Tanios Bekaii-Saab, MD: RAS Mutations and the Sequence of Therapies


Once a patient’s RAS status is known, does this inform the sequence of therapies? How can RAS testing be used to inform later lines of treatment?

The absence of a RAS mutation can help in terms of deciding on a treatment path for the patient. Let's start with the simplest way to look at this — if you have a RAS mutation, you're not going to get an EGFR inhibitor, so your only option is chemotherapy plus bevacizumab in the first-line. In the absence of a RAS mutation, which is what we call RAS wild type and is about half of the patients, then you have more options. You can choose chemotherapy plus bevacizumab, or chemotherapy plus an EGFR inhibitor.

The question is if there's any evidence that supports the use of an EGFR inhibitor versus a VEGF inhibitor in the first-line, or siltuximab panitumumab versus bevacizumab. There are 2 studies that looked at this question — Fire-3 from Europe, which essentially compared FOLFIRI siltuximab versus FOLFIRI bevacizumab. That study was powered for overall response rate, which is an unusual primary endpoint for a phase III study. Secondary endpoints included survival and progression free survival. The study was powered to detect superiority of response rate of siltuximab versus bevacizumab. The study was negative and did not show any differences in response rates between the FOLFIRI siltuximab arm and the FOLFIRI bevacizumab arm. Progression free survival was the same and overall survival was interestingly higher with the FOLFIRI siltuximab arm versus the FOLFIRI bevacizumab arm, but the separation of the curves happened after 2 years, so way after the patients stopped the one biologic or the other. This tells you that there were other factors, and not by the primary molecules that you're inhibiting. Again, the study was not powered for survival, so there's a limitation of how to interpret this.

CALGB-0405 asked the question of bevacizumab plus chemotherapy versus siltuximab plus chemotherapy. In this study, patients were allowed to have FOLFIRI or FOLFOX as the backbone. This study did not show any differences between the siltuximab and the bevacizumab arms, and if you look at FOLFIRI bevacizumab versus FOLFIRI siltuximab subgroup, the FOLFIRI bevacizumab did a little bit better in terms of survival. Essentially, if you take Fire-3 and CALGB-0405 and put all this together, what this tells you is there's really no preference of one versus the other.

This is how it gets complicated. How do you choose which biologic you start with? There are a lot of considerations that would lead you to choose one versus the other. Thee is the toxicity considerations, where bevacizumab tends to have silent toxicities, it doesn't exacerbate the toxicities from the chemotherapy. Then EGFR inhibitors like siltuximab have risk of rash, and in 10 to 12% of the patients the rash is quite severe and may require dose reductions. EGFR inhibitors increase the risk of diarrhea from chemotherapy and hypomagnesemia, so they come with their toxicities.

The other intriguing factor here is when they looked at the cost analysis from CALGB80405, the patients that received chemotherapy plus siltuximab versus those that received FOLFIRI bevacizumab, between acute care and cost of drug, it was cheaper to give chemotherapy plus bevacizumab than chemotherapy plus siltuximab. It ends up being cheaper.

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