Treating Advanced RAI-Refractory DTC: A Two-Way Street: Medical Oncology and Endocrinology - Episode 16
Lori J. Wirth, MD: LIBRETTO-001 was a phase 1/2 first-in-human trial investigating selpercatinib in patients with RET-altered cancers. We recently published the thyroid experience and the non–small cell lung cancer experience in The New England Journal of Medicine. Why don’t we talk about LIBRETTO-001 in thyroid cancer briefly?
The report in The New England Journal of Medicine described the experience with selpercatinib, a RET-specific inhibitor designed to inhibit the wild-type RET kinase that’s present in the RET fusion-driven cancers like papillary thyroid cancer or non–small cell lung cancer, as well as inhibit all of the oncogenic RET mutations that we see in medullary thyroid cancer [MTC], a subject for another day.
Additionally, selpercatinib was designed to be a specific inhibitor that targets the RET kinase as much as possible to limit the off-target kinase inhibition—particularly for VEGFR2 and the other kinases that the multikinase inhibitors inhibit—with the idea that the activity against VEGFR2 and some of the other kinases results in a lot of the adverse effect profile and toxicity of the therapy, which limits the potency of the RET inhibition that you can get. Therefore, you can’t drive up enough RET inhibition with a multikinase inhibitor the way we could hopefully with a specific drug like selpercatinib.
There were 2 MTC cohorts that had been reported—a patient cohort with RET-mutated MTC who had been treated previously with vandetanib and/or cabozantinib, the 2 drugs approved for MTC. Then there was a vandetanib/cabozantinib naїve patient cohort. But then we also enrolled patients with RET fusion-positive follicular-derived thyroid cancer. In The New England Journal of Medicine, we reported on a cohort of 19 patients. They had all received prior therapies for their advanced thyroid cancer. In terms of the histologies, most of the patients had papillary thyroid cancer, but we also saw poorly differentiated and even anaplastic thyroid cancer. One patient had a Hurthle cell thyroid cancer.
Overall, the safety or adverse event profile of selpercatinib was consistent with what we expected for a RET-specific inhibitor. There weren’t a long list of grade 3 and 4 adverse effects. The most common grade 3 adverse effect was hypertension. We also saw some transaminitis that was generally dealt with through dose holds and dose reductions. We also saw a little grade 3 diarrhea. But overall, most of the adverse effects that were seen were grade 1 and grade 2, which were treatable or reversible. We also saw the tolerability borne out in terms of the dose reductions and dose discontinuation. Overall, 30% of patients experienced dose reduction due to adverse events. That’s less than half of what we see generally with the other multikinase inhibitors. Two percent of patients did have discontinuation due to adverse events, which is a good discontinuation rate overall in oncology.
Frank Worden, MD: Yes, I agree totally.
Lori J. Wirth, MD: In terms of efficacy, in the follicular-derived RET fusion-positive thyroid cohort, we saw an overall response rate of 79%, which is promising. In 1 or 2 of the patients with anaplastic thyroid cancer, we saw a durable response in which the patient remained in response at the time of the publication. Overall, the 1-year progression-free survival [PFS] in this small cohort is 64%, but the median duration of response and PFS had not yet been reached. I certainly was thrilled when we saw the results.
Frank Worden, MD: I was too. This is a fantastic drug. We’re not really talking about MTC today, but that has been a challenging disease to treat. Even from the differentiated thyroid cancers that are refractory, selpercatinib has shown promising results. What’s so cool are the responses that you can see, the dramatic responses, the quality of life improvements in patients.
Also, the tolerability, as you mentioned, Lori, you don’t see the profound fatigue that these other drugs cause because selpercatinib attacks the direct RET kinase vs panning out to the other VEGF1 and VEGF2 kinases. Patients are more responsive in terms of their antihypertensive regimens. They respond quickly when we hold the drug and then restart at lower doses. I’ve had some issues with patients experiencing edema here and there, too. I would say that liver issues are probably the highest. We had 1 patient who developed hepatitis but recovered fully and went back on the drug. Selpercatinib is a landmark drug. This is practice changing for sure for these patients.
Lori J. Wirth, MD: I have to tell you an anecdote. My first patient with a RET fusion-positive thyroid cancer was started on therapy on a Friday, and his wife texted me on Sunday to say, “He’s feeling so good, he’s even doing the dishes!” I loved that text.
Frank Worden, MD: I had a patient who came in a wheelchair, and I was almost worried that she didn’t make the cutoff for performance status, but we said, “OK, you can do this, you’re at least a 2.” Within a week she said she put her wheelchair in the closet, and she was back to walking about 2 or 3 miles, her little route around the neighborhood. It was incredible.
Lori J. Wirth, MD: We are seeing rapid responses to selpercatinib when we look at the RECIST measurements over time, particularly in the follicular-derived thyroid cancers.
Transcript edited for clarity.