Join Barish Edil, MD, and Wells Messersmith, MD, as they present their multidisciplinary expertise on a range of cases pertaining to Metastatic Colorectal Cancer.

The management of metastatic colorectal cancer (mCRC) involves a continuum of care in which patients are exposed sequentially to a variety of active agents (5-FU/leucovorin, capecitabine, irinotecan, oxaliplatin, bevacizumab, ziv-aflibercept, cetuximab, panitumumab, regorafenib), either in combinations or as single agents. The choice of therapy is based on the goals of treatment (i.e., eradication of micrometastases in resectable patients, tumor shrinkage to obtain resectability, slowing of disease in unresectable patients), the type and timing of prior therapy, the different efficacy and toxicity profiles of the drugs, and the mutational status of the tumor. For the past several years, patients with tumor mutations in exon 2 of KRAS have not been offered panitumumab or cetuximab because tumors with such mutations are insensitive to these drugs.

Results from the PRIME trial were recently published, showing that 17% of patients without KRAS exon 2 mutations had mutations in exons 3 and 4 of KRAS or in exons 2, 3, and 4 of NRAS. A predefined retrospective subset analysis revealed that PFS (HR, 1.31; 95% CI, 1.07-1.60; P = .008) and OS (HR, 1.21; 95% CI, 1.01-1.45; P = .04) were decreased in patients with any KRAS/NRAS mutation who received panitumumab plus FOLFOX compared to those who received FOLFOX alone. In addition, updated analysis of the FIRE-3 trial showed that, when all KRAS and NRAS mutations were considered, PFS was significantly worse in RAS-mutant patients receiving FOLFIRI plus cetuximab than in RAS-mutant patients receiving FOLFIRI plus bevacizumab (6.1 vs. 12.2 months; P = .004). On the other hand, KRAS/NRAS wild-type patients showed no difference in PFS between the regimens (10.4 vs. 10.2 months; P = .54). Taken together, results from the PRIME and FIRE-3 trials indicate that panitumumab and cetuximab do not benefit patients with KRAS or NRAS mutations and may even have a detrimental effect in these patients.

The NCCN Colon/Rectal Cancer Panel now recommends that, in addition to exon 2 KRAS mutation status, NRAS and non-exon 2 KRAS mutation status be determined whenever possible in patients with mCRC. Patients with any known KRAS or NRAS mutation should not be treated with cetuximab or panitumumab.

In patients with mCRC, clinicians need to consider the goals of therapy (i.e., eradication of micrometastases in resectable patients, tumor shrinkage to obtain resectability, slowing of disease in unresectable patients), the different efficacy and toxicity profiles of the drugs, and patient preferences. Other considerations for the selection of therapy include the previous treatment history and, importantly, the tumor markers of the patient. Molecular testing has played an increasingly critical role for the determination of therapy.