Selpercatinib for Advanced RET-Driven Advanced Thyroid Cancer

Lori J Wirth, MD, Massachusetts General Hospital, Boston, Massachusetts, discusses the use of selpercatinib, a highly selective, potent RET inhibitor, for patients with advanced RET-mutant medullary thyroid cancer and RET fusion-positive, radioactive iodine-refractory differentiated thyroid cancer.

Dr Wirth commented, “I have to say, for patients with RET-driven thyroid cancer, the approval of selpercatinib for treatment of their illness is a game changer.”

Transcript:

Hi there. I am Lori Wirth. I'm a medical oncologist at Massachusetts General Hospital in Boston, and a Professor of Medicine at Harvard Medical School.

Prior to the approval of selpercatinib, what was the treatment landscape for patients with RET-mutant thyroid cancer?

There are 2 types of RET-driven thyroid cancers. The more common type is RET-mutated medullary thyroid cancer, and then we also have RET fusion-positive differentiated thyroid cancer. Prior to the approval of selpercatinib in those 2 different patient populations, we did have effective therapies for patients with progressive disease, namely the multi-kinase inhibitors (MKIs). For medullary thyroid cancer, we had cabozantinib and vandetinib that were both FDA-approved for the treatment of progressive medullary thyroid cancer. And then for iodine-refractory differentiated thyroid cancer, we have sorafenib and lenvatinib, both MKIs approved for the treatment of iodine-refractory differentiated thyroid cancer.

I mentioned that the drugs are effective. The one problem with those therapies is that while they're effective, patients can be on them for quite a while, and those multi-kinase inhibitors do engender a number of treatment-related adverse events that can be difficult for people to tolerate, especially over a long period of time.

How does it differ from the MKIs for thyroid cancer?

Selpercatinib is an oral small molecule inhibitor that was designed to inhibit the RET tyrosine kinase as potently and specifically as possible, and to have as little off-target kinase inhibition as possible. It was designed to not inhibit VEGFR-2, EGFR, MET, and so forth, and suppress RET as strongly as possible.

What were the methods of the LIBRETTO-531 study?

LIBRETTO-531 was an international multicenter randomized phase 3 trial of selpercatinib compared to physician's choice of vandetinib or cabozantinib in patients with treatment-naive, RET-mutated medullary thyroid cancer that had progressed in the year leading up to study enrollment.
Patients were randomized in a 2-to-1 fashion to selpercatinib versus vandetinib or cabozantinib. Now the study was not blinded because we knew, as investigators, if the patients were randomized to selpercatinib or vandetinib or cabozantinib because of the side effect profile. So the study didn't incorporate a blinding as to the arm that the patients were on. Then when patients did have disease progression and were on the control arm, taking either vandetinib or cabozantinib, and progression was confirmed centrally, patients were then offered crossover to receive open-label selpercatinib.

The primary endpoint of the trial was progression-free survival and key secondary endpoints included objective response rate, a relatively novel endpoint called treatment failure-free survival, and then also overall survival and safety, of course.

What was the efficacy seen in LIBRETTO-531 and how does the efficacy of selpercatinib differ for other MET-driven thyroid cancers?

In LIBRETTO-531, we saw very good efficacy with selpercatinib in RET-mutated medullary thyroid cancer. In our most updated analysis, the objective response rate is now greater than 80% and the median progression-free survival has still not yet been reached, while the median progression-free survival in the control arm was just about 14 months. That was highly statistically significant with a hazard ratio of 0.2. So, really great, very powerful results from LIBRETTO-531 in RET-mutated medullary thyroid cancer.

Selpercatinib, in patients with RAI-refractory, RET fusion-positive differentiated thyroid cancer, we don't have a randomized phase 3 trial to look at. However, we do have a number of patients with RET fusion-positive differentiated thyroid cancer who were enrolled in LIBRETTO-001, the phase 1/2 trial. And in that study, in the updated analysis, we've taken a look at patients who were MKI-naive and patients who had been previously treated with a multi-kinase inhibitor. In the patients who were MKI-naive, the objective response rate was actually 96%, and the median progression-free survival had not yet been reached at the time of the last analysis. However, for patients with previously treated RAI-refractory, RET fusion-positive differentiated thyroid cancer, the objective response rate wasn't quite that high. And in the latest analysis, we finally did meet the median progression-free survival, which is at 27 months for that patient population. But still for a previously treated patient population, those results are really excellent.

How significant is the approval selpercatinib for this patient population, and does it change clinical practice?

I have to say, for patients with RET-driven thyroid cancer, the approval of selpercatinib for treatment of their illness, it's a game changer. The efficacy of the therapy really is quite profound. In patients with thyroid cancer, the majority of patients will respond; we’re even seeing a high rate of complete responses in patients treated with selpercatinib, and the responses are very durable. People are remaining on therapy for a long, long time.

Not only is efficacy really good, but also the tolerability is really very good. Selpercatinib, like all of our cancer drugs, is no free ride, but the treatment-related adverse events are much more manageable for the vast majority of patients in the trials. We've had to discontinue selpercatinib because of adverse events much less frequently than with the multi-kinase inhibitors. Most of the adverse events that patients experience are grade 1 or grade 2, however, you can see grade 3 adverse events as well. You can see hypertension, which is usually manageable. You can see some transaminitis which might require dose reduction. Hypersensitivity is quite uncommon, but that's usually manageable as well. And then some other less common adverse events can be seen as well.

What advice would you give for practitioners regarding selpercatinib for this patient population?

In terms of how selpercatinib is now fitting into our arsenal of therapies that we have for patients with advanced thyroid cancer, I think we now have data from LIBRETTO-001 in medullary thyroid cancer that selpercatinib is the best first line drug of choice for patients with mutated medullary thyroid cancer. There's no question about it, that selpercatinib is the first-line drug of therapy for those patients. Now, we don't have a phase 3 comparison in RET fusion-positive differentiated thyroid cancer, but the efficacy in the first-line setting, the durability and the adverse event profile, in my mind means that selpercatinib really is the first-line drug of therapy for patients with RAI-refractory differentiated thyroid cancer that's progressing.

And what I would say is, one important corollary of this is that what this means is that all patients who have advanced thyroid cancer really need to have testing to identify those patients who carry driver alterations prior to the initiation of therapy. For medullary thyroid cancer, until now, all patients needed to have germline RET testing to confirm whether or not they have MEN2A or MEN2B syndrome. That's about 25% of all medullary thyroid cancer patients. However, now that we know that a majority of the patients with sporadic medullary thyroid cancer harbor somatic RET mutations, just in their tumor not in the whole germline. All patients need to have RET testing.

Those that are germline wild-type need to have their tumor tested to see if their tumor harbors a somatic RET mutation. Everyone with medullary thyroid cancer, we need to make sure doesn't have either a germline or a somatic RET mutation prior to starting any systemic therapy. And then I think the same is true for patients with advanced thyroid cancer. RET fusions are seen in about 10% or so of adults with differentiated thyroid cancer. They are seen more frequently in pediatric and young adults with thyroid cancer. But even though the hit rate might not be super high still, I really think that all patients need to be tested prior to starting therapy again, because selpercatinib works so well and is so well-tolerated and is a game changer, we really don't want to miss a single patient.

One piece of advice that I would give for practitioners who are seeing the rare patient with a RET-driven thyroid cancer is to make sure that patients are optimally managed prior to, and then on-therapy for selpercatinib. We don't have a lot of other options for these patients. And so, if a complication is encountered, like hypersensitivity for example, there actually are good methods for overcoming a hypersensitivity reaction for patients who develop hypersensitivity on selpercatinib. We don't want to throw the baby out with the bath water when we encounter a toxicity that isn't always easy to manage. QTC prolongation is another thing; it's very manageable. Hypertension, usually is very manageable. Sometimes you just have to take your time in managing those adverse events. That is one piece of advice in addition to the NGS testing that now I think every patient with advanced thyroid cancer needs.

What do you see in the future of treatment for RET-driven thyroid cancer?

In terms of future looking forward to the future for patients with RET-driven thyroid cancers, in a way, one thing I'd say is that selpercatinib works so well, it's going to be very difficult to come up with another therapy that might supplant selpercatinib in the first line setting. But that's a great problem to have, and I'll take that problem.
I think that there are a couple of questions that we have that are under investigation. For example, for patients present with a RET-driven cancer that's very bulky and may not be readily resectable, can we give neoadjuvant selpercatinib to debulk the disease with a systemic therapy, get a better surgical outcome, and maybe even cure more patients with thyroid cancer by incorporating neoadjuvant selpercatinib? There is a clinical trial that's underway taking a look at that.

And then one of the paradigms in thyroid cancer in terms of multi-kinase inhibitors is that there's always been a balance between efficacy and the impact of the adverse event profile. The field in general has gotten away from using multi-kinase inhibitors earlier in the course of disease and kind of holding off as long as possible so that you don't subject the patients to the adverse event profile for as long as possible. But I think that we really need to revisit that whole idea when we have a drug like selpercatinib that works so well and also is better tolerated. What's the reason for holding off as long as possible before initiating therapy? I'm not sure that there is a good one, and that's something that I think we need to question. Hopefully we can do so with good data going forward in the future.

Sources:

Hadoux J, Elisei R, Brose MS, et al. Phase 3 trial of selpercatinib in advanced RET-mutant medullary thyroid cancer. N Engl J Med. 2023;389:1851-1861. doi:10.1056/NEJMoa2309719

Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2022; 383:825-835. doi:10.1056/NEJMoa2005651