Therapies in Development to Improve Outcomes in BRAF-Mutated CRC

Tim G. Larson, MD

Tim G. Larson, MD

Patients with BRAF-mutated colorectal cancer (CRC) tend to have a poor prognosis and often do not respond to some of the currently available therapies, according to Tim G. Larson, MD.

The randomized phase III BEACON study evaluated both the combination of binimetinib, encorafenib, and cetuximab (Erbitux), and encorafenib and cetuximab in patients with BRAF V600E metastatic CRC whose disease progressed after 1 or 2 prior regimens in the metastatic setting.

Preliminary efficacy data support the benefit of adding binimetinib to encorafenib and cetuximab. The combination was found to be well tolerated, providing hope for this challenging patient population.

“This trial is offering some promising therapies to this patient population,” said Larson. “If I have a patient with a BRAF mutation, this is a trial that I would be interested in enrolling them to.”

OncLive: Please provide an overview of your presentation.

Is there a specific treatment that stands out to you as being the most promising?

What combinations are currently being explored with immunotherapy?

What ongoing clinical trials hold the most promise?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on GI Malignancies, Larson, who is of Minnesota Oncology, discussed emerging data involving immunotherapy for patients with microsatellite instability (MSI)/microsatellite stable (MSS) CRC and highlighted some of the identified molecular mutations in patients with CRC.Larson: Dr Axel Grothey covered the initial treatment of patients with mCRC and I discussed everything after that. Most of my talk was on the newer things that might be breaking into the clinic if they pan out, such as novel treatments and promising regimens that we heard about at the 2017 ESMO Congress and 2017 ASCO Annual Meeting.Everyone is interested in immunotherapies. While the MSI-high population is a small percentage of CRC, I believe that patients really could benefit from these therapies. We haven’t cracked the nut yet for the MSS population, which is about 95% of the metastatic CRC population. I presented data from investigators using unique combinations or unique novel molecules, which might be the first times where we could be making some progress. That is the most exciting area.I had one slide that looked at a variety of the drugs that investigators are currently using, such as biologics and targeted therapies. I allude to this one study done by Dr Tabernero, which looked at a novel antibody that links T cells to the tumor. Overall, there are a variety of approaches. One that will be opened at University of Rochester is called the BEACON trial. Dr Axel Grothey is the site investigator. It is for BRAF-mutated patients, which make up a small group of patients with CRC who have poor prognoses and do not respond to certain agents that we use otherwise. They have been a challenge. This trial is offering some promising therapies to this patient population.

What would you say is a significant unmet need for these patients?

Where are we currently with biomarker research for these patients?

What are the main takeaways from your lecture for the community oncologists in attendance?

At the Mayo Clinic and at University of Rochester, we’re looking at a drug called BBI-608, also known as napabucasin, which is a cancer stem cell inhibitor that is a unique class of drugs. In the second-line setting, which is the center of my talk, this phase III trial looks at standard second-line therapy with or without this oral BBI-608 agent. That is another trial that I would encourage people to enroll on. Trying to bring immunotherapy to [be effective] on the MSS patients, which is 95% of the population, is a huge unmet need. The future, in terms of trying to select therapies, continues to evolve. There are 4 main molecular subtypes of CRC and we are just now starting to apply some of them to the different therapies that we use day in and day out. We might find that certain subsets will be better served with a particular type of therapy. We will get smarter, but what the future holds remains to be seen. We are hoping that, when we look at molecular subtypes, they will hopefully be prognostic and predictive.The improvement that we have seen in survival in the last 20 to 25 years is less dependent on sequence and combination. More importantly, all the drugs that a patient is eligible for are given. We do have some new therapies that look quite promising. For this BRAF-mutant population, in particular, it seems like there are drugs off the shelf that we could use to help our patients with right away. I would favor enrolling them into the BEACON trial to determine certain strategies with combining the immunotherapies. At the end of the day, it looks like there are some strategies that might be helpful.

Huijberts S, Schellens JHM, Elez E, et al. BEACON CRC: safety lead-in for the combination of binimetinib, encorafenib, and cetuximab in patients with BRAF-V600E metastatic colorectal cancer. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 517P.