On July 17, 2009, changes were made to the product labels of cetuximab (Erbitux® ImClone Systems, Branchburg, NJ) and panitumumab (Vectibix ® Amgen, Thousand Oaks, CA). Retrospective subset analyses of trials in patients with colorectal cancers having KRAS mutations noted a lack of benefit associated with these monoclonal antibodies. The percentage of study populations for which KRAS status was assessed ranged from 23% to 92%.
Labeling changes have been implemented in the INDICATIONS AND USAGE, CLINICAL PHARMACOLOGY, and CLINICAL STUDIES sections of both cetuximab and panitumumab product labels.
The following new information has been added to the cetuximab label:
1 INDICATIONS AND USAGE
1.2 Colorectal Cancer:
Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1)].
The following new information has been added to the panitumumab label:
1 INDICATIONS AND USAGE
Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14) and Clinical Pharmacology (12.1)].
The following new information has been added to the product labels for both cetuximab and panitumumab:
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Signal transduction through the EGFR results in activation of wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is continuously active and appears independent of EGFR regulation.
14 CLINICAL STUDIES
14 Vectibix label
14.2 Erbitux label
Lack of Efficacy of Anti-EGFR Monoclonal Antibodies in Patients with mCRC Containing KRAS Mutations
Retrospective analyses as presented in Table 5 (Erbitux label), Table 2 (Vectibix label) across seven randomized clinical trials suggest that anti-EGFR monoclonal antibodies are not effective for the treatment of patients with mCRC containing KRAS mutations. In these trials, patients received standard of care (i.e., BSC or chemotherapy) and were randomized to receive either an anti-EGFR antibody (cetuximab or panitumumab) or no additional therapy. In all studies, investigational tests were used to detect KRAS mutations in codon 12 or 13. The percentage of study populations for which KRAS status was assessed ranged from 23% to 92%. [See Clinical Pharmacology (12.1).]
| Retrospective Analyses of Treatment Effect in the Subset of Patients with mCRC Containing KRAS Mutations Enrolled in Randomized Clinical Trials |
Population
(n: ITT1) |
Treatment |
Number of Patients with KRAS Results (% ITT) |
Number of Patients with KRAS mutant (mAb2/control) |
Effect of mAb on Endpoints: KRAS Mutant3 |
1st line treatment mCRC
(1198) |
FOLFIRI
± cetuximab |
540 (45%) |
105/87 |
PFS2: no difference
OS2: no difference
ORR2: decreased |
1st line treatment mCRC
(337) |
FOLFOX-4
± cetuximab |
233 (69%) |
52/47 |
ORR: decreased
PFS: decreased
OS: no difference |
1st line treatment mCRC
(1053)
|
oxaliplatin or irinotecan-based chemotherapy, bevacizumab
± panitumumab |
oxaliplatin
664 (81%) |
135/125 |
PFS: decreased
OS: no difference
ORR: increased |
irinotecan
201 (87%) |
47/39 |
ORR: decreased
PFS: decreased
OS: decreased |
1st line treatment mCRC
(736) |
bevacizumab, capecitabine, oxaliplatin
± cetuximab |
528 (72%) |
98/108 |
PFS: decreased
OS: decreased
ORR: decreased |
2nd line treatment mCRC
(1298) |
irinotecan
± cetuximab |
300 (23%) |
49/59 |
OS: decreased
PFS: no difference
ORR: increased |
Study 3
3rd line treatment mCRC
(572) |
BSC ± cetuximab
|
394 (69%) |
81/83 |
OS: no difference
PFS: no difference
ORR: increased |
3rd line treatment mCRC
(463) |
BSC ± panitumumab |
427 (92%) |
84/100 |
PFS: no difference
OS: no difference
ORR: no difference |
1 ITT: intent-to-treat.
2 mAb: EGFR monoclonal antibody; PFS: progression-free survival; ORR: overall response rate; OS: overall survival.
3 Results from the primary efficacy endpoint are in bold. A given endpoint is designated as “decreased” if there was a numerically smaller result and as “increased” if there was a numerically higher result in the mAb group than in the control group.
Full prescribing information for cetuximab (Erbitux®), including clinical trial information, safety, dosing, drug-drug interaction, contraindications is available at
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125084s168lbl.pdf
Full prescribing information for panitumumab (Vectibix®), including clinical trial information, safety, dosing, drug-drug interaction, contraindications is available at
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125147s080lbl.pdf
