Originally published as JCO Early Release 10.1200/JCO.2007.14.7116 on March 3 2008

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

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

From Amgen Inc, Thousand Oaks, CA; Ghent University Hospital, Ghent, Belgium; University Hospital Gasthuisberg, Leuven, Belgium; and the Ospedale Niguarda Ca’ Granda, Milan, Italy

Corresponding author: Rafael G. Amado, MD, Amgen, Inc, One Amgen Center Dr, MS 38-2-B, Thousand Oaks, CA 91320-1799; e-mail: ramado{at}amgen.com

	ABSTRACT

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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.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Epidermal growth factor receptor (EGFR) has been validated as a therapeutic target in several human tumors, including colorectal cancer (CRC).^1-4 Ligand occupancy of the EGFR activates the RAS/RAF/MAPK, STAT, and PI3K/AKT signaling pathways, which together modulate cellular proliferation, adhesion, angiogenesis, migration, and survival.^5,6 The anti-EGFR targeted antibodies cetuximab and panitumumab administered as monotherapy in CRC have shown response and disease stabilization rates of approximately 10% and 30%, respectively.^2,3 Although EGFR expression is used for patient selection, clinical experience shows that the level of EGFR expression as measured by immunohistochemistry does not predict clinical benefit.^2,7-9

KRAS, the human homolog of the Kirsten rat sarcoma-2 virus oncogene, encodes a small GTP-binding protein that acts as a self-inactivating signal transducer by cycling from GDP- to GTP-bound states in response to stimulation of a cell surface receptor, including EGFR.^10,11 KRAS can harbor oncogenic mutations that yield a constitutively active protein.^10-13 Such mutations are found in approximately 30% to 50% of CRC tumors and are common in other tumor types.^12,14-19 Several studies have indicated that the presence of mutant KRAS in lung and CRC tumors correlates with poor prognosis,^14,17,18,20 and is associated with lack of response to EGFR inhibitors.^{15,16,19,21,22} These published reports investigating the role of KRAS as a selection marker for EGFR inhibitor treatment were based on tumor samples from uncontrolled studies and included patients treated with anti-EGFR antibodies alone or in combination with irinotecan. Given the possible prognostic role of KRAS mutational status, these uncontrolled studies could not isolate the relative effect of antibody treatment on outcome by KRAS status from the prognostic implications of KRAS as a marker of poor clinical outcome in CRC.

We assessed the predictive role of KRAS in a phase III, randomized trial comparing panitumumab monotherapy with best supportive care (BSC) in patients with chemotherapy-refractory metastatic CRC.³ The primary objective of the biomarker analyses was to determine whether the effect of panitumumab monotherapy on progression-free survival (PFS) differed between patients whose tumors contain mutant versus wild-type (WT; ie, nonmutated) KRAS.

	PATIENTS AND METHODS

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Trial Design and Patient Population
The design of this controlled, panitumumab monotherapy study has been previously described.³ Briefly, patients with metastatic CRC with EGFR expression in 1% of tumor cells (assessed by immunohistochemistry) and documented evidence of disease progression after failure of fluoropyrimidines and prespecified exposure to oxaliplatin and irinotecan were randomly assigned to panitumumab 6 mg/kg plus BSC every 2 weeks or BSC alone. BSC patients could receive panitumumab after disease progression. Tumor status was assessed radiographically every 4 to 8 weeks from week 8 until disease progression using the Response Evaluation Criteria in Solid Tumors by blinded central review. The primary end point was PFS, defined as the interval from random assignment to radiologic progression or death. Secondary end points included objective response rate, overall survival (OS), and safety. All patients, including those with unassessable or missing assessments, were included in the response rate analysis. A best response of stable disease was determined at or after week 8 from random assignment. At enrollment, patients provided informed consent for study procedures including research on archived paraffin-embedded tumor samples (mostly from primary tumor resection) for identification of predictive biomarkers. The study protocol was approved by the ethics board at each research center.

Assay to Detect Mutant KRAS
Formalin-fixed, paraffin-embedded tumor sections were deparaffinized and air dried, and DNA was isolated using proteinase K and a DNeasy mini-spin column (Qiagen, Valencia, CA). Mutant KRAS was detected using a validated KRAS mutation kit (DxS Ltd, Manchester, United Kingdom) that identifies seven somatic mutations located in codons 12 and 13 (Gly12Asp, Gly12Ala, Gly12Val, Gly12Ser, Gly12Arg, Gly12Cys, and Gly13Asp) using allele-specific real-time polymerase chain reaction.^23-25 A central laboratory (HistoGeneX, Antwerp, Belgium) validated the assay for analytic and diagnostic performance, established acceptance criteria, included appropriate quality controls for each assay, and performed the KRAS analysis in a blinded fashion.

Statistical Analysis
The primary objective of the biomarker analyses was to examine whether the relative effect of panitumumab compared with BSC on PFS differed in patients with tumors bearing mutant versus WT KRAS. Additional objectives included examining whether panitumumab improved PFS, OS, and response rate in the WT KRAS group compared with the BSC group. Safety was assessed in both KRAS groups. Analyses were limited to patients with known KRAS status and were categorized by randomized treatment for efficacy and safety. Adverse events were graded per the National Cancer Institute Common Toxicity Criteria version 2.0 with the exception of selected skin toxicities, which were graded using version 3.0. Statistical analyses were performed at Amgen Inc. All analyses were prespecified in a statistical analysis plan before KRAS mutation assessment.

A quantitative-interaction test²⁶ at a two-sided 5% level was used to compare the PFS log-hazard ratio (HR; panitumumab relative to BSC) from a Cox model with covariates for the randomization factors between the WT and mutant KRAS groups. Based on an assessable sample size of 380 patients and assuming 60% WT prevalence, power was estimated at more than 99% if the HR was 1.0 in the mutant KRAS group and at 87% if the HR was 0.80 in the mutant KRAS group, assuming an overall HR of 0.54 among all patients. Kaplan-Meier methods were used to estimate PFS and OS. Conditional on a significant interaction test, sequential testing at a 5% level of PFS, followed by OS and overall response rate, were planned within the WT KRAS group between panitumumab versus BSC. A log-rank test was used for PFS, Wilcoxon for OS, and a generalized Cochran-Mantel-Haenszel test for response rate, each stratified by the randomization factors.

Maximum change in tumor burden per blinded central radiology review was summarized by treatment in each KRAS group. Propensity-score sensitivity analyses were performed to assess bias due to exclusion of patients with unknown KRAS status.

	RESULTS

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Patients
Of the 463 patients originally enrolled,³ 427 (92%) were included in the KRAS analyses (208 and 219 in the panitumumab and BSC arms, respectively; Fig 1). KRAS status could not be determined in 18 patients because of unavailable samples and in an additional 18 patients whose samples had insufficient or poor-quality DNA. KRAS mutations were identified in 184 (43%) of 427 patients (84 [40%] and 100 [46%] in the panitumumab and BSC arms, respectively). In the BSC arm, 76% of patients with WT KRAS and 77% of patients with mutant KRAS received panitumumab in a cross-over protocol, after a median PFS time in the original study (investigator assessment) of 7.1 weeks (95% CI, 7.0 to 7.6) and 6.3 weeks (95% CI, 5.1 to 7.1) for patients in the WT and mutant KRAS groups, respectively.

View larger version (32K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. CONSORT diagram. BSC, best supportive care; WT, wild-type.

View larger version (20K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Progression-free survival by treatment within KRAS groups. Progression-free survival by randomized treatment in (A) mutant and (B) wild-type KRAS groups. Hazard ratios (HR) are shown for panitumumab (panit.) versus best supportive care (BSC) adjusted for randomization factors (Eastern Cooperative Oncology Group score, geographic region).

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Subset analyses of progression-free survival in the KRAS wild-type group. Hazard ratio (HR; blue circle) and 95% CI (horizontal lines) adjusted for randomization factors for panitumumab (panit.) versus best supportive care (BSC). N, sample size; HR, hazard ratio; ECOG, Eastern Cooperative Oncology Group; Met, metastatic; EGFr, epidermal growth factor receptor; 1+, weak; 2+, moderate; 3+, strong.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Waterfall plots showing maximum percent decrease in target lesions (blinded central radiology). (A) Patients receiving panitumumab, mutant KRAS. (B) Patients receiving panitumumab, wild-type (WT) KRAS. (C) Best supportive care (BSC) patients, mutant KRAS. (D) BSC patients, WT KRAS. Percentages are best response within each KRAS group, excluding missing or nonassessable postbaseline tumor assessments. PR, partial response (gray); SD, stable disease (yellow); PD, progressive disease (blue).

Of 168 BSC patients in the KRAS assessable group that crossed over to receive panitumumab on progression, 20 (12%) experienced a response (including one patient with a complete response), and 55 (33%) had stable disease. All responders had WT KRAS, for a response rate of 20 of 91 (22%; 95% CI, 14% to 32%).

OS. At the time of these analyses, a total of 391 KRAS assessable patients (92%) had died (186 [89%] patients receiving panitumumab and 205 [94%] BSC patients). Median follow-up time was 14.1 months for the remaining 36 patients. No statistically significant OS difference was observed between treatment arms among all patients (HR, 0.97; 95% CI, 0.79 to 1.18), or in either of the KRAS groups; the HR for OS was 1.02 (95% CI, 0.75 to 1.39) and 0.99 (95% CI, 0.75 to 1.29) for the mutant and WT KRAS groups, respectively. OS was longer overall in the WT group than in the mutant group adjusting for stratification factors and randomized treatment (HR, 0.67; 95% CI, 0.55 to 0.82; both arms combined; Fig 5). Multivariate analysis showed that WT KRAS status was a predictor for OS in both the panitumumab (HR, 0.64; P = .004) and BSC (HR, 0.68; P = .007) arms. Similar results for OS were observed among the 168 BSC patients receiving panitumumab after progression (HR, 0.65; 95% CI, 0.47 to 0.90; median OS time of 6.8 months for WT v 4.5 months for mutant; online-only Fig A1B). For the 51 BSC patients who did not cross-over to panitumumab, no difference in OS was observed between WT and mutant KRAS groups (median OS time of 1.9 and 2 months, respectively).

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Kaplan-Meier curves for overall survival by treatment and KRAS status. Hazard ratio (HR) for wild-type (WT) versus mutant (MT) KRAS status adjusted for randomized treatment and randomization factors. Panit, panitumumab; BSC, best supportive care; events, deaths; N, sample size.

Grade 3 integument-related events occurred in 20% of all KRAS assessable patients (in 25% of WT KRAS patients and in 13% of mutant KRAS patients). In the mutant KRAS group, 1% of patients had a grade 4 integument-related event; there were no grade 4 events in the WT group. The time to any integument-related event or to an event grade 2 or higher was similar in both KRAS groups, suggesting that incidence differences for integument toxicity were due to differential exposure. Consistent with previous reports,^2,3 patients with the worst grade skin toxicity in the WT KRAS group appeared to experience better PFS and OS (data not shown). In the panitumumab arm, a higher incidence of diarrhea of any grade was observed (WT KRAS 24%; mutant KRAS 19%) but grade 3 diarrhea was comparable between groups (WT KRAS 2%; mutant KRAS 1%). The incidence of hypomagnesemia reported as an adverse event of any grade was 3% and 0% for WT and mutant KRAS groups, respectively. One grade 2 infusion reaction was reported as an adverse event in a patient with mutant KRAS.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
These results show that KRAS mutations predict for lack of clinical benefit to panitumumab therapy. The presence of a control arm made it possible to study the relative effect of panitumumab monotherapy by KRAS mutational status independent of the potential prognostic influence of KRAS mutations on outcomes, enabling us to conclude that the clinical benefit observed in the KRAS unselected population was entirely derived from the KRAS WT population. Given the cross-over design, conclusions are limited to the effect of KRAS mutational status on PFS and tumor response end points and not to OS. Indeed, the majority of BSC patients received panitumumab on disease progression early in the trial in both KRAS groups (median time to cross-over was 7.1 weeks), and, importantly, there was demonstrated benefit of panitumumab after cross-over in patients with WT KRAS tumors. The difference in OS in favor of the WT KRAS group in both treatment arms observed in our study may have reflected a potential prognostic value of KRAS mutational status in CRC or differential sensitivity to panitumumab treatment between KRAS groups.

Although these analyses were conducted retrospectively, several aspects relating to the methodology lend robustness to the results. First, the hypothesis that KRAS mutations may confer primary resistance to anti-EGFR antibodies was generated independently from previous trials. Second, to avoid inflation of type-1 error, samples were only subjected to one biomarker analysis, that of KRAS mutation. Third, the analyses were sufficiently powered and prespecified in a statistical analysis plan before knowledge of KRAS outcome. Fourth, testing was performed by an independent laboratory without patient-level knowledge of randomization or clinical outcomes. Fifth, the magnitude of the interaction observed is substantial. These considerations, together with consistency with previous studies, and the recognized biologic plausibility of the hypothesis, strongly support the validity of our results and conclusions.

To our knowledge, these are the first results arising from a randomized, controlled trial showing that the state of a signaling molecule downstream of a target plays a crucial role in predicting clinical benefit to a targeted therapeutic. These results also illustrate that the presence of a therapeutic target in itself may be insufficient to predict response to therapy in tumors with multiple molecular alterations. The high positive predictive value (100% for lack of objective response rate) for mutant KRAS suggests that inhibition of the RAS/RAF/MAPK signaling pathway is primarily responsible for the clinical activity of panitumumab in metastatic CRC, and raises the possibility that mutant KRAS may be predictive in other tumor types. Indeed, EGFR inhibitors have shown modest or no activity in pancreatic cancer, a disease with a high prevalence of KRAS mutations,^4,27 and in patients with lung cancer whose tumors harbor KRAS mutations.^22,28

In our study, WT KRAS status was shown to be required but not sufficient to confer sensitivity to panitumumab monotherapy. The mechanisms of primary and treatment-emergent resistance to panitumumab in patients with WT KRAS tumors are unknown. With regard to primary resistance, EGFR may not be a dominant oncogenic pathway in some tumors, regardless of KRAS status. In addition, while KRAS mutations occur early in the development of CRC,^29-31 they may also be subsequently acquired, leading to tumor cell heterogeneity. Moreover, while the assay employed in our study is known to detect more than 90% of known activating KRAS mutations in CRC, it would have missed additional mutations in codons 12 and 61. Other potential mechanisms of resistance include activation of additional tyrosine kinase receptors, such as vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and insulin-like growth factor 1 receptor⁷; activating mutations of additional signaling proteins downstream of the EGFR, such as PI3K,³³ and Src,³⁴ or downstream of KRAS such as RAF^15,35; and loss-of-function mutations of tumor-suppressor genes such as phosphatase and tensin homolog (PTEN).³³ Elucidating mechanisms of resistance to panitumumab will prove important for the selection of therapeutic combinations to maximize clinical benefit. In addition to ascertaining resistance mechanisms, other biomarkers such as EGFR gene copy number and expression levels of EGFR ligands in tumor cells may be useful to further refine the responder population.^32,36

The current results apply to the setting of panitumumab monotherapy and indicate that KRAS status should be considered when selecting mCRC patients as candidates for this treatment. Studies are currently underway to assess prospectively whether KRAS mutations also influence response to panitumumab in combination with chemotherapy in earlier lines of therapy. In addition to the relevance of these results to the current use and to the future development of anti-EGFR antibodies, these findings may have implications for the development of oncology therapeutics directed against other targets known to signal though the RAS/RAF/MAPK pathway.^37,38

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Rafael G. Amado, Amgen Inc (C); Michael Wolf, Amgen Inc (C); Daniel J. Freeman, Amgen Inc (C); Todd Juan, Amgen Inc (C); Robert Sikorski, Amgen Inc (C); Sid Suggs, Amgen Inc (C); Robert Radinsky, Amgen Inc (C); Scott D. Patterson, Amgen Inc (C); David D. Chang, Amgen Inc (C) Consultant or Advisory Role: Marc Peeters, Amgen Inc (C); Eric Van Cutsem, Amgen Inc (U), Merck (U) Stock Ownership: Rafael G. Amado, Amgen Inc; Michael Wolf, Amgen Inc, Dendreon Corp, YM BioSciences Inc; Daniel J. Freeman, Amgen Inc; Todd Juan, Amgen Inc; Robert Sikorski, Amgen Inc; Sid Suggs, Amgen Inc; Robert Radinsky, Amgen Inc; Scott D. Patterson, Amgen Inc; David D. Chang, Amgen Inc Honoraria: Marc Peeters, Amgen Inc Research Funding: Eric Van Cutsem, Amgen Inc, Merck Expert Testimony: Marc Peeters, Amgen Inc (C) Other Remuneration: Marc Peeters, Amgen Inc

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Rafael G. Amado, Michael Wolf, Salvatore Siena, Daniel J. Freeman, Todd Juan, Robert Sikorski, Robert Radinsky, Scott D. Patterson, David D. Chang

Administrative support: Rafael G. Amado, Robert Radinsky, Scott D. Patterson, David D. Chang

Provision of study materials or patients: Marc Peeters, Eric Van Cutsem, Salvatore Siena, Sid Suggs

Collection and assembly of data: Rafael G. Amado, Robert Sikorski, Sid Suggs

Data analysis and interpretation: Rafael G. Amado, Michael Wolf, Marc Peeters, Eric Van Cutsem, Salvatore Siena, Daniel J. Freeman, Todd Juan, David D. Chang

Manuscript writing: Rafael G. Amado, Michael Wolf, Daniel J. Freeman, David D. Chang

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

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. (A) Progression-free survival and (B) overall survival by KRAS status among patients receiving panitumumab after progression on best supportive care alone. HR, hazard ratio; WT, wild-type; MT, mutant; events, deaths; N, sample size.

	ACKNOWLEDGMENTS

 
We thank the patients, families, and the study staffs for study participation, and the following individuals from Amgen Inc: C. Tucknott and P. D’Avirro (study management); A. Rong (statistical planning and analyses); A. Bakker and S. Ildiko (sample management/assay coordination); and L. Runft (writing assistance). The ClinicalTrials.gov identifier numbers for studies 20020408 and 20030194 are NCT00113763 [ClinicalTrials.gov] and NCT00113776 [ClinicalTrials.gov] , respectively.

	NOTES

 
published online ahead of print at www.jco.orgon March 3, 2008.

Funded by Amgen Inc, Thousand Oaks, CA.

Presented in part in oral format at the 14th European Cancer Conference, Barcelona, Spain, September 23-27, 2007; and the American Society of Clinical Oncology Gastrointestinal Cancer Symosium, Orlando, FL, January 25-27, 2008.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted October 1, 2007; accepted November 20, 2007.

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