Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer: the influence of KRAS and

BRAF biomarkers on outcome: updated data from the CRYSTAL trial

Eric Van Cutsem*, I. Lang, G. Folprecht, M. Nowacki,

S. Cascinu, I. Shchepotin, J. Maurel,

D. Cunningham, P. Rougier,

I. Celik, C.H. Köhne

*University Hospital Gasthuisberg,

Leuven, Belgium

Background: The CRYSTAL trial

• KRAS wild-type mCRC patients treated 1st-line with cetuximab plus FOLFIRI compared with FOLFIRI alone experienced– Reduced risk of disease progression (Hazard Ratio, 0.68)1

– Increased chance of tumor response (59% vs 43%, p=0.0025)2

• In this final analysis we report– Increased follow-up time – Increased population of evaluable tumors for KRAS and BRAF

mutations– The impact of BRAF mutation status on cetuximab efficacy in

patients with KRAS wild-type tumors

1Van Cutsem E, et al. N Engl J Med 2009;360:1408-17;2 Van Cutsem E, et al. J Clin Oncol 2008;26: (suppl; abstr 2)

The CRYSTAL study

ECOG PS, Eastern Cooperative Oncology Group performance status; 5-FU, 5 fluorouracil; LV, leucovorin

Endpoints:•Primary- PFS time•Secondary- OS time, best overall response (OR) rate and safety

Retrospective subgroup analyses:•OS, PFS and OR by KRAS mutation status

Cetuximab + FOLFIRI

FOLFIRI

Previously untreatedmCRC

EGFR-expressing

Stratification factorECOG PS 0-1, 2

R

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

Treatment until progression, symptomatic deterioration or unacceptable toxicity

Background: BRAF

• 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; 28:466-74;2Di Nicolantonio F, et al. J Clin Oncol 2008;26:5705-12;

3Tejpar S et al on behalf of EU consortium, ECCO/ESMO, 2009

KRAS/BRAF evaluable population

666 (63%) KRAS wild-type

540/1198 subjects (45% of ITT)1: KRAS evaluable population

1063 (89%) subjects: updated KRAS evaluable population

625 (59%) KRAS wild-type/BRAF evaluable

KRAS wild-type/BRAF wild-type566/625 (91%)

KRAS wild-type/BRAF mutant 59/625 (9%)

• Sample numbers for KRAS and BRAF mutation status were increased using DNA extracted from tumor from paraffin blocks or formalin fixed paraffin embedded slide mounted sections prepared to evaluate tumor EGFR expression

• KRAS (codons 12/13) and BRAF (V600E) mutations were detected using a PCR clamping and melting curve technique• BRAF mutations were detected in a total of 60/1000 (6%) evaluable samples,1 patient was also KRAS mutant

1Van Cutsem E, et al. N Engl J Med 2009;360:1408-17

Baseline characteristics according to tumor KRAS/BRAF mutation status

KRAS wt(n=666)

KRAS wt/ BRAF wt (n=566)

KRAS wt/ BRAF mt(n=59)

Parameter FOLFIRI

(n= 350)

Cetuximab + FOLFIRI (n= 316)

FOLFIRI

(n= 289)

Cetuximab +FOLFIRI (n= 277)

FOLFIRI 

(n=33)

Cetuximab +FOLFIRI

(n=26)

Gender, male % 60 62 61 64 55 58

Median age, yrs (range)

59 (19–84)

61(24–79)

59 (19–84)

60 (24–79)

58 (25–75)

65 (34–79)

<65 yrs, % 67 63 67 64 67 50

ECOG PS 0-1, % 96 96 97 96 91 100

Liver-limited disease, % 21 22 22 21 12 35

Involved disease sites ≤2, % 84 88 86 88 72 81

Prior adjuvant chemotherapy , % 21 25 22 27 18 15

ECOG PS, Eastern Cooperative Group performance status; mt, mutant;wt, wild-type

PFS in patients with KRAS wild-type tumors

FOLFIRI

Number of patientsCetuximab + FOLFIRI 316 227 128 40 8 1

350 237 111 22 4 0

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

FOLFIRI Cetuximab + FOLFIRI

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 (log-rank)

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

Cetuximab + FOLFIRI

FOLFIRI

Subgroup (number of patients in Group A vs B) HR [95% CI] [95% CI]All ITT Subjects (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]

Leucocytes≤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 wild-type patients

HR and 95% CI

Group A, cetuximab + FOLFIRI; 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

OS in patients with KRAS wild-type tumors

FOLFIRI

Number of patientsCetuximab + FOLFIRI

CI, confidence interval; HR, hazard ratio; OS, overall survival

FOLFIRI Cetuximab + FOLFIRI

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 (log-rank)

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

Cetuximab + FOLFIRI

FOLFIRI

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 months

Subgroup (number of patients in Group A vs B) HR [95% CI] [95% CI]All ITT Subjects (316 vs 350) 0.80 [0.67, 0.95]Age

<65 years (200 vs 234) 0.71 [0.57, 0.89]≥65 years  (116 vs 116) 0.98 [0.73, 1.30]

GenderMale (196 vs 211) 0.82 [0.66, 1.03]Female (120 vs 139) 0.72 [0.55, 0.95]

ECOG PS 0 - 1 (303 vs 336) 0.78 [0.65, 0.93]2 (13 vs 14) 1.31 [0.57, 3.03]

Number of metastatic sites≤2 (277 vs 295) 0.81 [0.67, 0.98]>2 ( 33 vs 49) 0.69 [0.41, 1.14]

Liver metastases onlyYes ( 68 vs 72) 0.85 [0.57, 1.28]No (248 vs 278) 0.79 [0.65, 0.95]

Leucocytes≤10000/mm3 (258 vs 284) 0.78 [0.64, 0.94]>10000/mm3 (48 vs 58) 0.94 [0.61, 1.44]

LDH at baseline> upper normal range (138 vs 150) 0.72 [0.56, 0.93]≤ upper normal range (144 vs 161) 0.94 [0.72, 1.22]

Alkaline Phosphatase at baseline≥300 U/L (30 vs 42) 0.74 [0.43, 1.28]< 300 U/L (272 vs 295) 0.81 [0.67, 0.98]

Prior adjuvant chemotherapyYes (80 vs 73) 0.83 [0.58, 1.21]No (236 vs 277) 0.79 [0.65, 0.96]

OS by subgroups in KRAS wild-type patients

HR and 95% CIBenefit under cetuximab No benefit under cetuximab

0.3 0.4 0.5 1 2 3 4

Group A, cetuximab + FOLFIRI; Group B, FOLFIRI

CI, confidence interval; ECOG PS, Eastern Cooperative Group performance status; HR, hazard ratio; LDH, lactate dehydrogenase; OS, overall survival

Response in patients with KRAS wild-type tumors

FOLFIRI (n= 350)

Cetuximab + FOLFIRI (n= 316)

OR rate (%)[95% CI]

39.7[34.6–45.1]

57.3[51.6–62.8]

Odds ratio[95% CI]p-valuea

2.0693[1.5154–2.8258]

<0.0001aCochran-Mantel-Haenszel test

CI, confidence interval; OR, best overall response

Tumor regression according to treatment in patients with KRAS wild-type tumors

For patients receiving cetuximab + FOLFIRI compared with FOLFIRI alone, the mean difference in the best % change of the lesion (based on WHO criteria) was 13.9%

*Data for 16 patients were missing; **Data for 21 patients were missing

Cetuximab + FOLFIRI, n=316*

FOLFIRI, n=350**

Cha

nge

in le

sion

(%

)

-100

-80

-60

-40

-20

0

20

40

60

80

100

Clinical efficacy in KRAS wild-type tumors by BRAF mutation status

KRAS wt/BRAF wt (n=566)

KRAS wt/BRAF mt (n=59)

FOLFIRI 

(n= 289)

Cetuximab +FOLFIRI (n= 277)

FOLFIRI 

(n=33)

Cetuximab +FOLFIRI

(n=26)

Median OS mo[95% CI]

21.6[20.0–24.9]

25.1[22.5–28.7]

10.3[8.4–14.9]

14.1[8.5–18.5]

HR [95% CI]p-valuea

0.830 [0.687–1.004]0.0549

0.908 [0.507–1.624]0.7440

Median PFS mo[95% CI]

8.8[7.6–9.4]

10.9[9.4–11.8]

5.6[3.5–8.1]

8.0[3.6–9.1]

HR [95% CI]p-valuea

0.679 [0.533–0.864]0.0016

0.934 [0.425–2.056]0.8656

OR rate (%)[95% CI]

42.6[36.8–48.5]

61.0[55.0–66.8]

15.2[5.1–31.9]

19.2[6.6–39.4]

p-valueb <0.0001 0.9136

CI, confidence interval; OR, best overall response; OS, overall survival; PFS, progression-free survival; mo, months; mt, mutant; wt, wild-type

aStratified log-rank test; bCochran-Mantel-Haenszel test

Conclusions: KRAS in the CRYSTAL trial

• This final analysis shows for the first time in a randomized study that the addition of a targeted agent (cetuximab) to FOLFIRI in the 1st-line treatment of patients with metastatic colorectal cancer with KRAS wild-type tumors significantly improved OS compared to FOLFIRI alone

• This final analysis confirms KRAS tumor mutation status to be a predictive factor across all efficacy endpoints examined for cetuximab in combination with FOLFIRI

Conclusions: BRAF in the CRYSTAL trial

• The analysis suggests BRAF tumor mutation to be a poor prognostic factor in 1st-line mCRC

• BRAF mutation status does not appear to be a strong predictive biomarker for the addition of cetuximab to FOLFIRI in 1st-line treatment of mCRC

Acknowledgements

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