Dual Inhibitor Therapy Elicits Responses in Rare, BRAF-Mutant Cancers

Zev A. Wainberg, MD

Rare cancers with BRAF mutations are demonstrating responses to the combination of dabrafenib (Tafinlar) and trametinib (Mekinist), a molecularly targeted pairing that has approved indications in melanoma and non—small cell lung cancer. The most recent indication for the combination is for the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer with a BRAF V600E mutation and no options for locoregional therapy.

The FDA approved the combination based on results from the ROAR trial (NCT02034110), a phase II basket study that enrolled patients with rare cancers across tumor types harboring a BRAF V600E mutation. Dabrafenib targets BRAF protiens while trametinib inhibits MEK signaling; both are in the MAPK/ERK pathway.

In an interview with OncLive^®, Zev A. Wainberg, MD, an investigator on the ROAR trial, discussed the future of this BRAF/MEK combination in rare cancers and why oncologists should be testing patients for this mutation. Wainberg is an associate professor of medicine at the David Geffen School of Medicine, University of California, Los Angeles (UCLA), and co-director of the UCLA Gastro-Intestinal Oncology Program.

OncLive^®: Please comment on the emergence of the BRAF/MEK dual inhibitor therapy.

It has been known for a long time that BRAF mutations in melanoma are important and that large number of patients with melanoma present with one. The combination has shown to be effective in a number of settings in melanoma for many years.

Several years ago, there were a number of publications that suggested that the presence of BRAF mutations was a dominant oncogene and was relevant in a number of cancers. The importance of having a BRAF mutation was shown to be the case in as many as 10 different cancers, all with varying degrees of frequency—of course, the largest being melanoma, colorectal, and lung cancers.

Can you explain the rationale for the ROAR trial?

The ROAR trial was an example of a clear basket trial, which means you are [recruiting] patients, all of whom have the same mutation but represent different cancers. What we were enthusiastic about was that we knew that this would be a hard trial to enroll patients into, but if we enrolled a certain number of patients into each cohort and found a respectable response rate and clinical activity, [we thought] that [the responses] would prove to be durable.

That was the key—durability. And in that respect, we set out to enroll 10 to 30 patients [per cohort], depending on their specific cancer and how rare it was, to prove those endpoints.

How well do patients tolerate this combination?

Both dabrafenib and trametinib have some adverse effects that are known and have been well described [in other trials]. Some patients get low-grade fevers, some patients get fatigue, some patients get liver function abnormalities, but overall this is a well- tolerated combination. Certainly by and large, it is better tolerated than most chemotherapy regimens.

Are there any adverse events that would lead to discontinuation?

Very few patients discontinued the study due to adverse events. There were a couple: One patient had liver abnormalities and 1 patient had fevers that were not well controlled, but it was a very rare [for a patient] to discontinue because of adverse events.

How does this combination compare with other BRAF/MEK combinations?

We don’t have head-to-head comparisons [with other BRAF/MEK combinations], but we do have a number of studies that have been done with single-agent BRAF inhibitors and single agents without the MEK inhibitors.

The challenge [with single agents] is that the durability has been a concern. Adding in the MEK inhibitor both increases the durability of the response and the amount of time that a patient can stay on therapy. It also, interestingly, lessens adverse effects, and that has been described in the literature.

There are a number of other BRAF/MEK inhibitor combinations, but not that many that have been [studied] in this setting that we can compare [this with].

What are the next steps for this combination?

The ROAR trial has already led to an FDA approval in 1 indication, which is anaplastic thyroid cancer, a rare tumor. There are several other rare tumors that have been presented, including one that we presented publicly in January [at the 2019 Gastrointestinal Cancers Symposium] in biliary tract cancer.

Patients with biliary tract cancers are a big group, but the [sub]group of patients with BRAF mutations is quite small. Only 7% to 8% of them have the mutation. So, it is difficult to conduct another study that will be better than the one we did, because of the rarity of that cancer.

Our conclusion from our study was that all patients with biliary tract cancer, in my opinion, should be tested for the presence of a BRAF mutation and if they have one should be considered for this combination.

Our emphasis in this trial and on the biliary tract cohort, which has not had any new drug approvals in many years, is exciting. What we really want to get out of it is that oncologists and providers test for BRAF in every patient, so that even if it is 7% to 8% [of patients], we can find them, we can see the good results that we expect.