Treating Advanced RAI-Refractory DTC: A Two-Way Street: Medical Oncology and Endocrinology - Episode 9

Understanding Sequencing and What to Look for in DTC

January 18, 2021
Lori J. Wirth, MD, Massachusetts General Hospital

,
Jennifer Sipos, MD, Ohio State University

,
Frank Worden, MD

Lori J. Wirth, MD: You mentioned that you do sequencing. What are you looking for?

Jennifer Sipos, MD: We use a panel approach. We use a commercial panel sometimes, and sometimes we’ll use our in-house panel, to look specifically for BRAF or RAS mutation. But if we’re looking for a broader panel, we’ll send that out commercially. We’re looking to see if there are actionable driver mutations that have associated drugs that may work. If there’s a RET PTC [papillary thyroid cancer] rearrangement, we may use selpercatinib. For BRAF, we may use the dabrafenib and trametinib. We’re looking for actionable mutations.

Lori J. Wirth, MD: Yes, detecting the actionable mutations is definitely something we want to be thinking of in all our patients as we’re coming up with the optimal systemic therapy for them.

Across the different types of advanced thyroid cancers we have, all are really rich in potentially druggable targets. The first FDA approval was for NTRK-targeted therapies with larotrectinib and then entrectinib. We do see NTRK fusion rarely in about 2% of our thyroid cancers. However, that’s the case with NTRK fusions across solid tumors. There isn’t a particular solid tumor in adults that has a very high frequency of NTRK fusions. As a matter of fact, in the larotrectinib trial, the second most common tumor in adults who were enrolled was thyroid cancer. If looking for NTRK fusions is pertinent in someone with non–small cell lung cancer, it’s definitely pertinent in somebody with advanced, iodine-refractory DTC [differentiated thyroid cancer].

The second gene-specific therapy for iodine-refractory DTC approved recently was selpercatinib, the RET-specific inhibitor. Overall, in PTCs, we see slightly less than 10% of all papillary thyroid cancers harbor RET fusions, but RET fusions are more common in pediatric and young adults with thyroid cancer. They’re also more common in the radiation-induced thyroid cancers as well.

Outside clinical trials, in patients in whom an NTRK fusion or a RET fusion is detected, what is your sense of the best first-line therapy for someone with progressive iodine-refractory DTC? Should we be using a gene-specific therapy first, or should we be using a multikinase therapy like lenvatinib first? What’s your sense of the best sequence of these drugs?

Jennifer Sipos, MD: I don’t know of any head-to-head studies looking at that specifically, and there are very few studies in general. This is largely 1 of those issues that falls under the category of how you like to do it. At our center [The Ohio State University Comprehensive Cancer Center], we generally will utilize a gene-specific target therapy when available. We then reach for the multikinase inhibitors as a second option if the patient either doesn’t have 1 of those actionable mutations or cannot take 1 of those actionable drugs because of some contraindication. Then we can use the lenvatinib. When we don’t know the genomics of the tumor, in those patients who are more acute, we might just use lenvatinib. We’re generally trying to get the genomics. But it is challenging to get that covered with insurance at times. That can be a bit of a challenge in getting the genomic profile for the individual tumor.

Lori J. Wirth, MD: Hopefully that will be changing now that we have a second gene-specific approved therapy in these patients. Hopefully the insurers will understand that there is even greater rationale now for that testing.

Transcript edited for clarity.