Dr Abushahin on Biomarker Testing in mCRC

Laith Abushahin, MD, medical oncologist, Texas Oncology-Baylor Charles A. Sammons Cancer Center, discusses the evolution of targeted therapy for patients with metastatic colorectal cancer (mCRC) and the importance of biomarker testing in this patient population.

In the past, all subsets of mCRC were viewed as 1 disease, and patients with various disease subsets were enrolled in similar clinical trials and received similar first-line treatments, Abushahin says. However, it is now known that mCRC is not a heterogeneousdisease, so treatments should not follow a 1-size-fits-all approach, Abushahin explains.

Some patients with mCRC have microsatellite instability–high (MSI-H) disease and will often respond favorably to immunotherapy, which is the current first-line standard of care in this population, Abushahin notes. For instance, in 2020, the FDA approved first-line pembrolizumab (Keytruda) in patients with unresectable MSI-H or mismatch repair–deficient mCRC based on findings from the phase 3 KEYNOTE-177 trial (NCT02563002), in which pembrolizumab generated a median progression-free survival of 16.5 months vs 8.2 months with chemotherapy.

In addition, several disease subgroups exist among patients with microsatellite-stable mCRC, Abushahin emphasizes. Approximately half of these patients have RAS mutations in various forms, approximately 5% to 10% of these patients have BRAF mutations, and approximately 4% of these patients have HER2-amplified disease, according to Abushahin.

These biomarkers inform treatment selection in the first and later lines, Abushahin says. For example, tucatinib (Tukysa) plus trastuzumab (Herceptin) is approved for patients with RAS wild-type, HER2-positive mCRC, based on findings from the phase 2 MOUNTAINEER trial (NCT03043313), in which the combination elicited an overall response rate of 38.1% (95% CI, 27.7%-49.3%). Therefore, prior to initiating mCRC treatment, all patients with this disease should be tested for at least these 4 biomarkers: MSI status, RAS and RAF mutations, and HER2 amplification, Abushahin emphasizes. Biomarker testing is especially important for patients with RAS or RAF wild-type disease, Abushahin concludes.