Panitumumab response

Panitumumab is a monoclonal antibody used for the treatment of metastatic colorectal cancer (mCRC). Panitumumab is an epidermal growth factor receptor (EGFR) antagonist, which works by blocking the growth of cancer cells. It is administered every 14 days as an intravenous (IV) infusion, often with chemotherapy. Panitumumab is approved for first-line therapy with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and as monotherapy following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. The location of the primary tumor correlates whether an individual with mCRC is likely respond to anti-EGFR therapy. Individuals with left-sided tumors are more likely to respond well to anti-EGFR therapy and have a better prognosis. Individuals with right-sided tumors have a worse prognosis and respond poorly to anti-EGFR therapy. However, only the genetic variation status of the tumor, and not the location of the tumor, is discussed in the FDA drug label’s dosing recommendations. Resistance to panitumumab is associated with specific RAS mutations. The RAS is a family of oncogenes that includes the KRAS and NRAS genes. When mutated, these genes have the ability to transform normal cells into cancerous cells by providing a continual growth stimulus to cells. The KRAS mutations are particularly common, being detectable in 40% of metastatic colorectal tumors. The KRAS mutations often lead to constitutive activation of the EGFR and are associated with resistance to anti-EGFR drugs such as panitumumab. Mutations in NRAS and another gene, BRAF, have also been associated with poor response to anti-EGFR therapy. The 2017 FDA-approved label states that panitumumab is indicated for wild-type RAS (no mutations in either KRAS or NRAS) mCRC. The label states that an FDA-approved test must be used to confirm the absence of RAS mutations before starting panitumumab, and that panitumumab is not indicated for the treatment of individuals with colorectal cancer with RAS mutations (in either NRAS or KRAS), or when the RAS genetic variation status is unknown. Similarly, the 2015 Update from the American Society of Clinical Oncology (ASCO) states that anti-EGFR therapy should only be considered for the treatment of individuals whose tumor is determined to not have variations detected after extended RAS testing. The 2020 National Comprehensive Cancer Network (NCCN) guideline also strongly recommends KRAS/NRAS genotyping of tumor tissue in all individuals with mCRC. In addition, the guideline states the V600E mutation in the BRAF gene makes a response to panitumumab highly unlikely, unless given with a BRAF inhibitor.

Medical Genetics Summaries