous infusion)+ LV (every 2 weeks)
REGFR-detectable
mCRC
Primary endpoint– Progression-free survival time
(as assessed by blinded independent review)
Secondary endpoints– ORR (independent review)– OS– Quality of life (EORTC QLQ-C30)– Safety
First line: CRYSTAL trial (phase III)
17.7 17.5 [14.4–20.6] [15.6–20.2]
1.03 [0.74–1.44]
0.85
KRAS wild-type
FOLFIRI(n=176)
Cetuximab+ FOLFIRI
(n=172)
FOLFIRI(n=87)
Cetuximab+ FOLFIRI
(n=105)
KRAS mutant
Parameter
Median OS[95% CI]
Hazard ratio[95% CI]
P-value
ITT
FOLFIRI(n=599)
Cetuximab+ FOLFIRI
(n=599)
18.6 19.9 [16.6–19.8] [18.5–21.3]
0.93 [0.81–1.07]
0.30
Median follow up time: 30 months
21.0 24.9[19.2–25.7] [22.2–27.8]
0.84 [0.64–1.11]
0.22
Overall survival analysis based on K-ras status
Overall survival analysis based on K-ras status
Continuous* XELOX or FOLFOX Arm A
RFirst-line mCRC (n= 2,445) Arm B
Continuous XELOX or FOLFOX +
cetuximab
Arm CIntermittent‡ XELOX or FOLFOX
*Treatment until disease progression or unacceptable toxicity‡Stop and Go treatment (12 weeks then restart at progression)
MRC Sponsored study supported by Merck
109 UK and Irish Hospitals
65% XELOX; 35% FOLFOX(patient/physician choice)
Maughan, et al. ESMO 2009
First line: COIN trial (phase III)
Maughan, et al. ESMO 2009
COIN trial: response rates based on K-ras status
All patients KRAS wild-type KRAS mutant
FOLFOX/XELOX(n=815)
Cetuximab +
FOLFOX/XELOX(n=815)
FOLFOX/XELOX(n=367)
Cetuximab +
FOLFOX/XELOX(n=362)
FOLFOX/XELOX(n=268)
Cetuximab +
FOLFOX/XELOX(n=297)
ORR at 12 weeks (%) 45 49 50 59 41 40Odds ratio 1.17 (p=0.124) 1.44 (p=0.015) 0.97 (p=0.877)
Best overall response (%)
51 53 57 64 46 43
Odds ratio 1.08 (p=0.428) OR=1.35 (p=0.049) OR=0.88 (p=0.449)
The 045 Phase I: Study Design
FOLFIRI: irinotecan 180 mg/m2 over 30–90 min; FA 400 mg/m2 over 2 hours; 5-fluorouracil 200 mg/m2 as bolus and 2400 mg/m2 over 46 hours given every 2 weeks
CONTROL ARM (GROUP A)10-patient cohort
ERBITUX (400 mg/m2 on day 1,then 250 mg/m2 weekly)
EXPERIMENTAL ARM (GROUP B)
10-patient cohortsERBITUX at escalating doses for
successive cohorts: 400, 500, 600, 700 mg/m2 once every second week
6 weeks’ treatmentComplete PK profile obtained during this period
FOLFIRI added to patients’ current ERBITUX regimen
Evaluate best overall response
Progression-free survival
PART I
PART II
1º endpointDLT assessment
2º endpoints
Tabernero et al. ASCO GI 2008 (Abstract No. 435)
Study AIO 045 Maybe it is dose related…
KRAS status
Monotherapy Combination therapyWild-type
n=29Mutation
n=19Wild-type
n=29Mutation
n=19RR, n (%)[95% CI]
8 (27.6)[12.7–47.2]
0 (0)[0–17.7]
16 (55.2)[35.7–73.6]
6 (31.6)[12.6–56.6]
p=0.015 p=0.144
Median PFS, months[95% CI] — —
9.4[7.0–11.3]
5.6[3.3–12.2]
HR: 0.47, p=0.0475
• KRAS mutations were detected in 19 samples (40%) of KRAS evaluable population
Tabernero J, et al. ASCO GI 2008 (Abstract No. 435)
… Of course not
Panitumumab anyone?
KRAS wild-type
Amado et al. J Clin Oncol 2008;26
Panitumumab single agent
Amado RG, et al. J Clin Oncol 2008;26:1626-34
181 Trial (PFS) (2°line FOLFIRI+/-panitumumab)
Peeters et al. J Clin Oncol 2010
181 Trial (OS)
Peeters et al. J Clin Oncol 2010
PRIME trial (PFS)(1°line FOLFOX+/-Panitumumab)
Douillard et al. J Clin Oncol 2010
PRIME trial (OS)
Douillard et al. J Clin Oncol 2010
So, we can’t give THAT…But WHAT can we give?
Bevacizumab: IFL+/- Bevacizumab and K-ras status (PFS)
Hurwitz et al. The Oncologist 2009
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25
Duration of PFS (Months)
Prop
ortio
n Pr
ogre
ssio
n-Fr
ee
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25
Duration of PFS (Months)
Prop
ortio
n Pr
ogre
ssio
n-Fr
ee
Group: Mutant (n = 78) Group: Wild-type (n = 152)Median
PFS (mo)
IFL + placebo 5.5 IFL + BV 9.3
Median PFS (mo)
IFL + placebo 7.4 IFL + BV 13.5
HR :0.44; P < .0001HR: 0.41; P = .0008
Bevacizumab: IFL+/- Bevacizumab and K-ras status (OS)
Hurwitz et al. The Oncologist 2009
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25 30Duration of Survival (Months)
Prop
ortio
n Su
rviv
ing
Group: Mutant (n = 78) Group: Wild-type (n = 152)
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25 30Duration of Survival (Months)
Prop
ortio
n Su
rviv
ing
Median OS (mo)
IFL + placebo 13.6 IFL + BV 19.9
Median OS (mo)
IFL + placebo 17.6 IFL + BV 27.7
HR: 0.58; P = .04HR: 0.69; P = .26
• Primary endpoint– 6-month PFS
• Secondary endpoints– OS, PFS, toxicity, secondary resection of liver or lung metastases
Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD)R = randomisation; WT = wild-type; MT = mutant
Bevacizumab + CAPIRI(n=120)
[KRAS WT=44; KRAS MT=21]
Bevacizumab + CAPOX (n=127)
[KRAS WT=56; KRAS MT=21]
Previously untreated mCRC
(n=247)R
AIO 0604 study: design of the trial
Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD)
AIO 0604 study: CAPIRI arm
Reinacher-Schick, et al. ESMO 2010 (Abstract 584PD)
AIO 0604 study: CAPOX arm
Masi, et al. Lancet Oncology 2010
Avastin 5 mg/kg
Irinotecan165 mg/m2
Oxaliplatin85 mg/m2
L-LV200 mg/m2
5-FU continuous infusion3200 mg/m2
Day 1 Days 2–3
Cycles repeated every 2 weeks for 12 cyclesfollowed by maintenance Avastin until PD
FOIB study: design
K-rasa B-rafb
WT(n=34)
MT(n=21)
WT(n=45)
MT(n=10)
Responders, n (%) 28 (82) 15 (71) 34 (75) 9 (90)
Non-responders , n (%) 6 (18) 6 (29) 11 (25) 1 (10)
a Responders vs non-responders: p=0.503 (Fischer’s exact test)b Responders vs non-responders: p=0.430(Fischer’s exact test)
Masi et al. Lancet Oncology 2010
FOIB study: retrospective analysis on K-ras status, RR
Masi et al. Lancet Oncology 2010
Time (months)
100
75
50
25
0
Progression-free (%)
0 10 20 30
K-ras WT: median PFS: 13.4 monthsK-ras MT: median PFS: 12.6 months
Log-rank test: p=0.433
HR=0.78 95% CI: 0.38–1.51
FOIB study: retrospective analysis on K-ras status, PFS
Possible 1°line therapeutic options
– Bevacizumab+FOLFOX (XELOX)– Bevacizumab+FOLFIRI (XELIRI)– FOLFOXIRI
To sum up…
So… Where is the “Difficult” part?
Starting in a “knee-deep in trouble” situation…
K-ras is not only a PREDICTIVE factor…
It is also a PROGNOSTIC factor
Of a WORSE prognosis
K-ras prognostic: RASCAL
CRYSTAL study OS:K-ras also prognostic?
K-ras mutated: a name fits all?
7 more frequent mutations >98%
Rare mutations2%
The only mutation with prognostic value?
RASCAL II
Br J Cancer 2001
The G13D case: someone begs to differ…
So… not every Kras mutated tumor doesn’t respond to anti-EGFR…?
NORDIC VII: trial design
NORDIC VII: PFS according to K-ras status
NORDIC VII: OS according K-ras status
Cetuximab+ FOLFIRI
Cetuximab+ FOLFOX4
Cetuximab+ FOLFIRI
Cetuximab+ OxFp
Cetuximab + FOLFOX 6 or FOLFIRI
Cetuximab+ FOLFIRI
Cetuximab+ FOLFOX 6
Cetuximab+ capecitabine
Cetuximab (continuous)
+ FLOX
Cetuximab+ capecitabine + oxaliplatin
+ bevacizumab
2009 2009 2008 2009 2009 2008 2008 2009 2010 2009
Difference (wt-mt)
Response Rate
NORDIC VII: Comparison with other studies (OS)
Cetuximab+ FOLFIRI
Cetuximab+ FOLFOX4
Cetuximab+ FOLFIRI
Cetuximab+ OxFp
Cetuximab+ FOLFIRI
Cetuximab+ FOLFOX 6
Cetuximab+ capecitabine
Cetuximab (continuous)
+ FLOX
Cetuximab+ capecitabine + oxaliplatin
+ bevacizumab
2009 2009 2008 2009 2008 2008 2009 2010 2009
9,98,3
9,48,6 8,4
9,1 8,67,9
10,5
7,4
5,5 5,66,5
8,17,2
6,0
9,28,1
0
2
4
6
8
10
12
CRYSTAL OPUS EMR62202-045
COIN CECOGCORE 1
CECOGCORE 1
Rivera NORDIC VII(cont)
CAIRO 2
PFS,
mon
ths
KRAS wt KRAS mt
Difference (wt-mt)
PFS
NORDIC VII: Comparison with other studies (PFS)
CAPIRI + cetuximab(n=93)
CAPOX + cetuximab(n=92)
Previously untreated mCRC
(n=185)R
Stintzing, et al. ESMO 2010 (Abstract 582PD)
• Primary endpoint– response rate
• Secondary endpoints– TTP, disease control rate, tolerability
AIO KRK-0204: CAPIRI/CAPOX+Cetuximab
• CAPOX + cetuximab and CAPIRI + cetuximab are feasible, with acceptable toxicity profiles
• Both regimens are effective, with comparable efficacy
• KRAS status did not influence ORR
• KRAS WT patients showed only a trend towards longer OS and PFS vs KRAS MT patients
Stintzing, et al. ESMO 2010 (Abstract 582PD)
AIO KRK-0204: Conclusions
What is then the MOST predictive factor for anti-EGFR efficacy?
Douillard, et al. ASCO 2010
PRIME trial: efficacy by SKIN TOXICITY
Thanks for the attention…