First-Line Treatment in Left-Sided, RAS/BRAF Wild-Type Metastatic Colorectal Cancer: EGFR Inhibitors vs VEGF Inhibitors

Pashtoon M. Kasi, MD, MS, argued for epidermal growth factor receptor (EGFR) inhibitors as a superior first-line treatment in left-sided, RAS/BRAF wild-type metastatic colorectal cancer versus vascular endothelial growth factor (VEGF) inhibitors in a debate with Cathy Eng, MD, FACP, FASCO, at the 2022 Great Debates & Updates in Gastrointestinal Malignancies conference in New York, NY.

“If you look at the data for left-sided RAS/BRAF wild-type, anti-EGFR is superior to anti-VEGF across the board. Overall survival (OS) is what matters at the end of the day. The real-world outcomes are 43 months versus 28 months, 40 months versus 30, almost a minimum of one year of OS improvement,” explained Dr Kasi.

Dr Kasi elaborated that the reason why anti-EGFR inhibition is not the norm in the first-line setting compared to non-biomarker drugs correlates with colorectal cancer screenings and sequencing strategies.

“It’s baffling why anti-EGFR is not being used. It’s a testing issue. If you look at RAS testing in metastatic colorectal cancer patients in the United States, the problem is we never get the RAS/BRAF status back,” said Dr Kasi.

An additional problem with biomarker testing is time and accuracy. According to Dr Kasi, tests are typically sent back to request RAS/BRAF status and 81% of the time, results arrive in 15 days or longer. As for the RAS/BRAF wild-type status, results do not come back within the first two weeks in 93% of cases.

“Even in a well-designed prospective study, such as a phase 2 trial out of Japan that was published in Nature Medicine looking at prospective next generation sequencing (NGS) testing, their median turnaround time for tissue NGS was 33 days,” continued Dr Kasi.

Initial tissue acquisition represents a huge issue, according to Dr Kasi, and is a major factor as to why patients do not receive anti-EGFR inhibition despite robust data. Dr Kasi suggested blood-based testing may address the challenge of limited testing platforms and prolonged wait times for RAS/BRAF status.

Dr Kasi pointed to updated NCCN guidelines featuring blood-based profiling and genotyping tissue as an attractive candidate for healthcare practitioners to plan first-line precision medicine therapies.

“RAS mutation testing is the issue, not the therapy. We don’t have to split curves here. It’s almost a year survival, no matter if you look at randomized trials or real word data. It’s about identifying these patients thoroughly so we can act upon it,” concluded Dr Kasi.