Next Steps for RET-Mutated Medullary Thyroid Cancer

Lori J. Wirth, MD: In terms of the current unmet needs, 1 of the important questions, that we deal with in advanced thyroid cancer is when we should initiate therapy. Advanced thyroid cancers are a wide array of different diseases, but even in the same histologies or histologic subtypes we can still see a very wide array of natural histories. Not every patient who has a RET-mutant MTC [medullary thyroid cancer] has the same exact disease. There are patients who can have metastatic disease and be relatively asymptomatic even for years whereas other patients may progress much more rapidly than that.

One of the important questions is when we should initiate therapy. When patients do have slow growing asymptomatic disease in general there isn’t an urgent need to initiate therapy. However, in the era of the multikinase inhibitors when there was perhaps a slightly higher price to pay, our general tendency was to delay the initiation of therapy for as long as possible to avoid the patients having to deal with the adverse effect profile. Now I wonder if in the era of more specific gene, specific targeted therapy that’s very potent and has a tolerable adverse effect profile will patients do better if we initiate therapy earlier in the course of their disease rather than waiting as long as possible. That’s a question of the pendulum swinging 1 way in the era of multikinase inhibitors, and now in the era of precision medicine maybe it’s more appropriate for the pendulum to swing back to earlier therapy. We don’t have any clinical trial data to answer that question, but it is an important question.

Another important question is what is the best sequence of therapies? We now have 3 FDA-approved drugs for the treatment of medullary thyroid cancer, and that question really has not yet been answered. We do have a randomized phase 3 trial underway internationally randomizing patients with RET mutant MTC to selpercatinib versus either vandetanib or cabozantinib as the physician’s choice. I think that this is an important phase 3 study that is now enrolling patients across the world.

Another important question is the question of acquired resistance. We have now, unfortunately, seen in a small handful of patients treated on the LIBRETTO-001 NCT03157128 trial as well as in patients on the pralsetinib studies the emergence of acquired resistance. Of course, we must expect that we will be seeing more of this arise in the future. We need to understand better what the mechanisms of acquired resistance are to RET-specific inhibitors and then, of course, have new therapies to target the acquired resistance mechanisms in those patients.

One other setting in which we have an opportunity to act perhaps earlier in the course of the disease is in patients who postoperatively have no known metastatic disease but have rather rapidly rising calcitonin and CEA [carcinoembryonic antigen] levels so that we know that they are destined to develop metastatic or locally recurrent disease in the future. Can we act early in the course of those patients with rising calcitonin and CEA? We don’t have any data at all, I wouldn’t consider using a drug like selpercatinib in that setting but it’s an important clinical research question that hopefully we’ll have a chance to think about in the future.

Transcript Edited for Clarity