Dr Pederson on Novel Therapies for the Management of Targetable mCRC

Katrina S. Pedersen, MD, MS, associate professor, John T. Milliken Department of Medicine, Division of Oncology, Medical Oncology program leader, cofounder, Young Onset Colorectal Cancer Program, Washington University School of Medicine in St. Louis, Siteman Cancer Center, discusses key updates in the therapeutic landscape, highlighting emerging therapies for patients with molecularly targetable metastatic colorectal cancer (mCRC).

In 2023, notable advancements in the mCRC space included the FDA approval of the HER2 inhibitor tucatinib (Tukysa) in combination with trastuzumab (Herceptin) for patients with mCRC who have progressed after standard frontline and second-line chemotherapy, Pedersen begins. This approval marked the first FDA-approved anti-HER2 therapy for mCRC, providing new treatment options for this molecularly targeted subset of patients, she explains.

Another noteworthy development is the emergence of adagrasib (Krazati) in KRAS G12C-mutated disease, Pedersen continues. Trials investigating adagrasib demonstrated durable and meaningful benefits, particularly when combined with an estrogen receptor inhibitor like panitumumab (Vectibix), she states. For example, administration of adagrasib plus cetuximab (Erbitux) was well tolerated and demonstrated clinical activity in the multicohort phase 1b/2 KRYSTAL-1 study (NCT03785249) of patients with previously treated KRAS G12C-mutant locally advanced or mCRC. These data supported the acceptance of a supplemental new drug application for the combination for priority review by the FDA in February 2024. This experience parallels findings with other MAP kinase-targeted interventions such as BRAF inhibitors, which are currently under FDA review and show promise for future accessibility, Pedersen adds.

Data from the phase 2 SEAMARK trial (NCT05217446), focusing on patients with BRAF V600E mutations and concurrent microsatellite instability or DNA mismatch repair deficiency, are also highly anticipated, Pedersen notes. This trial aims to evaluate the efficacy of combining BRAF-targeted therapy, such as encorafenib (Braftovi), with immunotherapy in this selected patient population, she details. The rationale behind this approach is to explore potential synergies between BRAF inhibition and immune checkpoint blockade, leveraging the unique molecular characteristics of these tumors, Pedersen concludes.