Panitumumab Ineffective for Colorectal Cancers with Rare RAS Mutations

David H. Ilson, MD, PhD

Mutations beyond KRAS exon 2 also seem to negate benefit from EGFR-targeted therapy.

The epidermal growth factor receptor (EGFR)-targeted agents panitumumab and cetuximab have demonstrated single-agent activity in advanced colorectal cancer (CRC) and have improved response and survival when combined with chemotherapy. However, the benefit of these drugs is limited to KRAS–wild-type tumors. Activating KRAS mutations, which are present in at least 40% of colorectal cancers, make tumors resistant to EGFR-targeted therapies, and adding panitumumab or cetuximab to chemotherapy may worsen outcomes in patients with such mutations.

Now, to test whether EGFR-targeted therapy is influenced by rarer mutations in RAS (beyond the more common KRAS exon 2 mutations), investigators analyzed the impact of the full range of RAS mutations on treatment with chemotherapy plus panitumumab for patients with advanced CRC who were enrolled in the prior randomized, phase III, PRIME study (NEJM JW Oncol Hematol Jan 25 2011). RAS status was assessed in 1060 (90%) of 1183 patients, of whom 512 (48%) had no RAS mutation and 548 (52%) had any RAS mutation; among the 548 patients with any RAS mutation, 108 (17%) of evaluable patients were previously characterized as having no KRAS exon 2 mutations.

Among the 108 patients with non–KRAS exon 2 mutations, progression-free survival (PFS) and overall survival (OS) trended shorter in those treated with panitumumab plus chemotherapy versus chemotherapy alone, but the differences was not significant. However, when these patients were included among the 548 with any RAS mutation, PFS was significantly shorter with panitumumab (7.3 vs. 8.7 months; P=0.008) as was OS (15.5 vs. 18.7 months; P=0.04). Patients with no RAS mutation achieved longer PFS with panitumumab (10.1 vs. 7.9 months; P=0.04) as well as longer OS (25.8 vs. 20.2 months; P=0.009). Mutated RAS status was not prognostic in patients treated with chemotherapy alone. Patients with BRAF mutation, although overall having a worse prognosis, had improved PFS and OS when treated with panitumumab.

Citation(s):

Douillard J-Y et al. Panitumumab–FOLFOX 4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013 Sep 12; 369:1023.