Brose Sheds Light on Targeted Therapies in Thyroid Cancer

Marcia Brose, MD

Marcia Brose, MD, assistant professor, Abramson Cancer Center, Department of Otolaryngology, Head & Neck Surgery, Department of Medicine, Division of Hematology/Oncology, Department of Dermatology at The University of Pennsylvania, sat down with OncLive.com to discuss the recent advances in the treatment of thyroid cancer at the Chemotherapy Foundation Symposium in New York City.

OncLive: What are some of the results and findings from the DECISION trial?

Brose: DECISION was a placebo-controlled, randomized trial testing the efficacy of sorafenib in papillary and differentiated thyroid cancers. And what we basically did was we took patients, who had differentiated thyroid cancer that had progressed following radioactive iodine, and they had to have progressing disease, and they were randomized to either sorafenib or placebo 1:1.

The results that we presented at ASCO showed that the progression-free survival in the sorafenib arm was significantly increased to 10.8 months compared to 5.8 months in the placebo arm. And this was statistically significant with a hazard ratio of 0.587 and a P value of less than .0001.

What did the additional analysis of the DECISION trial presented at the European Cancer Congress show?

We did additional analysis that was presented at ESMO that looked at whether or not the BRAF mutation status or the RAS mutation status had an implication for whether or not sorafenib was effective. The end results were basically that neither BRAF nor RAS predicted for outcome or response to sorafenib. In other words, using genetic markers should not be used to determine which patients should receive therapy.

Interestingly, in the univariate analysis, it looked like BRAF might be a positive prognostic sign. So in the univariate it was positive but in the multivariate analysis, it was not an independent prognostic factor. RAS conversely looked like it was a negative prognostic sign, however in the multivariate analysis it was not an independent prognostic factor.

So this means that it may actually reflect more the histologies of the subtypes that have those mutations and may not be independent.

Do you see BRAF mutations as target in thyroid cancer or is there a predictive role?

I think that they’re absolutely a target. As for whether or not there going to be predictive or not, I think that it’s all going to depend on the agent. So if an agent has a very good mechanism that’s very strong that’s not related to the actual BRAF status, then obviously it won’t matter.

When we talk about prognostic, I think there probably is a prognostic role depending on how you look at the study. You might be able to see it. At the end of the day, I think what happens is that these two pathways are extremely dynamic. And so, if you have a BRAF mutation it just basically says that the MAP-Kinase pathway is probably a strong pathway that needs to be considered. But even in a BRAF wild type, I think what we’re seeing is that it probably is already and important pathway.

The MAP-Kinase pathway is important regardless of whether they’re upregulated or not. And I think that is what the data is saying. When it’s sort of ambivalent, I think it’s saying that “yes, that is one mechanism, but dynamically that pathways still can be very important to the tumor cells and still a very good target for targeted therapy development.”

What is cabozantinib’s role in medullary thyroid cancer?

So cabozantinib, I love that drug as far as its mechanism. So it actually hits MET, VEGF Receptor 2 and RET. And interestingly it’s obviously the number one targeted agent for medullary because we have all of those.

What we really saw in the EXAM trial is that patients had wonderful responses and durable responses.  So it’s a very good agent, it’s an active agent. The design of that trial was different than the vandetanib trial because they were being realistic and realized that if patients who have medullary thyroid cancer are stable, there is no reason to be giving them toxicity. So they did what the other trials have done and clearly defined a high-risk group and they took the patients who had clear progression of disease with medullary thyroid cancer and randomized them. The placebo arm was really only about 4 months and the cabozantinib increased progression-free survival to over 11 months, so really an incredibly active agent. I have patients on it right now who are benefitting from it.

An interesting thing about that drug though, is that if you think about those pathways- VEGF Receptor 2, RET, differentiated thyroid cancer has RET translocations and MET may be an escape pathway as it is in many other cancers. And so we’ve actually started looking at cabozantinib in the phase II setting in differentiated thyroid cancer. And so, yet another drug crossing over, like vandetanib. I think it may actually have a great role, especially in patients who failed other agents in differentiated thyroid cancer and we’re looking forward to more data on that.