Panitumumab in Wild-Type KRAS and RAS Metastatic Colorectal Cancer

Panitumumab is a fully human anti–epidermal growth factor receptor (EGFR) monoclonal antibody indicated for the treatment of wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use. This agent is used either in combination with FOLFOX for first-line treatment or as monotherapy following disease progression, after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy.1 An overall survival (OS) benefit in WT KRAS (exon 2) mCRC was not seen with panitumumab monotherapy in study 20020408 possibly due to a crossover of patients in the best supportive care (BSC) arm.2 Retrospective analyses have indicated that other KRAS and NRAS mutations beyond KRAS (exon 2) are predictive of anti-EGFR treatment effects. Kim and colleagues reported on the results of the phase 3 study 20100007 that assessed the OS benefit of panitumumab in chemorefractory WT KRAS (exon 2) mCRC; this is the first phase 3 trial to prospectively evaluate the effect of panitumumab in WT RAS (exons 2, 3, and 4 of KRAS and NRAS) mCRC.3

Anti-EGFR–naïve, previously treated, WT KRAS mCRC patients were randomized 1:1 to receive panitumumab (6 mg/kg every 2 weeks) + BSC or BSC alone. KRAS (exon 2) and RAS mutation status of tumors were determined centrally. The primary end point was OS in WT KRAS (exon 2) mCRC. Secondary end points were OS and progression-free survival (PFS) in WT RAS mCRC, and PFS, objective response rate (ORR), and safety in both WT KRAS (exon 2) and WT RAS groups. A total of 377 patients with WT KRAS (exon 2) mCRC were enrolled. OS was significantly improved with panitumumab + BSC versus BSC in both WT KRAS (exon 2) (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.57-0.93; P = .0096) and WT RAS (HR, 0.70; 95% CI, 0.53-0.93; P = .0135) mCRC. Patients with mutant RAS mCRC did not benefit from panitumumab therapy (OS HR, 0.99; 95% CI, 0.49-2.00). No new safety signals with panitumumab treatment were observed; grade 3/4 adverse events included RASh, dermatitis, hypomagnesemia, pruritus, and fatigue (all <10%). The authors concluded that panitumumab significantly improved OS and PFS in chemorefractory WT KRAS (exon 2) mCRC. The treatment effects in OS and PFS were even more pronounced in those with WT RAS mCRC, further substantiating the importance of RAS testing as a predictive biomarker at diagnosis to best inform the use of panitumumab in treating patients with mCRC.

  1. Vectibix® (panitumumab) package insert. Amgen. 2015.
  2. Patel SB, et al. Onco Targets Ther. 2015;9:75-86.
  3. Kim TW, et al. ASCO 2016 Gastrointestinal Cancers Symposium. Abstract 642.