Debates and Updates of VEGF Superiority in RAS Wild-Type CRC

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

“We all remember FIRE-3; this was an interesting study. It was very odd to use at the time when it was developed, because the primary endpoint was response and we could never conduct such a study in the US where the primary endpoint would be response,” explained Dr Eng.

The secondary endpoints for the FIRE-3 trial were progression-free survival (PFS) and overall survival (OS), where PFS was not statistically significant, but OS was with the initial findings for KRAS. The researchers were impressed by all other RAS data. These results garnered interest in anti-EGFR therapy in the frontline setting.

“In regard to long term follow-up, patients had more than 70 months of follow-up, and, once again PFS was not statistically different, but OS was compelling with anti-EGFR therapy upfront, including all extended RAS analysis,” continued Dr Eng.

Dr Eng noted that 47% of patients from the investigational arm went on to receive bevacizumab, a targeted VEGF therapy, and then 41% of those on this regimen went on to receive anti-EGFR therapy.

“The CALGB/SWOG 80405 trial is the largest study that’s been conducted. The primary endpoint here was OS. 70% of patients received FOLFOX-based therapy versus 30% that received FOLFIRI-based therapy, and with extended RAS analysis, they noted no difference in OS,” said Dr Eng.

Although patients in the FOLFIRI-bevacizumab arm demonstrated notably positive results, not many patients chose to go on FOLFIRI, according to Dr Eng. Further, the FOLFOX patient population was not powered to determine a difference for left-sided tumors that were all RAS wild-type, even though it appeared that there was a trend for an improved benefit for anti-EGFR therapy.

“In a cross-trial comparison between FIRE-3 and 80405, 67% and 88% of patients proceeded onto second line therapy, respectively. 27% of patients received FOLFIRI-based treatment. What else can we learn from this? Once again, OS was a secondary endpoint, PFS was never found to be statistically significant. 41% proceeded to anti-EGFR therapy in the second line setting, whereas here in the US, most of us would probably continue bevacizumab beyond progression,” elaborated Dr Eng.

Dr Eng shifted her focus to adverse events (AEs) and associated multiple toxicities and electrolyte disturbance with anti-EGFR therapy. With cetuximab, an EGFR inhibitor, there is a potential risk for allergic hypersensitivity reactions. Additionally, quality of life data from the 80405 trial was in favor of anti-VEGF therapy upfront.

“What was not mentioned by Dr Kasi is drug resistance. If you give anti-EGFR therapy, you are going to develop acquired resistance, and that was noted in a pivotal paper published in Nature. It showed that we need to check if patients are still RAS wild-type and we need to follow them with circulating tumor DNA to determine whether patients will benefit from anti-EGFR therapy down the road,” noted Dr Eng.

Dr Eng concluded her presentation by confirming that not all left-sided RAS wild-type patients should receive anti-EGFR therapy in the frontline setting. Neither the FIRE-3 or 80405 trials were powered for the life-sided all RAS tumor type. Additionally, there are additional costs to circulating tumor DNA for longitudinal testing for acquired KRAS resistance or all RAS resistance.—Alexa Stoia