Panitumumab-FOLFOX4 Therapy Extends Survival in Patients with CRC without RAS Mutations
Testing for KRAS mutations is recommended to guide treatment decisions in patients with metastatic colorectal cancer (CRC) by pointing to the patients who would most likely benefit from anti–epidermal growth factor receptor (EGFR) therapies. The KRAS mutation is a predictive biomarker of resistance to anti-EGFR therapy in this patient population. Specifically, patients with KRAS mutations in exon 2 do not benefit from this therapy and may have poor outcomes if an anti-EGFR is combined with an oxaliplatin (Eloxatin)-containing chemotherapy regimen. Other activating RAS mutations (KRAS or NRAS) may also be negative predictive biomarkers for anti-EGFR therapy. A team of researchers investigated whether the presence of activating mutations in the KRAS or NRAS genes may further identify patients who would not respond to anti-EGFR therapies (Douillard JY, et al. N Engl J Med. 2013;369:1023-1034).
They conducted a biomarker analysis of the treatment effect of the full spectrum of the currently characterized RAS (ie, KRAS and NRAS) and BRAF mutations, using data from the randomized, phase 3 Panitumumab Randomized Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME). In this secondary, exploratory, prospective-retrospective analysis, the safety and efficacy of panitumumab (Vectibix) plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) were compared with FOLFOX4 alone in the first-line treatment of patients with metastatic CRC, according to KRAS exon 2 status. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and safety.
The study included 1060 patients in whom RAS status could be ascertained—512 patients had tumors with nonmutated RAS, and 548 had tumors with RAS mutations in exons 2, 3, or 4. Among the subgroup of patients without RAS mutations, panitumumab-FOLFOX4 therapy was associated with a significant improvement in PFS compared with FOLFOX4 alone—10.1 months versus 7.9 months, respectively (P = .004), and the OS was also significantly improved by 5.8 months with the panitumumab-FOLFOX4 regimen compared with FOLFOX4 alone—26.6 months versus 20.2 months, respectively (P = .04).
Shorter Survival in the Absence of Mutation
A total of 108 patients (17%) without KRAS mutations in exon 2 had mutations in other RAS exons. In this subgroup of patients, outcomes in the primary analysis and in the exploratory updated analysis of OS showed that PFS and OS were shorter in the group receiving panitumumab-FOLFOX4 than in the group receiving FOLFOX4 alone, but the difference was not significant. These findings were consistent with those observed in the subgroup of patients with KRAS mutations in exon 2. In this subgroup, PFS in the primary analysis was considerably shorter (7.3 months) in the panitumumab-FOLFOX4 group versus the FOLFOX4-alone group (8.8 months; P = .02).
The incidence rates, types, and severity of adverse events associated with panitumumab-FOLFOX4 in the nonmutated RAS and mutated RAS subgroups were similar to the previously reported safety findings in the PRIME study.
In addition, in the subgroup of patients without RAS and BRAF mutations, a 7.4-month increase in OS was seen in the combined regimen of panitumumab plus FOLFOX4. However, as was seen in other trials, BRAF mutations overall were associated with a negative prognosis in these patients, regardless of the treatment regimen.
The study investigators concluded, “Panitumumab plus oxaliplatin-containing regimens have no value in patients with metastatic colorectal cancer and mutated RAS,” noting that the benefit-risk profile of the panitumumab-FOLFOX4 regimen was improved by excluding patients with CRC associated with RAS mutations.