Updates on Biomarker-Directed Therapy for Solid Tumors: Focus on NTRK, RET, and NRG-1 - Episode 11

Tumor Agnostic RET Inhibition: The LIBRETTO-001 Trial

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Lori Wirth, MD, reviews the phase 1/2 LIBRETTO-001 trial.

Mark Socinski, MD: Lori, talk to us about the LIBRETTO-001 trial. It obviously changed our world, at least in the realm of lung cancer treatment, from the RET fusion point of view. Talk us through the design and so forth.

Lori Wirth, MD: One thing I want to comment on is that, interestingly, the dirty kinases like vandetanib used in MTC [medullary thyroid cancer] have much better activity than in RET-fusion non–small cell lung cancer, which is such a curious thing. I do not know why that is, but we can see really good responses with both vandetanib and cabozantinib in patients with MTC. However, we do now have specific inhibitors. Selpercatinib was designed along the same lines as larotrectinib, to potently and specifically inhibit just the RET kinase as much as possible and have as little off-RET inhibition as possible. It was also particularly designed to have as little KDR, VEGFR2 activity as possible, with the idea that with the MKIs [multikinase inhibitors] that do have RET activity, that off-target toxicity not only causes a lot of adverse effects, but it also limits the dose escalation you can get. So you cannot get really potent RET inhibition because of the dose limitation factors of the other kinase inhibitors.

Selpercatinib was designed just to hit RET as hard and as specifically as possible. Pralsetinib was designed similarly. Selpercatinib was also designed to inhibit all of the RET fusions that we see in non–small cell lung cancer and other cancers. It was designed to inhibit all of the known RET mutations seen in medullary thyroid cancer. Then it was also designed to head off acquired gatekeeper resistance mutations at the codon V804, which was hypothesized to account for acquired resistance. Subsequently, that was shown in several patients who were treated with cabozantinib or vandetanib and then developed resistance. The LIBRETTO-001 trial was a phase 1/2 trial that enrolled patients with RET-altered cancers. There were several different cohorts, including patients with non–small cell lung cancer that had been previously treated, and non–small cell lung cancer with RET fusions that had not been previously treated. There were 3 thyroid cancer cohorts. The first thyroid cancer cohort included patients with RET-mutated MTC who had previously received either cabozantinib, vandetanib, or both. Then there was a cohort of patients with RET-mutated MTC who had received neither cabozantinib nor vandetanib. There was also a smaller cohort of patients with RET fusions and advanced thyroid cancer who had been previously treated.

There were 2 separate publications in The New England Journal of Medicine. The lung publication reported on the primary analysis set of all of the consecutively enrolled patients with lung cancer who had been previously treated. Then we did the same with the thyroid cancer publication. The primary analysis set concerned patients with RET-mutated MTC who had previously been treated with cabozantinib, vandetanib, or both. In that primary analysis set of patients with medullary thyroid cancer who had been previously treated, the overall response rate was 69%. When we looked at patients who hadn’t received prior vandetanib or cabozantinib, the overall response rate for that patient population was 73%. In that smaller group of patients with advanced RET fusion thyroid cancer, their overall response rate was 79%. These responses are all very durable. In the primary analysis set, the median duration of response and median PFS [progression-free survival] were not yet reached by the time of the data maturity for the publications. In terms of non–small cell lung cancer, we see similar degrees of activity; the previously treated RET fusion cohort had an overall response rate of 64%, with a median duration of response of 17.5 months.

There was an 85% overall response rate in patients who had not been previously treated. In terms of safety, we see primarily grade 1 and 2 adverse events, and these are reversible. There are some treatment-related grade 3 or 4 adverse events that we observed, the most common of which included hypertension, transaminitis, and diarrhea. A small number of patients had QTc [corrected QT interval] prolongation; a couple of patients had grade 3 QTc prolongation. That is certainly something of which to be aware. Overall, however, selpercatinib is very well tolerated. One of the ways we can specifically take a look at tolerability in our patient population with thyroid cancer is by analyzing the frequency of dose discontinuation. With the other multikinase inhibitors, we often see rates of dose discontinuation of 15% to 20% of patients in the trials who have thyroid cancer. With selpercatinib, only 2% of patients had to have dose discontinuations due to treatment-related adverse events.

Mark Socinski, MD: One of the questions I have had about selpercatinib concerns how much VEGF effect it may have. I cannot remember, what was the grade 3 hypertension rate? It was not insignificant, if I remember correctly.

Lori Wirth, MD: It was 11%, I believe.

Mark Socinski, MD: Yes, it was 11% or 17%, or something like that.

Lori Wirth, MD: I think it is about 11%, if I am remembering correctly. S. Mike Rothenberg, MD, PhD, is a friend of mine who was involved in the development of selpercatinib early on; he would say, “There’s definitely a little tickle of KDR there.” So we are seeing some off-target VEGFR2 activity, but certainly, it is nothing compared to our other friends we have discussed.