APPENDIX

SUPPLEMENTAL METHODS

Study Design and Patients

The ASPECCT study was an open-label, randomized, multicenter, phase 3 noninferiority study.

Eligible patients (≥18 years) had histologically or cytologically confirmed metastatic

adenocarcinoma of the colon/rectum with wild-type KRAS exon 2 tumor status, measurable

disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern

Cooperative Oncology Group (ECOG) performance status ≤2, and disease progression with or

intolerance of irinotecan- and oxaliplatin-based therapy. Exclusion criteria included prior anti-

EGFR therapy, antitumor therapy within 30 days, serum magnesium below lower limit of normal,

and inadequate hematologic, renal, or hepatic function.

Assessments

Response was evaluated by investigators per RECIST version 1.1. Adverse events (AEs)

occurring through 30 days after the last dose day were graded according to the National Cancer

Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0, except

skin/nail-related toxicities, which were graded using NCI-CTCAE version 3.0 with modifications.

KRAS Testing

KRAS tumor status in formalin-fixed, paraffin-embedded tumor tissue sections was assessed

before randomization. Presence or absence of the seven most common KRAS exon 2

mutations was evaluated using the therascreen KRAS assay (Qiagen; Venlo, Netherlands).

Statistical Analysis

This OS inferiority null hypothesis tested in this study (at a 1-sided, 2.5% significance level) was

designed to demonstrate that panitumumab preserves ≥50% of the cetuximab OS treatment

versus BSC. The predicted effect of cetuximab versus BSC on OS was based on the CO.17

study (hazard ratio [HR]=0.55; 95%CI=0.41–0.74). A synthesis approach with an asymptotic

standard normal test statistic ZPC (Hung et al, 2003; Rothmann et al, 2003) was used. SAS

version 9.2 was the software used for analyses. Nonproportionality of hazards between the

treatment arms was tested using SAS version 9.2 software (SAS Institute Inc., Cary, NC) The

final analysis was a repeated analysis using updated study data; all P-values were nominal.

Multivariate analysis was performed for the subgroup of patients with prior bevacizumab

exposure because efficacy and safety were compared between treatment arms. A stepwise

model building procedure was used with a 10% significance level for the joint test for the

addition or removal of a covariate. The covariates with a significant joint test at 10% in the final

model were baseline ECOG, number of metastatic sites, and baseline LDH. Multivariate

analysis was not performed for the subgroups of patients with skin toxicity or hypomagnesemia

because efficacy and safety were compared between patient subsets defined by post-

randomization outcomes within a treatment arm.

Table A1. Post-progression antitumor therapy

Primary Analysis Set Patients with Prior Bevacizumab Exposure

Panitumumab(n=499)

Cetuximab(n=500)

Panitumumab(n=126)

Cetuximab(n=132)

Received antitumor therapy, n (%) 209 (42) 219 (44) 59 (47) 69 (52)

Cytotoxic chemotherapy 167 (34) 180 (36) 48 (38) 58 (44)

Anti-EGFR monoclonal antibodies 50 (10) 58 (12) 22 (17) 26 (20)

Anti-VEGF therapy 37 (7) 37 (7) 13 (10) 10 (8)EGFR=epidermal growth factor receptor; VEGF=vascular endothelial growth factor.

Table A2. Objective response rate*

Panitumumab(n=486)

Cetuximab(n=485)

Best tumor response, n (%)

CR 2 (0.4) 0 (0)

PR 105 (21.6) 96 (19.8)

SD or non-CR/non-PR 226 (46.5) 236 (48.7)

PD 121 (24.9) 124 (25.6)

Objective response,† n (%) 107 (22.0) 96 (19.8)

Objective response rate, % (95%CI) 22.0 (18.4–26.0) 19.8 (16.3–23.6)

Odds ratio (95%CI) 1.15 (0.8–1.6)CR=complete response; PD=progressive disease; PR=partial response; SD=stable disease*Patients from the primary analysis set with ≥1 uni-directionally measurable lesion per RECIST version 1.1 were included. †Objective response is defined as a best tumor response of CR or PR.

Table A3. Baseline demographics and disease characteristics for patients who received prior bevacizumab treatment

Panitumumab(n=126)

Cetuximab(n=132)

Men 87 (69.0) 77 (58.3)

White 80 (63.5) 96 (72.7)

Median (range) age, y 60 (32–79) 60 (26–82)

Region

North America/Western Europe/Australia 58 (46.0) 71 (53.8)

Rest of world 68 (54.0) 61 (46.2)

ECOG PS

0 44 (34.9) 52 (39.4)

1 71 (56.3) 67 (50.8)

2 11 (8.7) 13 (9.8)

Prior radiotherapy 29 (23.0) 31 (23.5)

Location of primary tumor

Colon 79 (62.7) 94 (71.2)

Rectum 47 (37.3) 38 (28.8)

Sites of metastatic disease

Liver only 12 (9.5) 17 (12.9)

Other sites ± liver 114 (90.5) 115 (87.1)

Data are expressed as n (%) unless otherwise noted. ECOG PS=Eastern Cooperative Oncology Group Performance Status.

Table A4. Baseline demographics and disease characteristics for patients included in the skin toxicity analysis

Panitumumab Cetuximab

Worst-grade skin toxicity 2–4

(n=264)

Worst-grade skin toxicity ≤1

(n=232)

Worst-grade skin toxicity 2–4

(n=265)

Worst-grade skin toxicity ≤1

(n=238)

Men 180 (68.2) 133 (57.3) 182 (68.7) 138 (58.0)

White 152 (57.6) 113 (48.7) 150 (56.6) 109 (45.8)

Median (range) age, y 61.0 (25–84) 61 (19–86) 61 (25–89) 60 (20–89)

Region, n (%)

North America/Western Europe/Australia 92 (34.8) 60 (25.9) 96 (36.2) 62 (26.1)

Rest of world 172 (65.2) 172 (74.1) 169 (63.8) 176 (73.9)

ECOG PS

0 95 (36.0) 58 (25.0) 93 (35.1) 71 (29.8)

1 150 (56.8) 151 (65.1) 158 (59.6) 141 (59.2)

2 19 (7.2) 23 (9.9) 14 (5.3) 26 (10.9)

Prior radiotherapy 64 (24.2) 65 (28.0) 67 (25.3) 63 (26.5)

Prior bevacizumab 74 (28.0) 51 (22.0) 77 (29.1) 56 (23.5)

Location of primary tumor

Colon 159 (60.2) 132 (56.9) 170 (64.2) 157 (66.0)

Rectum 105 (39.8) 100 (43.1) 95 (35.8) 81 (34.0)

Sites of metastatic disease

Liver only 37 (14.0) 15 (6.5) 34 (12.8) 16 (6.7)

Other sites ± liver 227 (86.0) 217 (93.5) 231 (87.2) 222 (93.3)

Data are expressed as n (%) unless otherwise noted. ECOG PS=Eastern Cooperative Oncology Group Performance Status.

Table A5. Baseline demographics and disease characteristics for patients included in the hypomagnesemia analysis

Panitumumab Cetuximab

Any grade hypomagnesemia

(n=144)

No hypomagnesemia

(n=352)

Any grade hypomagnesemia

(n=97)

No hypomagnesemia

(n=406)

Men 90 (62.5) 223 (63.4) 65 (67.0) 255 (62.8)

White 96 (66.7) 169 (48.0) 55 (56.7) 204 (50.2)

Median (range) age, y 62 (25–80) 60 (19–86) 63 (33–82) 60 (20–89)

Region

North America/Western Europe/Australia 51 (35.4) 101 (28.7) 31 (32.0) 127 (31.3)

Rest of world 93 (64.6) 251 (71.3) 66 (68.0) 279 (68.7)

ECOG PS

0 39 (27.1) 114 (32.4) 28 (28.9) 136 (33.5)

1 91 (63.2) 210 (59.7) 63 (64.9) 236 (58.1)

2 14 (9.7) 28 (8.0) 6 (6.2) 34 (8.4)

Prior radiotherapy 32 (22.2) 97 (27.6) 29 (29.9) 101 (24.9)

Prior bevacizumab 42 (29.2) 83 (23.6) 27 (27.8) 106 (26.1)

Location of primary tumor

Colon 91 (63.2) 200 (56.8) 61 (62.9) 266 (65.5)

Rectum 53 (36.8) 152 (43.2) 36 (37.1) 140 (34.5)

Sites of metastatic disease, n (%)

Liver only 20 (13.9) 32 (9.1) 16 (16.5) 34 (8.4)

Other sites ± liver 124 (86.1) 320 (90.9) 81 (83.5) 372 (91.6)

Data are expressed as n (%) unless otherwise noted. ECOG PS=Eastern Cooperative Oncology Group Performance Status.

FIGURE LEGENDS

Figure A1. Kaplan-Meier curves. Overall survival (A) and progression-free survival

(B) for patients who did not receive prior bevacizumab treatment.

Figure A2. Kaplan-Meier curves. Progression-free survival by worst skin toxicity for

patients treated with panitumumab (A) and cetuximab (B).

Figure A3. Kaplan-Meier curves. Overall survival in the panitumumab arm for

patients with and without hypomagnesemia at week 5 (A) and patients

with ≥20% decrease and <20% decrease in magnesium levels from

baseline at week 5 (B).

Figure A4. Kaplan-Meier curves. Overall survival in the cetuximab arm for patients

with and without hypomagnesemia at week 5 (A) and patients with ≥20%

decrease and <20% decrease in magnesium levels from baseline at week

5 (B).

Figure A5. Kaplan-Meier curves. Progression-free survival by presence or absence

of hypomagnesemia for patients treated with panitumumab (A) and

cetuximab (B).

Figure A1

A

B

Figure A2

A

B

Figure A3

A

B

Figure A4

A

B

Figure A5

A

B