Christopher Lieu, MD

GI Oncology Now

Christopher Lieu, MD, University of Colorado Medicine, shares his list of top targeted therapies for metastatic colorectal cancer, highlighting immunotherapy for MSI-high tumors, the encorafenib-cetuximab-FOLFOX regimen for BRAF V600E mutations, and KRAS G12C inhibitors combined with EGFR antibodies for previously treated patients.&mdash;Dr. Lieu: What are the top three targeted agents or therapies for mutations in colorectal cancer?<ol>
<li data-start="269" data-end="1142">Microsatellite instability-high, or MSI-high Immunotherapy has been proven to improve outcomes compared to chemotherapy in the frontline setting for patients with metastatic colorectal cancer that is MSI-high. This is critically important. First, we now know that immunotherapy should be the initial treatment in this setting. Additionally, combination immunotherapy&mdash;specifically nivolumab plus ipilimumab&mdash;has demonstrated better outcomes than single-agent nivolumab. This matters because, for patients with MSI-high metastatic colorectal cancer, we not only want to initiate immunotherapy first, but in the appropriate patients, we should begin with the doublet immunotherapy. Although it comes with a slightly higher risk of toxicity, it also leads to higher response rates and improved progression-free survival compared to single-agent immunotherapy.</li>
<li data-start="1144" data-end="1966">BRAF V600E This mutation is associated with a poor prognosis in metastatic colorectal cancer. The BREAKWATER study evaluated the addition of encorafenib and cetuximab to FOLFOX chemotherapy in the frontline setting for patients with BRAF V600E-mutated colorectal cancer. This study is particularly important because the combination of encorafenib, cetuximab, and chemotherapy improved both response rates and progression-free survival. Preliminary data also suggest a trend toward improved overall survival. This regimen&mdash;encorafenib plus cetuximab with FOLFOX&mdash;has received FDA accelerated approval. Therefore, it is essential to test for BRAF status in all patients with newly diagnosed metastatic colorectal cancer, as those with the mutation should be started on FOLFOX with encorafenib and cetuximab.</li>
<li data-start="1968" data-end="2639">KRAS G12C KRAS mutations are found in a significant proportion of patients with colorectal cancer, but the G12C mutation specifically is present in only about 4 percent of metastatic cases. Despite its rarity, it is an important subset. There are now two FDA-approved regimens for patients with KRAS G12C-mutated metastatic colorectal cancer: adagrasib in combination with cetuximab and sotorasib in combination with panitumumab. These treatments are available for patients who have previously received therapy, and they represent a significant advance by providing targeted options that can meaningfully improve outcomes in this specific population.</li>
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Dr. Christopher Lieu shares his list of top targeted therapies for metastatic colorectal cancer.