Optimizing Use of RET Inhibitors in Patients With RR DTC


Shared insight on the optimal use of RET inhibitor therapy in select patients with RET-rearranged radioiodine-refractory differentiated thyroid cancer.


Lori J. Wirth, MD: Ezra and Marcia, I’d love to hear more thoughts on the case that Frank presented and your brilliant wisdom.

Ezra Cohen, MD, FRCPSC, FASCO: I’d like to ask Frank why he chose the RET inhibitor that he did. Do you have a preference? Because I tend to use pralsetinibbecause it’s once a day, but you probably have more experience than I do.

Francis P. Worden, MD: To be honest, I was involved with the selpercatinib studies up front, so I had a lot of experience treating both medullary [disease], a couple of patients with lung cancer, and those with RETfusions and differentiated thyroid cancers. It’s my comfort with the medication. In terms of the adverse effect profile, perhaps there are similar hematologic issues that can arise with pralsetinib. I agree: the once-daily dosing of that drug does offer an advantage. I’m interested in what others have to say, but sometimes I’ve had issues with adverse effects. Despite lowering the dose, making adjustments with intervals, or even treating adverse effects, patients can’t overcome them. I’ve stopped that and put them on pralsetinib, for example, or vice versa. I’ve seen them tolerate the other RET inhibitor quite well without the adverse effects they were experiencing with the initial drug. My go-to is still selpercatinib. If for some reason there’s a tolerability issue, then I’ll shift to pralsetinib.

Marcia S. Brose, MD, PhD: There are some interesting data related to that. I had both trials open at the same time, and what happened with the pralsetinib is exactly what Frank was alluding to: there was more trouble with hematologic malignancies. I had some real issues with patients getting very anemic, and it’s probably related to the fact that it’s not as specific for RET as selpercatinib. Selpercatinib is much more narrow, and pralsetinib also hits JAK as well as ROS and other targets. Because of that, you have a larger adverse effect footprint. I can handle blood pressure issues, which you do get a little of in addition to EGFR2. But for the most part, the biggest issue with selpercatinib is that we get patients with a lot of edema in their tissues. The interesting thing is that every patient I’ve had with that, if I dose reduce them, it goes away—80 mg or even 120 mg twice a day can get that to go away to a tolerable level.

On the other side of it, with pralsetinib, I didn’t have that success. I had patients who were having real trouble with severe anemia even needing transfusions, so I stopped it. They would change over to selpercatinib. All my patients in the study on pralsetinib eventually ended up on selpercatinib. I have 1 patient from the original study who’s still on pralsetinib. She was a teenager who had a neck that went straight out. She came in 1 month before her 18th birthday, her prom, and her graduation. We were all panicking because she could barely talk, and we were afraid she was going to lose her airway. The trial was going to allow us to enroll her when she was 18, so we watched her like a hawk. We sent her off for her birthday, her prom, and her graduation and started her on the pralsetinib a week later. It has been 5 years, and she’s going to be going to nursing school soon. It’s pretty amazing to watch this transition from 1 to another. She took an extra year to get through college because of her illnesses, but it’s amazing when you see the degree of improvement. By the way, her neck is completely normal. You’d look at her and say she’s a normal teenager. You’d have no idea that before she had no neck. It went from her ears straight to her shoulders. She had such a huge mass. These are phenomenal responses.

The other data point I want to point out is that in phase 2—we can’t compare with phase 2 trials because they’re not the same population—in addition to the increased LFT [liver function test] abnormalities and hematologic abnormalities that you see with pralsetinib, and a little more grade 2/3 than grade 1/2. The response rate is a little lower with pralsetinib. It’s more like a 50% response rate instead of the higher end of the 60% range with selpercatinib. When I want that RET inhibition, I go to selpercatinib first. Twice-a-day dosing doesn’t make that big of a difference, and I’d rather get the higher response rate.

Francis P. Worden, MD: I don’t find that to be a problem either. Twice-a-day dosing hasn’t affected my patient population with compliance.

Transcript edited for clarity.

Related Videos
Experts on lung cancer
Luis Raez, MD, an expert on lung cancer
Expert on MM
Expert on MM
Joshua K. Sabari, MD, an expert on lung cancer
Experts on lung cancer
Experts on MM
Expert on MM
Experts on lung cancer
Expert on MM
Related Content