BERLIN—A pair of colon cancer trials using panitumumab (Vectibix) not only proved the efficacy of the drug in patients with nonmutated KRAS but also highlighted the importance of ascertaining KRAS status. Trial 181 evaluated panitumumab in combination with FOLFIRI as a second-line treatment for metastatic colorectal cancer, while trial 203 paired the anti-EGFR agent with FOLFOX4 as first-line treatment.
The phase III trials “show the very powerful value of KRAS status in order to make treatment decisions in these patients,” said Jean-Yves Douillard, MD, PhD, who led trial 203. “We think that based on these data, KRAS-mutated patients should not receive treatment with panitumumab or any other anti-EGFR.” Dr. Douillard is the director of clinical and translational research in the medical oncology branch at Centre de Lutte Contre le Cancer Nantes Atlantique Ren Gauducheau in Nantes-Saint-Herblain, France.
Marc Peeters, MD, PhD, principal investigator for trial 181, pointed out that the results of his trial illustrated the clinical utility of KRAS as a predictive marker. Dr. Peeters is coordinator of the digestive oncology unit at University Hospital Ghent in Belgium.
Trial 203 was originally designed to compare the effect of panitumumab treatment in the overall population, but it was amended to analyze outcomes in the presence or absence of KRAS. For the multicenter study, panitumumab (6.0 mg/kg) plus FOLFOX4 once every two weeks (arm 1) was compared with FOLFOX4 alone (arm 2). Eligible patients had metastatic adenocarcinoma of the colon or rectum; patients may have received adjuvant chemotherapy, excluding oxaliplatin but no chemotherapy for metastatic disease; and available tumor tissue for biomarker testing. Randomization was stratified by ECOG performance status (0-1 vs 2) and region. The primary endpoint was progression-free survival (PFS).
The addition of panitumumab significantly improved PFS in patients with KRAS wild-type metastatic colon cancer: 9.6 months in arm 1 and eight months in arm 2 (hazard ratio [HR] = 0.80; P = .02). In contrast, in patients who had tumors with KRAS mutations, PFS was inferior in arm 1 (7.3 months) compared with arm 2 (8.8 months; HR = 1.29; P = .02).
In terms of adverse events, grade 3 panitumumab-related infusion reactions were reported in fewer than 1% of patients in arm 1. An interim analysis of overall survival (OS) also found proof of a reduction in OS in patients with KRAS mutant tumors who received panitumumab. The median OS for patients with wild-type KRAS is expected later this year (ECCO/ESMO 2009 abstract 10LBA).
In trial 181, patients were randomized to receive either panitumumab (6 mg/kg) plus FOLFIRI once every two weeks (arm 1) or FOLFIRI alone (arm 2). A total of 1,186 patients were included (591 in arm 1; 595 in arm 2). Of the total patient population, 55% had wild-type KRAS tumors, while 45% had mutated KRAS tumors.
Dr. Peeters said that 68%-71% of the patients received oxaliplatin as first-line therapy, while bevacizumab (Avastin) was used as first-line therapy in 17%-21% of the patients. In patients with wild-type KRAS tumors, the median PFS was 5.9 months for arm 1 and 3.9 months for arm 2 (HR = 0.73; P = .004). The median OS was 14.5 months for arm 1 and 12.5 months for arm 2 (HR = .85; P = .115). Finally, the response rate was 35% in arm 1 and 10% in arm 2. There was no difference in PFS, OS, or response rate among patients with mutated KRAS tumors who received panitumumab. Again, panitumumab-related grade 3/4 infusion reactions were reported in fewer than 1% of the patients (abstract 14LBA).
Both studies achieved a first with biomarker testing, according to Dr. Douillard and Dr. Peeters. In trial 203, tumor KRAS status was available for 93% of the 1,183 patients. In trial 181, tumor KRAS status was determined in 91% of the 1,186 patients.
“It was important to have as much tumor tissue sampling as possible to do the biomarker test,” Dr. Peeters said. “We have more than 90% of the samples available from our patients...this is the highest rate reported in a phase III setting.”
Dr. Douillard said that the trials offer real-world illustrations of how powerful a therapy can be if the appropriate target is selected. “By looking at it prospectively, we now have the proof that in this patient population, there is a detrimental effect of anti-EGFR agents,” he said.