Rationale for Sequencing in Second Line

Lori J. Wirth, MD: The FDA did give a line-agnostic approval for selpercatinib in RET-mutated MTC [medullary thyroid cancer], as well as RET fusion-positive thyroid cancer. You divulged your answer to the question already that you would use it as first-line therapy. 

Frank Worden, MD: Yes, for sure. 

Lori J. Wirth, MD: I agree with you. I wonder if there is a rationale, in terms of the line of therapy, in thinking about second-line therapy. If we see acquired resistance emerging on a RET-specific inhibitor, do we need to think about that when we’re thinking about what the right sequence of these agents is? 

Frank Worden, MD: That does come to mind. Interestingly enough, pralsetinib is also approved. I have had some patients, 1 or 2, who came off of selpercatinib either for adverse effect profile or progression. They did respond to the BLU-667 agent pralsetinib. Perhaps there is something there; the drugs are similar, but there is enough variance and difference that we can see responses with one if the other doesn’t work. The next-generation RET kinase inhibitors to follow are being worked on now and being studied. That would be really important for us. The good news, as you mentioned, is that the progression-free survival hasn’t been reached yet. I’ve had patients on these drugs for over 2 years now or more, and I’m crossing my fingers and hoping for the best that we’re going to continue to see progression-free survival.

I suppose the question comes up, what happens if and when patients progress? At this point, that’s part of the reason we do the entire genomic sequencing through our studies to see if there are PIK3CA or other mutations that we should be looking at. I know with ITOG [International Thyroid Oncology Group] we had added immunotherapy to the multikinase inhibitor lenvatinib. Maybe there’s some benefit there, but it remains to be determined.

Lori J. Wirth, MD: That’s a good time to biopsy a patient who is on one of the gene-specific therapies. If you have an opportunity to biopsy a progressing lesion, then you may be able to identify the mechanism of acquired resistance. We still need to figure out more about what those mechanisms are, but that can definitely guide the next line of therapy.  

Fran Worden, MD: Correct. 

Lori J. Wirth, MD: If for some reason biopsy is not possible, we’re learning more about liquid biopsies in patients with thyroid cancer, too. 

Transcript edited for clarity.