English - the European Oncology Nursing Society

mutated gene had a median PFS of 5.5 months in the cetuximab armbest supportive care (BSC) in patients with refractory mCRC (20).30 - newsletter fall 2008This analysis was conducted to determine whether the effect ofpanitumumab monotherapy on PFS differed between patients withtumours having a mutant KRAS and those with tumours having awild-type KRAS. When panitumumab was compared to BSC alone, acompared with 8.6 months in the chemotherapy-only arm (P = .02),showing that the addition of cetuximab to FOLFOX had a detrimentaleffect on outcomes in patients who had tumours with KRAS mutationscompared with those who had received FOLFOX alone (34).statistically significant improvement in PFS was observed in patientswhose tumours harboured wild-type KRAS; median PFS was 12.3weeks for panitumumab and 7.3 weeks for BSC (P < .0001). Incontrast, panitumumab treatment conferred no additional benefitcompared with BSC alone (median PFS = 7.4 vs 7.3 weeks) inpatients carrying the mutant KRAS gene (Table 1) (20). Consistentwith these findings, the response rate to panitumumab was 17% inthe wild-type KRAS group, while no patients in the KRAS mutationgroup responded to therapy.The EVEREST trial evaluated the benefit of cetuximab in combinationwith irinotecan after the failure of irinotecan-based treatment. In thisstudy, the PFS estimate in patients with a mutant KRAS was 83 dayscompared to 173 days for patients with the nonmutated KRAS (37).Taken together, these trials provide compelling evidence of thepredictive nature of KRAS in EGFR-targeted therapy. The KRASmutation is a biomarker for nonresponse to panitumumab andto cetuximab, both as monotherapy and in combination withTable 1: Randomised Trials of Anti-EGFR Agents Based on Mutationalchemotherapy. It should be noted that a similar correlation withStatusKRAS mutant status has also been observed in patients treated withsmall-molecule TKIs in non–small cell lung cancer (38-40), as well asMedian PFS (HR) pancreatic cancer (41).Patients, Mutant Wild-typeStudy Treatment No. KRAS KRASImplications for Nursing PracticeIt is imperative that oncology nurses understand the clinicalAmado BSC vs 427 7.3 vs 7.3 vs relevance of these data to treatment decisions for patients with CRC.panitumumab 7.4 wk 12.3 wk Like human epidermal growth factor receptor 2 (HER2) status for(third-line) (HR = 0.99) (HR = 0.45;breast cancer, KRAS status is the first indicator allowing personalisedP < .0001)treatment of CRC. KRAS testing is likely to become a criticalVan Cutsem FOLFIRI vs 540 8.1 vs 8.7 vs(CRYSTAL) FOLFIRI + 7.6 mo 9.9 mocomponent in patient selection for anti-EGFR therapy.All patients being considered for panitumumab or cetuximabtherapy, as well as all patients with newly diagnosed advancedcetuximab(first-line)(HR = 1.07;P = .75)(HR = 0.68;P = .017)Bokemeyer FOLFOX vs 233 8.6 vs 7.2 vs CRC, should have their tumour biopsies tested for EGFR mutation(OPUS) FOLFOX + 5.5 mo 7.7 mo status. Tumour samples should therefore be obtained at the timecetuximab (HR = 1.83; (HR = 0.57; of surgery, regardless of whether the surgery is for diagnostic or(first-line) P = .02) P = .02) therapeutic purposes. Available data indicate that both the primaryTejpar Irinotecan + 148 83 d 173 d and metastatic colorectal tumours exhibit the same KRAS mutation(EVEREST) cetuximabstatus because the mutation of the KRAS gene occurs early in the(irinotecanrefractorypatients may present at the clinic with metastatic disease that wasdevelopment of the disease (42). This is important because manypatients)diagnosed following surgical resection of their primary site or mayBSC, best supportive care; FOLFIRI, irinotecan, 5-fluorouracil,leucovorin ; FOLFOX, 5-fluorouracil, leucovorin, oxaliplatin.; HR,hazard ratio.only have testing results available from the metastatic site. Oncologynurses may play a key role in ensuring that testing for the KRASmutation is requested at the time of surgery and completed prior tothe initiation of treatment.The same result has been found with cetuximab and is the basisfor the recent recommendation by the EMEA to restrict the use ofcetuximab to patients with EGFR-expressing, KRAS wild-type mCRC.The most recent data on this subject come from the retrospectiveanalyses of 3 randomised trials of cetuximab in combination withchemotherapy, the CRYSTAL trial (33), the OPUS trial (34), and theEVEREST trial (37) (see Table 1).Nurses may also play a key role in educating patients about theclinical relevance of the mutant KRAS. It is extremely importantto convey to patients who have a KRAS mutation that currentchemotherapy regimens remain active and effective against theirdisease. The use of the KRAS mutation as a marker for nonresponseallows clinicians to avoid treatment delays with other potentiallyeffective regimens. In addition, clinicians now have a tool to avoidIn the randomised phase 3 CRYSTAL trial, the addition of cetuximabto folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) in the overallunselected patient population resulted in a small PFS benefit forprescribing costly therapies with known toxicities to those patientswho may derive little or no benefit; and as a result, both the patientand the healthcare system benefit.cetuximab(8.9 vs 8.0 months, P = .0479) (17). As shown in Table1, patients with wild-type KRAS had a median PFS of 9.9 monthswhen treated with chemotherapy plus cetuximab compared with 8.7months when treated with chemotherapy alone (P = .017). Patientswith the mutated gene had a median PFS of 7.6 months in thecetuximab arm compared with 8.1 months in the chemotherapy-onlyarm (P = .75) (33).ConclusionAs new agents are being introduced into clinical practice, moreoptions are available to oncology healthcare professionals and to thepatients they treat. Targeted therapies, and in particular EGFR-directedtherapies, are a key component of treatment for patients with CRC,and the optimal use of these agents is essential. As we enter theera of personalised medicine, the discovery that the mutation in theSimilar results were observed in the OPUS trial, which evaluatedthe benefit of adding cetuximab to folinic acid, 5-fluorouracil, andKRAS gene is a biomarker for nonresponse to the anti-EGFR agentspanitumumab and cetuximab promises to be practice-changing.oxaliplatin (FOLFOX) chemotherapy (see Table 1). In this retrospectiveanalysis, patients with wild-type KRAS had median PFS of 7.7 monthswhen treated with chemotherapy plus cetuximab compared with7.2 months when treated with chemotherapy alone (P = .02), thusconfirming the benefit of cetuximab in this population. Patients with theAcknowledgementsThe author thanks Mary Jensen Camp, Pharm D, BCOP, and SupriyaSrinivasan, PhD, for writing and editorial support. Amgen (Europe)GmbH sponsored an external agency for writing support.