Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial

Table 1 Patient characteristics at baseline

Characteristic	ITT population		KRAS population
			KRAS wild-type		KRAS mutant
	FOLFOX6 plus cetuximab (n = 77)	FOLFIRI plus cetuximab (n = 74)	FOLFOX6 plus cetuximab (n = 34)	FOLFIRI plus cetuximab (n = 28)	FOLFOX6 plus cetuximab (n = 23)	FOLFIRI plus cetuximab (n = 32)
Gender, n (%)
Male	43 (56)	45 (61)	22 (65)	17 (61)	11 (48)	21 (66)
Female	34 (44)	29 (39)	12 (35)	11 (39)	12 (52)	11 (34)
Age (yr)
Median (Q1-Q3)	62.0 (54-67)	62.5 (54-68)	62.5 (55-67)	64.0 (56-68)	63.0 (49-68)	62.5 (54-70)
< 65, n (%)	46 (60)	46 (62)	19 (56)	17 (61)	13 (57)	19 (59)
> 65, n (%)	31 (40)	28 (38)	15 (44)	11 (39)	10 (43)	13 (41)
ECOG PS, n (%)
0	46 (60)	38 (51)	20 (59)	17 (61)	13 (57)	14 (44)
1	31 (40)	36 (49)	14 (41)	11 (39)	10 (43)	18 (56)
Primary tumor location, n (%)
Colon	52 (68)	47 (64)	26 (76)	15 (54)	13 (57)	22 (69)
Rectum	25 (32)	27 (36)	8 (24)	13 (46)	10 (43)	10 (31)
Metastasis1, n (%)	45 (58)a	46 (62)	17 (50)	18 (64)	16 (70)	18 (56)
Organs with metastases, n (%)
1-2	59 (77)	56 (76)	28 (82)	23 (82)	17 (74)	26 (81)
> 2	18 (23)	18 (24)	6 (18)	5 (18)	6 (26)	6 (19)
Metastatic sites2, n (%)
Intestine/bowel	12 (16)	12 (16)	3 (9)	6 (21)	6 (26)	5 (16)
Liver	66 (86)	63 (85)	30 (88)	24 (86)	20 (87)	26 (81)
Lung	27 (35)	28 (38)	11 (32)	10 (36)	8 (35)	10 (31)
Lymph nodes
Chest	7 (9)	5 (7)	2 (6)	2 (7)	3 (13)	2 (6)
Abdomen	22 (29)	24 (32)	9 (26)	8 (29)	5 (22)	8 (25)
Bone	2 (3)	4 (5)	0 (0)	1 (4)	2 (9)	1 (3)
Other	10 (13)	10 (14)	5 (15)	3 (11)	2 (9)	4 (13)
Duration of disease, mo
CRC, median (Q1-Q3)	2.1a (1-15)	1.9 (1-14)	2.2 (1-18)	1.8 (1-6)	1.8 (1-3)	2.4 (1-18)
mCRC median (Q1-Q3)	1.4 (1-2)	1.2 (1-2)	1.1 (1-2)	1.0 (1-2)	1.3 (1-2)	1.4 (1-2)
EGFR status, n (%)
Detectable	43 (56)	46 (62)	21 (62)	20 (71)	17 (74)	24 (75)
Undetectable	17 (22)	12 (16)	10 (29)	4 (14)	5 (22)	7 (22)
Non evaluable	17 (22)	16 (22)	3 (9)	4 (14)	1 (4)	1 (3)
Prior treatment, n (%)
At least 1 therapy	63 (82)	59 (80)	31 (91)	22 (79)	19 (83)	29 (91)
Adjuvant chemotherapy3	14 (18)	10 (14)	9 (26)	2 (7)	2 (9)	6 (19)
Surgery	61 (79)	58 (78)	30 (88)	22 (79)	18 (78)	29 (91)
Other	8 (10)	5 (7)	3 (9)	2 (7)	3 (13)	2 (6)

¹Metastases detected within 1 mo of tumor diagnosis;

²Patients with >1 metastasis per organ site, the organ site was counted once only;

³Three patients included with rectal cancer received neoadjuvant therapy;

^aValue determined from 76 patients. Patients receiving FOLFOX6 plus cetuximab (arm A) and those receiving FOLFIRI plus cetuximab (arm B). ITT: Intention to treat; FOLFOX: 5-fluorouracil (5-FU) folinic acid (FA) and oxaliplatin; FOLFIRI: 5-FU FA and irinotecan; ECOG: Eastern Cooperative Oncology Group; PS: Performance status; Q1-Q3: Interquartile range; mCRC: Metastatic colorectal cancer.

Table 2 Treatment exposure in the safety population

Characteristic	FOLFOX6 plus cetuximab (arm A, n = 77)	FOLFIRI plus cetuximab (arm B, n = 74)
Exposure to cetuximab (Q1-Q3)
Median duration, wk	28.0 (17-46)	29.1 (13-46)
Median number of infusions	26.0 (14-40)	26.0 (12-42)
Relative dose intensity, n (%)
Only initial dose	4 (5)	3 (4)
< 60%	2 (3)	3 (4)
60% to < 80%	15 (19)	8 (11)
80% to < 90%	21 (27)	20 (27)
≥ 90%	35 (45)	40 (54)
Exposure to chemotherapy (Q1-Q3)
Median duration, wk	25.1 (19-28)	25.5 (14-28)
Median number of cycles	12 (7-12)	12 (6-12)
Relative dose intensity, n (%)
Oxaliplatin
No dose	1 (1)	74 (100)
< 60%	4 (5)	-
60% to < 80%	24 (31)	-
80% to < 90%	22 (29)	-
≥ 90%	26 (34)	-
Irinotecan
No dose	77 (100)	2 (3)
< 60%	-	3 (4)
60% to < 80%	-	18 (24)
80% to < 90%	-	13 (18)
≥ 90%	-	38 (51)
Bolus 5-FU
No dose	1 (1)	2 (3)
< 60%	1 (1)	2 (3)
60% to < 80%	28 (36)	19 (26)
80% to < 90%	19 (25)	14 (19)
≥ 90%	28 (36)	37 (50)
Continuous infusion 5-FU
No dose	1 (1)	2 (3)
< 60%	1 (1)	3 (4)
60% to < 80%	21 (27)	14 (19)
80% to < 90%	13 (17)	11 (15)
≥ 90%	41 (53)	44 (59)
Dose reductions1, n (%)
Cetuximab	9 (12)	5 (7)
Chemotherapy	25 (32)	17 (23)
Treatment delays1, n (%)
Any cetuximab
≥ 3 d	59 (77)	47 (64)
≥ 16 d	12 (16)	8 (11)
Any chemotherapy
≥ 3 d	59 (77)	51 (69)
≥ 14 d	25 (32)	15 (20)
Treatment discontinuation1, n (%)
Cetuximab	13 (17)	9 (12)
Chemotherapy	9 (12)	4 (5)

¹Dose reductions, treatment delays and discontinuations due to adverse events.

Table 3 Efficacy in the ITT population

Characteristic	FOLFOX6 plus cetuximab (arm A, n = 77)	FOLFIRI plus cetuximab (arm B, n = 74)
PFS
Events, n (%)	61 (79)	59 (80)
Median1, mo (95% CI)	8.6 (6.3-9.7)	8.3 (7.4-8.7)
Log rank P-value	0.7375
Hazard ratio (95% CI)	1.06 (0.74-1.52)
PFS rate1, % (95% CI)
3 mo	92 (85-98)	78 (68-88)
6 mo	69 (58-80)	69 (58-80)
9 mo	45 (33-58)	34 (23-46)
12 mo	18 (8-27)	18 (8-27)
Overall survival
Events, n (%)	54 (70)	50 (68)
Median1, mo (95% CI)	17.4 (14.9-22.6)	18.9 (14.7-23.9)
Logrank P-value	0.9230
Hazard ratio2 (95% CI)	0.98 (0.67-1.44)
Survival rate1, % (95% CI)
9 mo	79 (70-88)	79 (70-89)
12 mo	70 (60-80)	71 (60-81)
18 mo	46 (35-57)	53 (42-65)
24 mo	33 (22-44)	38 (26-50)
Best overall response, n (%)
CR	2 (3)	6 (8)
PR	31 (40)	27 (36)
SD	31 (40)	24 (32)
PD	6 (8)	9 (12)
NE	7 (9)	8 (11)
Objective response rate, n (%)	33 (43)	33 (45)
95% CI	32-55	33-57
Odds ratio (95% CI)	0.93 (0.49-1.77)

¹Median time and rates are based on Kaplan-Meier estimates;

²Hazard ratio and corresponding 95% CI based on unadjusted Cox proportional hazard model: hazard rate FOLFIRI plus cetuximab divided by hazard rate FOLFOX6 plus cetuximab. CR: Complete response; NE: Not evaluable; PD: Progressive disease; PFS: Progression-free survival; PR: Partial response; SD: Stable disease.

Table 4 Efficacy in the KRAS population

Parameter	KRAS population		FOLFOX6 plus cetuximab (arm A)		FOLFIRI plus cetuximab (arm B)
	KRAS wild-type (n = 62)	KRAS mutation (n = 55)	KRAS wild-type (n = 34)	KRAS mutation (n = 23)	KRAS wild-type (n = 28)	KRAS mutation (n = 32)
PFS
Events, n (%)	46 (74)	47 (85)	26 (76)	20 (87)	20 (71)	27 (84)
Median1, mo (95% CI)	8.9 (7.3-11.1)	7.8 (6.4-8.4)	9.1 (8.3-11.1)	7.2 (5.5-9.7)	8.4 (3.2-11.3)	8.1 (7.3-8.5)
Logrank P-value	0.0051		0.0196		0.1737
HR2 (95% CI)	0.55 (0.36-0.84)		0.49 (0.27-0.91)		0.66 (0.36-1.21)
PFS rate1, % (95% CI)
3 mo	81 (70-91)	88 (80-97)	90 (80-100)	91 (79-100)	69 (51-87)	87 (75-99)
6 mo	70 (58-82)	70 (57-83)	77 (62-92)	62 (41-83)	61 (42-80)	76 (60-91)
9 mo	49 (35-62)	26 (14-39)	53 (35-71)	31 (11-52)	43 (24-63)	23 (7-39)
12 mo	29 (17-41)	11 (2-20)	28 (12-45)	10 (0-24)	30 (12-49)	11 (0-24)
Overall survival
Events, n (%)	37 (60)	45 (82)	21 (62)	20 (87)	16 (57)	25 (78)
Median1, mo (95% CI)	20.8 (16.6-26.9)	15.9 (14.4-18.9)	22.5 (17.1-28.9)	15.2 (11.1-17.3)	19.9 (11.9-na)	18.9 (14.5-23.9)
Logrank P-value	0.0296		0.0201		0.3608
HR2 (95% CI)	0.62 (0.40-0.96)		0.48 (0.26-0.90)		0.74 (0.39-1.40)
Survival rate1 (95% CI)
9 mo	79 (69-89)	87 (78-96)	85 (73-97)	83 (67-98)	71 (54-88)	90 (80-100)
12 mo	72 (61-83)	74 (63-86)	76 (62-91)	65 (46-85)	67 (49-85)	81 (67-95)
18 mo	55 (42-68)	41 (28-55)	55 (38-72)	24 (6-42)	56 (37-74)	54 (36-72)
24 mo	44 (31-57)	24 (12-36)	43 (25-61)	14 (0-29)	45 (26-65)	32 (14-49)
Best overall response, n (%)
CR	6 (10)	1 (2)	2 (6)	-	4 (14)	1 (3)
PR	27 (44)	19 (35)	17 (50)	7 (30)	10 (36)	12 (38)
SD	14 (23)	26 (47)	9 (26)	12 (52)	5 (18)	14 (44)
PD	8 (13)	6 (11)	3 (9)	3 (13)	5 (18)	3 (9)
NE	7 (11)	3 (5)	3 (9)	1 (4)	4 (14)	2 (6)
ORR, n (%)	33 (53)	20 (36)	19 (56)	7 (30)	14 (50)	13 (41)
95% CI	40-66	24-50	38-73	13-53	31-69	24-59
Odds ratio (95% CI)	1.99 (0.95-4.18)		2.90 (0.95-8.84)		1.46 (0.53-4.07)

¹Median time and rates are based on Kaplan Meier estimates;

²Hazard ratio and corresponding 95% CI based on unadjusted Cox proportional hazard model: Hazard rate KRAS mutation divided by KRAS wild-type. na: Not available; ORR: Objective response rate.

Table 5 Grade 3/4 adverse events related to study treatment and special adverse event categories in the safety and KRAS populations n (%)

Adverse event	FOLFOX6 plus cetuximab (arm A)		FOLFIRI plus cetuximab (arm B)
	Grade 3/4a	Grade 4	Grade 3/4a	Grade 4
Safety populationb
Any related AE	48 (62)	12 (16)	37 (50)	6 (8)
Neutropenia	22 (29)	9 (12)	15 (20)	4 (5)
Diarrhea	7 (9)	-	9 (12)	-
Rash	5 (6)	-	3 (4)	-
Dermatitis acneiform	4 (5)	-	2 (3)	-
Special AE categories
Skin reactionsc	11 (14)	-	6 (8)	-
Acne-like rashd	10 (13)	-	6 (8)	-
Infusion-related reactionse	5 (6)	2 (3)	1 (1)	1 (1)
Allergy/anaphylaxis	5 (6)	2 (3)	1 (1)	1 (1)
KRAS wild-type populationf
Any related AE	24 (71)	5 (15)	10 (36)	1 (4)
Neutropenia	12 (35)	3 (9)	3 (11)	1 (4)
Diarrhea	3 (9)	-	2 (7)	-
Dermatitis acneiform	3 (9)	-	-	-
Mucosal inflammation	3 (9)	-	-	-
Rash	2 (6)	-	-	-
Neuropathy peripheral	2 (6)	-	-	-
Hypersensitivity	2 (6)	1 (3)	-	-
Special AE categories
Skin reactionsc	6 (18)	-	1 (4)	-
Acne-like skin rashd	5 (15)	-	1 (4)	-
Infusion-related reactionse	2 (6)	1 (3)	-	-
Allergy/anaphylaxis	2 (6)	1 (3)	-	-
KRAS mutation populationg
Any related AE	14 (61)	4 (17)	18 (56)	4 (13)
Neutropenia	6 (26)	3 (13)	9 (28)	2 (6)
Diarrhea	3 (13)	-	4 (13)	-
Thrombocytopenia	2 (9)	-	-	-
Rash	1 (4)	-	2 (6)	-
Mucosal inflammation	-	-	2 (6)	-
Dehydration	-	-	2 (6)
Special AE categories
Skin reactionsc	2 (9)	-	3 (9)	-
Acne-like rashd	2 (9)	-	3 (9)	-
Infusion-related reactionse	2 (9)	1 (4)	1 (3)	1 (3)
Allergy/anaphylaxis	2 (9)	1 (4)	1 (3)	1 (3)

^aGrade 3/4 adverse events occurring in ≥ 5% of patients in either treatment group in each population are reported;

^bSafety population: 77 patients received FOLFOX6 plus cetuximab in arm A, 74 patients received FOLFIRI plus cetuximab in arm B; ^c-eComposite categories. Skin reactions include the terms: acne*, acne pustular*, cellulitis, dermatitis acneiform*, dry skin*, erysipelas, erythema*, face edema, folliculitis*, hair growth abnormal, hypertrichosis, nail bed infection, nail disorder, nail infection, paronychia, pruritus*, rash*. Of these, all terms marked with an asterisk constituted the acne-like rash subset of the skin reaction category. Infusion-related reactions refer to special adverse-event categories, including the MedDRA preferred terms: acute myocardial infarction, acute respiratory failure, anaphylactic reaction, **anaphylactic shock, **anaphylactoid reaction, **anaphylactoid shock, **angina pectoris, apnea, bronchial obstruction, bronchospasm, cardiac failure, cardiopulmonary failure, chills, clonus, convulsion, cyanosis, drug hypersensitivity, **dyspnea, dyspnea at rest, dyspnea exacerbated, dyspnea exertional, epilepsy, hyperpyrexia, hypersensitivity, **hypotension, **hypoxia, infusion-related reaction, loss of consciousness, myocardial infarction, myocardial ischemia, orthopnea, pyrexia, respiratory distress, respiratory failure, shock, sudden death, syncope. A double asterisk refers to those included regardless of when they occurred, all other terms were included only if the onset of the adverse event occurred on the same day as the first administration of cetuximab;

^gPatients with KRAS wild-type tumors: 34 in arm A, 28 in arm B;

^fPatients whose tumors harbored KRAS mutations: 23 in arm A, 32 in arm B. AE: Adverse event.