Several presentations at the 2008 annual meeting of the American Society of Clinical Oncology (ASCO) reported confirmatory data that treatment with epidermal growth factor receptor (EGFR) inhibitors such as Erbitux® (cetuximab) and Vectibix® (panitumumab) is only effective among patients with the normal KRAS gene, while those with a mutated KRAS gene demonstrate virtually no response to these agents.¹ In essence, global consent was achieved at this year’s ASCO that all patients eligible for EGFR-targeted therapies should first undergo KRAS testing prior to initiation of therapy.

The recent approval and addition of EGFR inhibitors to standard therapy have demonstrated improved outcomes among patients with select EGFR-positive cancers compared with standard chemotherapy regimens and tend to be associated with less overall severe toxicity. However, a significant portion of patients with EGFR-overexpressing cancers never demonstrate a response to EGFR inhibitors, an issue that prompted research to try to identify potential markers or properties that predict responsiveness to these agents. Ultimately, individualizing therapy through understanding which patients will respond to EGFR inhibitors will allow unresponsive patients to avoid ineffective therapies during a crucial therapeutic window when anticancer treatment should be initiated, while obviously eliminating associated side effects, expense, and time for therapies from which no benefit is derived. Furthermore, omission of patients with KRAS mutations from studies involving EGFR inhibitors may ultimately provide a clearer picture of the true clinical benefit of these agents.

Updated results from the CRYSTAL study were presented at this year’s ASCO. The original study included nearly 2,000 patients with advanced colorectal cancer who were randomized to Erbitux (400 mg/m2 as an initial dose and then 250 mg/m2 per week) plus FOLFIRI, (irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-fluorouracil bolus 400 mg/m2, and 5-fluorouracil infusion 2400 mg/m2 over 46 hours administered every two weeks) or FOLFIRI only as initial therapy for their disease. Overall, the results indicated an approximate 15% in progress-free survival for patients treated with Erbitux.

The updated results presented at this year’s ASCO included tumor samples from 587 of the patients from the original CRYSTAL study, which were evaluated for KRAS mutations and associated outcomes.

• Patients with a normal KRAS had a nearly 60% response rate to Erbitux plus FOLFIRI and only a 43% response rate to FOLFIRI only.
• Patients with a normal KRAS experienced a 32% reduced risk of progression with the addition of Erbitux to FOLFIRI compared with FOLFIRI only.
• Patients with KRAS mutations did not experience a benefit from the addition of Erbitux to FOLFIRI when compared with FOLFIRI only.
• There is no need for fresh tumor sampling to acquire KRAS mutation status with reproducible results.

A second study was presented at ASCO that was an update from the Phase II OPUS trial, a trial that was very similar to CRYSTAL, except that FOLFOX (Eloxatin®, 5-fluorouracil, leucovorin) was used as the chemotherapy regimen.³ In the OPUS trial, 134 patients with metastatic colorectal cancer were randomized to receive either Erbitux plus FOLFOX or FOLFOX only. Upon analyses for KRAS status, the following was reported:

• In the original OPUS trial, there was no significant benefit from the addition of Erbitux to FOLFOX compared with FOLFOX only.
• When stratified for KRAS mutation status, it was found that patients with KRAS mutations again had virtually no response to the addition of Erbitux, while those with a normal KRAS gene derived great benefit from the addition from Erbitux.

KRAS mutation status also affects other EGFR inhibitors such as Vectibix. KRAS status was ascertained in 427 patients involved in a Phase III trial comparing Vectibix as monotherapy to best supportive care among patients with metastatic colorectal cancer.

• Patients with wild-type KRAS had a significantly improved response rate, progression- free survival, and overall survival compared with patients with a mutated KRAS.
• Not one patient with a mutated KRAS responded to therapy with Vectibix.

The researchers concluded that KRAS mutation can predict which patients may derive benefit from any epidermal growth factor receptor; in particular, patients with KRAS mutations do not appear to derive any benefit from EGFR agents such as Erbitux and Vectibix and should be excluded from treatment including the agent. The researchers stated that patients who are to receive treatment with an EGFR targeted agent should first be tested for KRAS mutation status. Although further studies are ongoing to confirm these findings and identify other polymorphisms that may also impact responses to EGFR-targeted agents, there does not appear to be any reason at this point to not test for KRAS mutations among patients eligible for treatment with ERFR inhibitors.

Reference: 

¹ E. Van Cutsem, I. Lang, G. D'haens. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Proceedings from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #2.

² Amado R, Wolf M, Peeters M, et al. Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer. Journal of Clinical Oncology. 2008;10: 1626-1634.

³ Bokemeyer C, Bondarenko I, Hartmann J, et al. KRAS Status and Efficacy of First-Line Treatment of Patients with Metastatic Colorectal Cancer (mCRC) with FOLFOX with or without Cetuximab: The OPUS Experience. Proceedings from the 2008 annual meeting of the American Society of Clinical Oncology (ASCO). Abstract #4000.