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Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer
Open accessAbstract
Purpose: Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. Patients and Methods: KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. Results: KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Conclusion: Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
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In the citing paper
“KRAS mutation is a predictive biomarker for resistance to cetuximab (Erbitux®) in metastatic colorectal cancer (mCRC).”
From Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab (2011) · cites this paper as Amado et al., 2008
Experimental — accuracy not yet measuredIn the citing paper
“Patients must have KRAS wt tumors for panitumumab to be effective [22,23].”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [22]
In the citing paper
“Although exclusion of patients with KRAS (exon 2)-mutant tumors has arithmetically increased the percentage of responders up to 13–17 %”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [32]
In the citing paper
“most KRAS wild-type tumors still do not respond to anti-EGFR moAbs [26, 32].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [32]
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“• The usefulness of anti-EGFR antibody drugs has been reported in metastatic colorectal cancer without KRAS gene mutations [38–41, 47, 53, 55, 85–90].”
Background
Metadata
- Authors
- Amado, R. G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D. J., Juan, T., Sikorski, R., Suggs, S., Radinsky, R., Patterson, S. D., & Chang, D. D.
- Affiliations
- Ghent University Hospital (BE)
- Amgen (United States) (US)
- From Amgen Inc, Thousand Oaks, CA; Ghent University Hospital, Ghent, Belgium; University Hospital Gasthuisberg, Leuven, Belgium; and the Ospedale Niguarda Ca’ Granda, Milan, Italy
- Venue
- Journal of Clinical Oncology
- Published
- 2008-04-01
- Volume
- 26
- Issue
- 10
- Pages
- 1626-1634
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2106789440
- Cited by
- 3,207
- References
- 38
- Citations by year
- 2026: 32 · 2025: 48 · 2024: 59 · 2023: 77 · 2022: 112 · 2021: 123 · 2020: 106 · 2019: 135 · 2018: 131 · 2017: 163 · 2016: 181 · 2015: 253 · 2014: 280 · 2013: 254 · 2012: 288
- FWCI
- 169.59
- Type
- journal article
- Language
- en
- Update notices
- new_edition (2023-06-14)
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Funders
- Amgen
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- panitumumab, KRAS wild-type, KRAS mutation, metastatic colorectal cancer, anti-EGFR therapy, epidermal growth factor receptor, biomarker selection, progression-free survival, best supportive care, treatment toxicity, patient selection
- MeSH terms
- Panitumumab, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Agents, Female, Humans, Male, Middle Aged, Mutation, Proto-Oncogene Proteins, Biomarkers, Tumor, Colorectal Neoplasms, Polymerase Chain Reaction, Proto-Oncogene Proteins p21(ras), Disease-Free Survival, ras Proteins, Drug Resistance, Neoplasm, Kaplan-Meier Estimate
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