On June 30, 2017, the U.S. Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) for panitumumab (Vectibix) for patients with wild-type RAS (defined as wild-type in both KRAS and NRAS as determined by an FDA-approved test for this use) metastatic colorectal cancer as first-line therapy in combination with FOLFOX. The drug was also approved as monotherapy following disease progression after prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan-containing chemotherapy. Panitumumab is the first fully human monoclonal anti–epidermal growth factor receptor (EGFR) antibody approved by the FDA for this patient population.
As part of this new indication, the FDA approved the first multigene, next-generation sequencing-based test to identify the RAS mutation status of a patient's tumor. This companion diagnostic is designed to help identify patients that are more likely to benefit from treatment with panitumumab.
“Of the few biomarkers in colorectal cancer, RAS mutation status provides actionable information when deciding on a first-line treatment option in metastatic colorectal cancer patients,” said Marwan G. Fakih, MD, Co-Director of the Gastrointestinal Cancer Program at City of Hope in Duarte, California. “Panitumumab has demonstrated a significant overall survival benefit to patients whose metastatic colorectal cancer does not have mutations in RAS, providing physicians with a novel targeted treatment option and allowing us to develop a personalized approach as we help patients fight this devastating disease,” he added.
Approval Based on Phase III Trials
The full approval for panitumumab as a treatment for patients with wild-type KRAS metastatic colorectal cancer was based on results from the phase III PRIME and ASPECCT trials.1–4 The approval of a refined indication for the treatment of patients with wild-type RAS metastatic colorectal cancer was based on a retrospective analysis from the PRIME study and prospective, predefined analyses from the phase III '0007 study.5Error loading Partial View script (file: ~/Views/MacroPartials/TAP Article Image Widget 2.cshtml)
The '0007 study evaluated the efficacy of panitumumab plus best supportive care vs best supportive care alone in patients with chemorefractory, wild-type KRAS metastatic colorectal cancer. Data from a key secondary endpoint showed that patients with wild-type RAS (exons 2, 3, and 4 of KRAS and NRAS) metastatic colorectal cancer treated with panitumumab plus best supportive care resulted in a statistically significant improvement in overall survival of 10 months compared to 6.9 months for patients treated with best supportive care alone (hazard ratio = 0.70; 95% confidence interval = 0.53–0.93, P = .0135).
Safety and Toxicity
The safety profile of panitumumab in patients with wild-type RAS metastatic colorectal cancer is consistent with that seen previously in patients with wild-type KRAS metastatic colorectal cancer.
Most common adverse reactions (≥ 20%) of panitumumab as monotherapy are skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea. Most common adverse reactions (≥ 20%) with panitumumab plus FOLFOX are diarrhea, stomatitis, mucosal inflammation, asthenia, paronychia, anorexia, hypomagnesemia, hypokalemia, rash, acneiform dermatitis, pruritus, and dry skin. The most common serious adverse reactions (≥ 2%difference between treatment arms) were diarrhea and dehydration. ■
1. Douillard JY, Oliner KS, Siena S, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369(11):1023-34, 2013.
2. Douillard JY, Siena S, Cassidy J, et al: Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 25(7):1346-1355, 2014.
3. Douillard JY, Siena S, Cassidy J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 28(31):4697-4705, 2010.
4. Price TJ, Peeters M, Kim TW, et al: Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 15(6):569-579, 2014.
5. Kim TW, Elme A, Kusic Z, et al: A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer. Br J Cancer 115(10):1206-1214, 2016.