Upcoming Advancements in the Treatment of BRAF-Mutant, Metastatic Colorectal Cancer

At the 2023 World Congress on Gastrointestinal Cancers, Erika Martinelli, MD, PhD, Università degli Studi della Campania “L. Vanvitelli”, Caserta, Italy, highlighted key upcoming advancements in the treatment of BRAF-mutant metastatic colorectal cancer.

Dr Martinelli highlighted key advancements coming from trials investigating precision medicine, MSI-high disease, and targeted therapies, which will allow physicians to “optimize the treatment to our patients.”

Transcript:

I am Erika Martinelli, medical oncologist coming from University Vanvitelli of Naples in Italy, and today we are in the World GI Congress 2023 and my talk is on the BRAF population.

BRAF population represent the 10% of metastatic colorectal cancer, the mutated one, and it's very important to identify this kind of patient—why, because they have a poor prognosis unfortunately.

The first thing to do is to perform, before starting a treatment, the molecular characterization of the tumor. We want to know, just before starting and deciding a treatment what is the molecular characterization of the tumor, and if we are dealing with BRAF-mutated patient and I'm referring to V600E, we should know.

First of all, because in the firstline actually, we do not have some specific treatment, many recommend to use chemotherapy, mainly a doublet combination with an anti-androgenic drug with bevacizumab. But what has been really changing during this year—now in second-line we have a precision medicine and we can apply precision medicine to this population. We have two drugs, combined: one is encorafenib, which is a BRAF inhibitor, in combination with cetuximab, which is an anti-EGF receptor inhibitor. This combination showed activity within the BEACON trial, which was a phase 3 randomized trial in which more than 420 patients were randomized to receive encorafenib and cetuximab versus the control. The trial was positive because the targeted agent was superior to control, and thanks to this trial we can now use [this combination] in our clinical practice and it is also recommended on our guidelines, the use of targeted agent in second-line.

But, of course, we want to use personalized medicine also in early line but, up to now we cannot do it because we have to wait until some phase 3 trials that are currently running will be ready. We have a big trial, the BREAKWATER trial, in which in first-line, patients will be randomized to receive encorafenib and cetuximab plus FOLFOX versus the standard of care that will be defined by the physician. Up to now, we can only treat BRAF-mutated patients only in the second-line so, we have to wait for the BREAKWATER trial.

Another thing to consider is that 20% of patients with BRAF mutations are also MSI-high. So, which is the best treatment in these patients? We can use still in first-line the immune checkpoint inhibitor and in second-line the targeted agent but of course, also in this case, we want to know and intensify the treatment by offering these patients a combination with an immune checkpoint inhibitor with the targeted agent. But up to now, we cannot do it because we should wait for the results from another important phase 2 trial that is currently running in the world, which is the SEAMARK trial in which patients with BRAF-mutated V600E and MSI-high [disease] will be randomized to receive the immune checkpoint pembrolizumab alone or pembrolizumab in combination with encorafenib and cetuximab. The trial is just started so we have to finish and wait until it will be finished.

Finally, of course, we have targeted therapy. We want to optimize the treatment to our patients. We have some new data on possible biomarkers that are responsible for sensitivity to encorafenib and cetuximab, like the mutation of RNF43. But up to now, there is no predictive biomarker to be used for patient selection so, we the only considerable choice to offer is encorafenib and cetuximab according to BRAF mutation.

In this field, there is a lot of new that will come in the near future, and it is very important because these patients, as I already mentioned, have a very poor prognosis. Thank you very much for your attention.

Source:

Martinelli, E. BRAF mutant tumors: Strategy and new data. Presented at the 2023 World Congress on Gastrointestinal Cancers; June 28-July 1, 2023; Barcelona, Spain.