Dr. Wu on the Current Utility of Targeted Therapy in CRC

Christina Wu, MD, gastrointestinal medical oncologist, Mayo Clinic, discusses key targeted therapies under investigation in patients with colorectal cancer (CRC).

KRAS and NRAS mutations are well known molecular markers for CRC and are commonly targeted in drug development efforts. However, there are now a slew of mutations to test for based on actionable targets that will impact patient outcomes, Wu says. Moreover, patients with KRAS and NRAS mutations were found to be eligible for anti-EGFR therapy in the first-line setting, as demonstrated by the phase 3 PARADIGM trial (NCT02394795), Wu explains. Data from the phase 3 PARADIGM trial, examining panitumumab (Vectibix) plus mFOLFOX6 vs bevacizumab (Avastin), were presented at the 2022 ASCO Annual Meeting.

Targeting KRAS G12Cmutations have also specifically garnered significant interest across the treatment landscape. Data coming down the pike with KRAS G12C inhibitors from trials such as the phase 1/2 KRYSTAL-1 trial (NCT03785249) and the CodeBreaK 100 (NCT03600883) have produced promising response rates, Wu emphasizes.

Several other actionable targets have been identified, including BRAF V600e mutations and HER2 amplification.

The phase 3 BEACON CRC trial (NCT02928224) evaluated encorafenib (Braftovi) plus cetuximab (Erbitux) with or without binimetinib (Mektovi) or standard chemotherapy in patients with pretreated BRAF V600e-mutated CRC. This trial demonstrated that treatment regimens consisting of a second-line BRAF inhibitor and an anti-EGFR agent can improve patient responses and increase overall survival. Ongoing studies, such as the phase 3 BREAKWATER trial (NCT04607421), continue to examine this combination alongside chemotherapy, Wu notes.

HER2 amplification is another key target for therapeutic development, as it is often observed in patients with RAS wild-type tumors. The HER2 TKIs tucatinib (Tukysa) and trastuzumab (Herceptin) were investigated for patients with HER2-positive CRC in the phase 2 MOUNTAINEER trial (NCT03043313) and elicited a promising overall response rate. These agents are now being investigated alongside other targeted therapies to determine the optimal combination to treatpatients with HER2-positive CRC. The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu)has also been studied for patients with refractory, HER2-amplified CRC, Wu adds.

Lastly, the efficacy and safety of fruquintinib (Elunate) vs placebo was investigated in the phase 3 FRESCO-2 trial (NCT04322539). Although this agent does not directly correspond with a specific biomarker, it generally targets the VEGF signaling pathway, making it a promising option for patients who progressed on prior chemotherapy.

Overall, screening for these biomarkers alongside mismatch repair–deficiency/microsatellite instability–high status should become a normalized in clinical practice, Wu concludes.