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Cetuximab plus FOLFIRI: Final data from the CRYSTAL study on the association of KRAS and BRAF biomarker status with
treatment outcome
Eric Van Cutsem*, I. Lang, G. Folprecht, M. Nowacki, C. Barone, I. Shchepotin, J. Maurel, D.
Cunningham, I. Celik, C-H. Köhne.
*University Hospital Gasthuisberg, Leuven, Belgium
(Presenting author)
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Background (1)
• In the CRYSTAL study,1 patients with KRAS wild-type tumors (KRAS wt) treated 1st-line with FOLFIRI plus cetuximab compared with FOLFIRI alone experienced:– A significantly reduced risk of disease progression (hazard ratio
[HR], 0.68, p=0.02)– An increased chance of tumor response (odds ratio, 1.91)
• This confirmed earlier findings that cetuximab efficacy was confined to patients with KRAS wt metastatic colorectal cancer (mCRC)2,3,4
1Van Cutsem E, et al. N Engl J Med 2009;360:1408-172Bokemeyer C, et al. J Clin Oncol 2009;27:663-71
3De Roock W, et al. Ann Oncol 2008;19:508-154Lievre A, et al. J Clin Oncol 2008;26:374-9
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Background (2)
• Serine-threonine kinase BRAF is a direct downstream effector of KRAS
• BRAF gene mutations have been detected in 8% of colon cancers (stage II/III – PETACC-3)1
• BRAF mutation status has been suggested to be predictive of cetuximab efficacy in pretreated patients with mCRC2,3
1Roth A, et al. J Clin Oncol 2010; 28:466-742Di Nicolantonio F, et al. J Clin Oncol 2008;26:5705-12
3Tejpar S et al on behalf of EU consortium, ECCO/ESMO, 2009
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Background (3)
• An updated analysis of the CRYSTAL study primary analysis population showed:– Significantly longer survival in the FOLFIRI plus cetuximab vs
FOLFIRI alone arm (HR 0.88, p=0.04)1
• In an updated retrospective analysis, the impact of BRAF mutation status on cetuximab efficacy in patients with KRAS wt tumors was investigated
1Lang I, et al. Eur J Cancer Supplements 2009; 7: S345; P-607
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CRYSTAL study endpoints
• Primary endpoint– Progression-free survival (PFS)
• Secondary endpoints– Overall survival (OS), best overall response (OR), safety
• Retrospective analysis– The effect of KRAS and BRAF tumor mutation status on PFS
time, OR and OS time
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The CRYSTAL study
FOLFIRI + cetuximab
FOLFIRI
EGFR- expressing mCRC
Stratification factor: ECOG PS 0-1, 2
R
Treatment until progression, symptomatic deterioration or unacceptable toxicity
Irinotecan
5-FU
LV
FOLFIRI (q2w)
400 mg/m2 initial dose then
250 mg/m2 weekly
180 mg/m2, day 1
400 mg/m2 bolus then
600 mg/m2 infusion, day 1 and 2
200 mg/m2, day 1
Cetuximab
ECOG PS, Eastern Cooperative Oncology Group performance status; 5-FU, 5-fluorouracil; LV, leucovorin
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KRAS/BRAF tumor mutation analysis
• Sample numbers for KRAS and BRAF mutation status were increased by using DNA extracted from formalin fixed paraffin embedded slide mounted tumor sections prepared to evaluate tumor EGFR expression
• KRAS mutations at codons 12/13 and BRAF (V600E) mutations were detected using a polymerase chain reaction clamping and melting curve technique1
1Van Cutsem E, et al. N Engl J Med 2009;360:1408-17
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CRYSTAL study data cut-offs
• PFS and overall response by independent review committee– 27 July, 2006
• Overall survival– 31 May, 2009
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Patient characteristics (1)
• Of 1198 patients in the primary analysis population – 1063 (89%) were evaluable for KRAS mutation status – 1000 (83%) were evaluable for BRAF mutation status
• BRAF mutations were detected in 60/1000 (6%) evaluable samples– 1 tumor was both KRAS mt and BRAF mutant (BRAF mt)
• 666/1063 (63%) patients had KRAS wt tumors
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Patient characteristics (2)
• 625 KRAS wt tumors were evaluable for BRAF mutation analysis– 566 (91%) were BRAF wt– 59 (9%) were BRAF mt
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Patient characteristics (3)
• Baseline characteristics were generally balanced across populations and by treatment group1
• Noteworthy differences were in patients with KRAS wt/BRAF mt tumors receiving FOLFIRI plus cetuximab vs FOLFIRI:– ≥65 years old (50% vs 33%)– Liver metastases only (35% vs 12%)– ECOG PS 2 (0 vs 9%)
1Van Cutsem E, et al. ASCO Gastrointestinal Cancer Symposium Proceedings 2010: Abstract 281
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Efficacy data in patients with KRAS wt tumorsKRAS wt(n=666)
KRAS wt/BRAF wt(n=566)
KRAS wt/BRAF mt(n=59)
FOLFIRI
n=350
FOLFIRI + cetuximab
n=316
FOLFIRI
n=289
FOLFIRI + cetuximab
n=277
FOLFIRI
n=33
FOLFIRI + cetuximab
n=26
Overall survival
Median, mo[95% CI]
20.0[17.4‒21.7]
23.5[21.2‒26.3]
21.6[20.0‒24.9]
25.1[22.5‒28.7]
10.3[8.4‒14.9]
14.1[8.5‒18.5]
Hazard ratio[95% CI] p-value
0.796[0.670‒0.946]
0.0093
0.830[0.687‒1.004]
0.0547
0.908[0.507‒1.624]
0.7435
PFS
Median, mo[95% CI]
8.4[7.4‒9.2]
9.9[9.0‒11.3]
8.8[7.6‒9.4]
10.9[9.4‒11.8]
5.6[3.8‒8.1]
8.0[3.6‒9.1]
Hazard ratio[95% CI]P-value
0.696[0.558‒0.867]
0.0012
0.673[0.528‒0.858]
0.0013
0.934[0.425‒2.056]
0.8656
Tumor response
OR rate (%)[95% CI]
39.7[34.6‒45.1]
57.3[51.6‒62.8]
42.6[36.8‒48.5]
61.0[55.0‒66.8]
15.2[5.1‒31.9]
19.2[6.6‒39.4]
Odds ratio[95% CI] p-value
2.069[1.515‒2.826]
<0.0001
2.175[1.551‒3.051]
<0.0001
1.084[0.264‒4.446]
0.9136
CI, confidence interval; mt, mutant; PFS, progression-free survival; OR, best overall response rate; OS, overall survival; wt, wild-type
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Tumor regression according to treatment status in patients with KRAS wt tumors
In patients with KRAS wt tumors the addition of cetuximab to FOLFIRI compared with FOLFIRI alone, led to a mean difference in the best % change in sum of the product diameters of 13.9
*Data for 21 patients were missing; **Data for 16 patients were missingwt, wild-type; SOPD, sum of the product diameters
FOLFIRI + cetuximab, n=316**
FOLFIRI, n=350*
% c
hang
e in
lesi
on (
SO
PD
)
-100
-80
-60
-40
-20
0
20
40
60
80
100
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Subgroup (number of patients in Group A vs B) HR [95% CI]All KRAS wt (316 vs 350) 0.70 [0.56‒0.87]Age
<65 years (200 vs 234) 0.66 [0.50‒0.87]≥65 years (116 vs 116) 0.79 [0.54‒1.15]
GenderMale (196 vs 211) 0.60 [0.44‒0.80]Female (120 vs 139) 0.83 [0.59‒1.17]
ECOG PS 0 - 1 (303 vs 336) 0.68 [0.54‒0.85]2 (13 vs 14) 1.03 [0.44‒2.43]
Number of metastatic sites≤2 (277 vs 295) 0.70 [0.55‒0.89]>2 (33 vs 49) 0.78 [0.43‒1.42]
Liver metastases onlyYes (68 vs 72) 0.56 [0.32‒0.97]No (248 vs 278) 0.74 [0.58‒0.94]
Leukocytes≤10000/mm3 (258 vs 284) 0.70 [0.55‒0.90]>10000/mm3 (48 vs 58) 0.73 [0.43‒1.26]
LDH at baseline> upper normal range (138 vs 150) 0.75 [0.54‒1.05]≤ upper normal range (144 vs 161) 0.69 [0.50‒0.97]
Alkaline phosphatase at baseline≥300 U/L (30 vs 42) 0.77 [0.39‒1.52]<300 U/L (272 vs 295) 0.68 [0.53‒0.86]
Prior adjuvant chemotherapyYes (80 vs 73) 0.77 [0.49‒1.21]No (236 vs 277) 0.67 [0.52‒0.87]
PFS by subgroups in KRAS wt patients
HR and 95% CI
Group A, FOLFIRI + cetuximab; Group B, FOLFIRI
0.3 0.4 0.5 1 2 3 4
Benefit under cetuximab No benefit under cetuximab
CI, confidence interval; ECOG PS, Eastern Cooperative Group performance status; HR, hazard ratio; LDH, lactate dehydrogenase; PFS, progression-free survival; wt, wild-type
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PFS in patients with KRAS wt tumors
FOLFIRI
Number of patients
FOLFIRI + cetuximab 316 227 128 40 8 1
350 237 111 22 4 0
CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; wt, wild-type
FOLFIRI
(n=350)
FOLFIRI + cetuximab
(n=316)
No of events 189 146
Median PFS 8.4 months 9.9 months
[95% CI] [7.4‒9.2] [9.0‒11.3]
HR [95% Cl]
p-value
0.696 [0.558‒0.867]
0.0012
Pro
bab
ility
of
PF
S
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
120 4 8 16 20
FOLFIRI + cetuximabFOLFIRI
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OS in patients with KRAS wt tumors
FOLFIRI
Number of patients
FOLFIRI + cetuximab
CI, confidence interval; HR, hazard ratio; OS, overall survival; wt, wild-type
FOLFIRI*
(n=350)
FOLFIRI + cetuximab**
(n=316)
No of events 288 242
Median OS 20.0 months 23.5 months
[95% CI] [17.4‒21.7] [21.2‒26.3]
HR [95% Cl]
p-value
0.796 [0.670‒0.946]
0.0093
Pro
bab
ility
of
over
all
surv
ival
Time (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
FOLFIRI + cetuximabFOLFIRI
180 6 12 24 5430 36 42 48
316 281 237 198 144 108 82 65 21 4
350 311 246 179 132 92 64 48 18 2
Median follow up was *46 .9 months and **46.2 months.
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Treatment interactions
• Significant interactions between treatment outcome and KRAS tumor mutation status were observed for:1
– Tumor response (p=0.0005)– PFS (p=0.003)– OS (p=0.046)
• No significant interactions between treatment outcomes and BRAF tumor mutation status were observed for:– Tumor response (p=0.87)– PFS (p=0.56)– OS (p=0.25)
1Lang I, et al. Eur J Cancer Supplements 2009; 7: S345. P-607
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Conclusions: KRAS
• This final analysis shows for the first time in a randomized study that patients with KRAS wt mCRC treated with FOLFIRI plus a targeted agent (cetuximab) in the 1st-line setting had significantly prolonged OS compared with FOLFIRI alone
• For all efficacy endpoints including survival, this analysis confirms the value of KRAS mutational status as a predictor of treatment outcome in patients with mCRC receiving FOLFIRI plus cetuximab 1st-line
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Conclusions: BRAF
• The analysis suggests that a mutation in BRAF is an indicator of poor prognosis in patients receiving 1st-line treatment for mCRC
• The role of BRAF mutation as a predictive biomarker for the efficacy of cetuximab added to FOLFIRI 1st-line in patients with mCRC is not proven in this study
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Acknowledgments
• The authors would like to thank patients, investigators, co-investigators and the study teams at each of the participating centers and at Merck KGaA, Darmstadt, Germany