Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

Amado, Rafael G.; Wolf, Michael; Peeters, Marc; Van Cutsem, Eric; Siena, Salvatore; Freeman, Daniel J.; Juan, Todd; Sikorski, Robert; Suggs, Sid; Radinsky, Robert; Patterson, Scott D.; Chang, David D.

doi:10.1200/jco.2007.14.7116

Cited by 3,207Colorectal Cancer Treatments and StudiesLung Cancer Treatments and MutationsHER2/EGFR in Cancer Research

Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

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Amado, Rafael G., Wolf, Michael, Peeters, Marc, Van Cutsem, Eric, Siena, Salvatore, Freeman, Daniel J., Juan, Todd, Sikorski, Robert +4 more·2008·Journal of Clinical Oncology

DOI 10.1200/jco.2007.14.7116

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Abstract

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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KRAS mutation is a predictive biomarker for resistance to cetuximab in metastatic colorectal cancer.
“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
The Introduction reports that mutant KRAS is associated with lack of response to EGFR inhibitors, citing studies that included cetuximab-treated patients. It cautions that those uncontrolled studies could not separate a predictive treatment effect from KRAS’s possible prognostic role. The paper’s own randomized evidence concerns panitumumab, not cetuximab, so it does not establish the claim as stated. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Patients must have KRAS wt tumors for panitumumab to be effective.
“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]
Exclusion of patients with KRAS exon 2-mutant tumors has increased the percentage of responders to anti-EGFR monoclonal antibodies to 13-17%.
“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]
Most KRAS wild-type colorectal tumors still do not respond to anti-EGFR monoclonal antibodies.
“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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Tumor KRAS Status Predicts Responsiveness to Panitumumab in Japanese Patients with Metastatic Colorectal Cancer
Doi, T., Tahara, M., Yoshino, T., Yamazaki, K., Tamura, T., Yamada, Y., Yang, B., Oliner, K. S., Otani, S., & Asahi, D. (2010) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyq229 · Cited by 11 · see citing works
Clinical outcome of panitumumab for metastatic colorectal cancer with wild-type KRAS status: a meta-analysis of randomized clinical trials
Ibrahim, E. M., & Abouelkhair, K. M. (2011) · Medical Oncology · doi:10.1007/s12032-010-9760-4 · Cited by 17 · see citing works
Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer
Garrido‐Laguna, I., Patel, S. B., & Gill, D. M. (2015) · OncoTargets and Therapy · doi:10.2147/ott.s68558 · Cited by 9 · see citing works
CO191 The Efficacy of Panitumumab Plus Chemotherapy As Initial Treatment for KRAS Wild-Type Unresectable, Metastatic Colorectal Cancer: A GRADE-Approach Systematic Review and Meta-Analysis
Ahmadu, C., Wantling, J., Morris, T., & Darlington, O. T. (2025) · Value in Health · doi:10.1016/j.jval.2025.04.276

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
ORCID: Amado, Rafael G.
Peeters, Marc
Siena, Salvatore
Patterson, Scott D.
Chang, David D.
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2008-04-01
Volume: 26
Issue: 10
Pages: 1626-1634
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2007.14.7116
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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Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

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