Cetuximab plus irinotecan in pretreated metastatic colorectal cancer patients: The ELSIE study

Table 1 Patients and disease characteristics at baseline (intention-to-treat/safety population)

Characteristic	Patients(n = 123)
Patient characteristics
Median age, yr (range)	56 (24-78)
Age categories, n (%)
< 65 yr	92 (74.8)
≥ 65-75 yr	28 (22.8)
≥ 75 yr	3 (2.4)
Gender, n (%)
Male	73 (59.3)
Female	50 (40.7)
Ethnic origin, n (%)
Caucasian	9 (7.3)
Asian (Chinese)	66 (53.7)
Asian (non Chinese)	48 (39.0)
Karnofsky performance status, n (%)
80	39 (31.7)
90	52 (42.3)
100	32 (26.0)
Disease characteristics
Median duration of CRC, mo (range)	15.7 (2-78)
Median duration of mCRC, mo (range)	8.8 (1-56)
Localization of tumor, n (%)
Colon	71 (57.7)
Rectum	49 (39.8)
Colon and rectum	3 (2.4)
No. of organs with metastasis, n (%)
1	51 (41.5)
2	53 (43.1)
3	12 (9.8)
> 3	7 (5.7)
Previous treatment, n (%)
No. of previous treatment lines (non-adjuvant)
1	66 (53.7)
2	37 (30.1)
3	20 (16.3)
Previous adjuvant chemotherapy	37 (30.1)
Previous non-adjuvant oxaliplatin therapy	50 (40.7)
Most recent irinotecan therapy, n (%)
100 or 125 mg/m2 weekly for 4 consecutive wk followed by 2 wk of rest	1 (0.8)
100 or 125 mg/m2 weekly for 2 consecutive wk out of 3	15 (12.2)
180 or 210 mg/m2 every 2 wk1	94 (76.4)
300 or 350 mg/m2 every 3 wk	9 (7.3)
Other	4 (3.3)
Type of therapy, n (%)
Irinotecan monotherapy	10 (8.1)
Irinotecan + 5-FU or analog	104 (84.6)
Irinotecan + 5-FU or analog + other	8 (6.5)
Irinotecan + other	4 (3.3)
Median duration, wk (Q1-Q3)	14.3 (7.3-22.4)
Best overall response to most recent irinotecan treatment, n (%)
Complete response	3 (2.4)
Partial response	17 (13.8)
Stable disease	43 (35.0)
Progressive disease	59 (48.0)
Missing	1 (0.8)

¹One patient received 210 mg/m² and 93 received 180 mg/m² every 2 wk. CRC: Colorectal cancer; 5-FU: 5-fluorouracil; mCRC: Metastatic colorectal cancer; PD: Progressive disease; Q1-Q3: Interquartile range.

Table 2 Extent of exposure to cetuximab and irinotecan (intention-to-treat/safety population)

Characteristic	Patients (n = 123)
	Cetuximab1	Irinotecan2
Duration, wk
Median	12.0	12.0
Q1-Q3	6.0-25.0	6.0-25.6
Total number of infusions, n (%)
0	0	2 (1.6)
1-5	13 (10.6)	57 (46.3)
6-10	42 (34.1)	35 (28.5)
11-20	30 (24.4)	19 (15.4)2
21-30	20 (16.3)	6 (4.9)
31-40	7 (5.7)	2 (1.6)
41-50	5 (4.1)	1 (0.8)
> 50	6 (4.9)	1 (0.8)
Cumulative dose, mg/m2
Median	3143.7	894.8
Q1-Q3	1650.8-6110.6	532.0-1980.4
Cetuximab dose intensity, mg/m2 per week
Median	246.7
Q1-Q3	236.0-250.3
Irinotecan dose intensity, mg/m2 per 6 wk
Median		507.8
Q1-Q3		407.6-539.5
Relative dose intensity, n (%)
< 60%	2 (1.7)	5 (4.3)
60% to 80%	5 (4.2)	21 (17.9)
80% to 90%	6 (5.0)	15 (12.8)
≥ 90%	107 (89.2)	76 (65.0)
Patients who stopped irinotecan and received cetuximab, n (%)	14 (11.4)
Median duration of cetuximab monotherapy after stopping irinotecan, wk (range)	2.5 (0.9-23.0)
Patients who stopped combination treatment and received irinotecan only, n (%)	0

¹Relative dose intensity calculated for patients receiving at least 1 maintenance dose only, the initial dose was excluded for the calculation of relative dose intensity; ²Duration, cumulative dose by cycle and relative dose intensity overall and by cycle were not calculated for 4 patients who received “other” irinotecan regimens (n = 119 for these calculations).

Table 3 Treatment activity (intention-to-treat/safety population)

Parameter	Patients (n = 123)
Response, n (%)
Complete response	1 (0.8)
Partial response	16 (13.0)
Stable disease	44 (35.8)
Progressive disease	52 (42.3)
Not evaluable	10 (8.1)
Objective response (95% CI)	17 (13.8) (8.3-21.2)
Disease control rate (95% CI)	61 (49.6) (40.5-58.8)
PFS
No. of events, n (%)	117 (95.1)
Median PFS time, wk (95% CI)	12.1 (9.7-17.7)
PFS rate, % (95% CI)
6 wk	72 (64-80)
12 wk	50 (41-59)
18 wk	39 (30-48)
24 wk	25 (17-33)
30 wk	17 (10-23)
36 wk	11 (6-17)
Overall survival
No. of events, n (%)	105 (85.4)
Median survival time, mo (95% CI)	9.5 (7.5-11.6)
Survival rate, % (95% CI)
6 mo	65 (53-73)
12 mo	38 (29-46)
18 mo	25 (18-33)
24 mo	14 (7-20)

PFS: Progression-free survival; CI: confidence interval.

Table 4 Overall survival in patient subgroups (intention-to-treat/safety population)

Prognostic factors	n	No. of deaths n (%)	Median survival
			Months	95% CI
Age (yr)
< 65	92	77 (83.7)	9.6	(7.9-11.8)
≥ 65	31	28 (90.3)	7.5	(5.7-12.9)
Gender
Male	73	64 (87.7)	9.5	(7.3-11.7)
Female	50	41 (82.0)	8.9	(6.4-16.5)
Stage based on TMN classification at first diagnosis
I/II	11	10 (90.9)	12.8	(5.6-14.6)
III	24	22 (91.7)	9.3	(5.1-11.3)
IV	80	67 (83.8)	9.5	(7.5-13.0)
unknown	8	6 (75.0)	4.9	(2.9-NA)
Karnofsky performance status
≤ 80	39	36 (92.3)	5.7	(2.6-11.3)
> 80	84	69 (82.1)	10.3	(8.9-13.3)
No. of previous non-adjuvant lines
1	66	57 (86.4)	11.2	(9.1-13.3)
2	37	31 (83.8)	5.9	(3.8-9.1)
≥ 3	20	17 (85.0)	9.3	(3.6-17.7)
Time from end of last course of most recent irinotecan treatment to progression
≤ 30 d	86	76 (88.4)	8.8	(7.1-11.3)
> 30 d	37	29 (78.4)	10.6	(5.7-14.6)
Best response of most recent irinotecan schedule1
CR/PR	20	14 (70.0)	15.6	(8.6-9.4)
PD/SD	102	90 (88.2)	8.9	(7.0-11.0)
No. of metastatic sites
1	51	44 (86.3)	10.6	(7.9-13.3)
≥ 2	72	61 (84.7)	8.4	(6.9-11.0)
BSA
≤ 1.6 m2	42	34 (81.0)	8.6	(6.4-16.5)
> 1.6 m2 to ≤ 1.8 m2	48	41 (85.4)	10	(6.9-13.0)
> 1.8 m2	33	30 (90.9)	9.5	(5.7-11.8)
Early acne-like rash during the first 21 d2
No	38	34 (89.5)	6.2	(3.3-11.3)
Yes	85	71 (83.5)	9.5	(7.2-12.3)
Grade 1 or 2	81	67 (82.5)	9.6	(7.4-13.7)
Grade 3 or 4	4	4 (100)	3	(2.1-10.9)

¹Best response was missing for 1 patient who died at 2.5 mo;

²Landmark analysis. BSA: Body surface area; NA: Not available; TMN: Tumor, node, metastasis; CR: Complete response; PR: Partial response; PD: Progressive disease; SD: Stable disease.

Table 5 Adverse events

Preferred term	Grade 3 or 4	Any grade
Any, n (%)	68 (55.3)	123 (100)
Diarrhea	17 (13.8)	71 (57.7)
Neutropenia	11 (8.9)	30 (24.4)
Rash	7 (5.7)	70 (56.9)
Vomiting	7 (5.7)	48 (39.0)
Abdominal pain	4 (3.3)	22 (17.9)
Anemia	4 (3.3)	12 (9.8)
Fatigue	4 (3.3)	21 (17.1)
Febrile neutropenia	4 (3.3)	4 (3.3)
Nausea	4 (3.3)	55 (44.7)
Blood alkaline phosphatase increased	3 (2.4)	9 (7.3)
Dehydration	3 (2.4)	4 (0.3)
Hypersensitivity	3 (2.4)	9 (7.3)
Infection	3 (2.4)	4 (3.3)
Neutrophil count	3 (2.4)	3 (2.4)
Paronychia	3 (2.4)	16 (13.0)
White blood cell count decreased	3 (2.4)	7 (5.7)
Anorexia	2 (1.6)	35 (28.5)
Constipation	2 (1.6)	27 (22.0)
Stomatitis	1 (0.8)	26 (21.1)
Composite AE categories1
Infusion-related reactions2	3 (2.4)	19 (15.4)
Acne-like rash3	10 (8.1)	99 (80.5)

Grade 3/4 AEs (Adverse events) in > 2% and any grade AEs in > 20% of patients in the intention-to-treat/safety population and composite AE categories of special interest.

¹Composite categories where several Medical Dictionary for Regulatory Activities preferred terms have been pooled;

²Terms included acute myocardial infarction, acute respiratory failure, anaphylactic reaction, ^*anaphylactic shock, ^*anaphylactoid reaction, ^*anaphylactoid shock, ^*angina pectoris, apnea, asthma, blood pressure decreased, 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, and syncope;

³Terms included acne, acne pustular, dermatitis acneiform, dry skin, erythema, folliculitis, pruritus, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin hyperpigmentation, telangiectasia, and xerosis; ^*Preferred terms included in the infusion-related reactions category regardless of when they occurred; all other preferred terms in this category were included only if the onset date of the AE was on the day of the first cetuximab administration.

Table 6 Outcome in metastatic colorectal cancer patients receiving cetuximab with irinotecan-based chemotherapy from different geographical regions

	ELSIE	LABEL	MABEL	BOND
Reference	Current study	Buzard et al[15]	Wilke et al[14]	Cunningham et al[7]
No. of patients	123	79	1147	218
Geographical region	Asia-Pacific	Latin America	Europe	Europe
Response rate, % (95% CI)	13.8 (8.3-21.2)1	26.6 (17.3-37.7)1	20.1 (17.9-22.6)2	22.9 (17.5-29.1)3
Disease control rate, % (95% CI)	49.6 (40.5-58.8)1	55.7 (44.1-66.9)1	45.2 (42.3-48.2)2	55.5 (48.6-62.2)3
Median PFS, wk (95%CI)	12.1 (9.7-17.7)1	17.4 (11.7-18.9)1	14.1 (13.0-17.1)1	18.0 (12.0-18.0)3
PFS rate at 12 wk, % (95% CI)	50 (41-59)1	57 (46-68)1	61 (58-64)1	564 (48.7-62.6)3
Median survival, mo (95% CI)	9.5 (7.5-11.7)	9.2 (7.9-10.8)	9.2 (8.6-9.8)	8.6 (7.9-9.6)
OS rate at 1 yr, % (95% CI)	38 (29-37)	38 (27-48)	38 (35-41)	29 (22-37)

¹World Health Organisation (WHO) criteria by investigator;

²Subjective assessment by investigator;

³WHO criteria by independent review committee;

⁴In the BOND study the PFS rate was assessed at 3 mo. ELSIE: Erbitux^® pre-License Study In the East; LABEL: Latin American Erbitux Pre-License Study; MABEL: Monoclonal Antibody Erbitux in a European Pre-License Study.