cetuximab plus folfiri: final data from the crystal study on the association of kras and braf...
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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)
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
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
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
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
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
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
CRYSTAL study data cut-offs
• PFS and overall response by independent review committee– 27 July, 2006
• Overall survival– 31 May, 2009
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
Patient characteristics (2)
• 625 KRAS wt tumors were evaluable for BRAF mutation analysis– 566 (91%) were BRAF wt– 59 (9%) were BRAF mt
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
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
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
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
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
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.
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
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
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
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