The Future of Selpercatinib in the RET-Altered Thyroid Cancer Population

Lori Wirth, MD, an associate professor of medicine at Harvard Medical School and Medical Director of the Center for Head and Neck Cancers at Massachusetts General Hospital, discusses the future of selpercatinib (Retevmo) in RET-altered thyroid cancers. 

Selpercatinib was studied in this patient population in the phase 1/2 LIBRETTO-001 study (NCT03157128) in patients with RET-altered medullary thyroid cancer (MTC) or advanced thyroid cancer. According to Wirth, most patients enrolled in the trial had a response to therapy and remained in response at follow-up.

However, as patients inevitably progress, it’s important to understand the mechanisms of progression, according to Wirth. However, a second generation of RET inhibitors are in clinical trials.

One challenge that remains is balancing the efficacy of multikinase inhibitors (MKIs) with tolerability. According to Wirth, it is because of this dilemma that care providers hold off on prescribing MKIs. However, selpercatinib has a good safety profile, so it may be possible to move it to earlier in treatment. Additionally, questions remain over whether selpercatinib can be used to help get a patient with unresectable thyroid cancer to the point where they can have a successful operation.

0:08 | What’s next with selpercatinib in the patient population of RET-altered thyroid cancers is more selpercatinib. Most patients originally enrolled on LIBRETTO-001 had responses to therapy and remain in response at this time, so 1 critical question is what will the median progression-free survival be? What will the median duration of response be? It's good that we don't know the answer to that question because so far, we have not yet met those medians despite the length of time that we've had in follow-up thus far.

0:50 | With this paradigm of gene-specific therapy in oncology, we have seen acquired resistance emerge. In other settings, we are beginning to see that in patients that are treated with the RET-specific inhibitors, such has been reported in non-small cell lung cancer, with acquired resistance solvent front mutations now being reported. I do think that we will eventually, unfortunately, be seeing more patients progress, so I think we still have a lot to learn about what those mechanisms of escape will be. There are, however, already the second generation of RET inhibitors that are in clinical trials. I think we'll be seeing more drugs come online and in the phase 1 setting as well. Will there be other patients for whom a drug like selpercatinib is applicable? It’s a RETspecific drug, so I don’t anticipate that there will be activity in cancers that aren’t driven by RET.

2:04 | I do think however, given the drug has great activity, is well tolerated, one important question in thyroid cancer is how we can best take advantage of this good drug in thyroid cancer. Particularly with MTC when patients can be relatively asymptomatic, or RET fusion-positive advanced thyroid cancer when patients can be relatively asymptomatic? Sometimes we hold off as long as possible when starting a multikinase inhibitor therapy because of the balance of efficacy and side effect profile that you have to deal with, but when the efficacy is really good, and the side effect profile isn't as troublesome, should we be using these drugs earlier in the course of disease rather than holding off for as long as possible? I think that's a really important question. There are other questions as well, such as if patients present with unresectable thyroid cancer, can we use these drugs even prior to surgery for thyroid cancer to get patients to be able to have a successful operation?