Patient Scenario 1: RR DTC Managed With Frontline Lenvatinib

Transcript:

Marcia S. Brose, MD, PhD: This first case is really a bread and butter case. I took the setting of a patient who I already knew did not have a mutation. So as I said, I took the point after that, where the patient already was tested and did not have an NTRK or RET fusion. This was a patient who noticed her neck looked puffy, her throat was closing up. In January 2020, she went to the OR [operating room] and had a resection that was aborted because she had so much adherent tissue and what was considered a sticky cancer, all adherent to her esophagus and her trachea. Only a biopsy was performed and it was read as invasive, poorly differentiated thyroid cancer [DTC], and on the genetic testing there were no NTRK fusions, no RET fusions; there was an HRAS Q61R point mutation.

Then the question was what do we do for this person? On the right you can see the large mass that’s abutting her trachea and was starting to cause her difficulty swallowing. So no completion thyroidectomy was felt to be feasible, and because she didn’t have a resection, and the HRAS mutation pointed in the direction that this is not a patient who’s a good candidate for radioactive iodine, it was decided that we would go ahead and treat her with systemic therapy as her first therapy. In this case, because she had such an aggressive disease and she had lymph nodes involved all the way down her chest, I also did an abdominal CT for staging. And in her abdominal CT, you can see here on the right a large right renal mass. This was just an incidental finding.

Between January/February and April when I was able to start treatment, she underwent a nephrectomy on the right to remove this renal cell cancer. It was T3, NX, MX and was not felt to be the likely cause of her metastatic disease, and we had already biopsied her other nodes. We had the histologist compare because there have been times when we’ve had papillary thyroid cancers that do land in the kidney. So it is important because you’ve had a renal cancer that you have the histologist compare them. The pathologist looked at them, and they were definitely different histologies, so we had 2 separate primaries and we opted for just observation of the renal cell.

She did start systemic therapy for the poorly differentiated thyroid cancer. With the lack of the fusions, my first choice for her was lenvatinib, and she started on that in April 2020. She started on 24 mg a day on May 4, and her [blood] pressure shot up right away, which is not unexpected with this. We know that 63% of patients will have to have their dose reduced because of this. She was started on lisinopril right away because I anticipated it. We had already ordered it, she just had to go and pick it up at the CVS [pharmacy]. She also was complaining right away, by her first- or second-week visit, that she was having pain in her hands and feet. The dose was dropped to 20 mg a day, she was able to do OK for a couple of months, but it was in August that she went down to 20 mg a day.

But she seemed to be having more trouble as time went on with her blood pressure, and she had a severe headache in late September and presented to the ED [emergency department] with what they thought was a stroke. It turned out that she had not had a stroke, she just had high blood pressure, a severe headache, and there was no evidence of any bleeding or other issues. So we had stopped her lenvatinib during that time, we restarted it again at a lower dose of 14 mg, and made sure to maximize her lisinopril. We also added amlodipine and confirmed that her blood pressure was well controlled before she left the hospital.

Lori J. Wirth, MD: Marcia, I don’t want to interrupt, but let me ask you a quick question. Would you say that this kind of hypertension that’s not particularly easy to manage is typical of what patients experience on lenvatinib? And do you sometimes turn to cardiology colleagues to help manage hypertension in patients on lenvatinib?

Marcia S. Brose, MD, PhD: Yes, that’s a very good point. I’d say in my practice about a third of them are what I would call difficult [cases] like this one was. Another third of them are what I would say are busy patients, they require me to start things, but I feel like we can do it pretty successfully. And then the other third tolerate it remarkably well. In this case, we did involve cardiology, and they were on board when she was in the hospital and we were restarting her antihypertensives. There was a question about how religiously she was taking lisinopril, and that might have been part of why she had had these breakthrough headaches and things. But she did do much better when she had amlodipine started. We did give lisinopril 12 hours apart, but we know that the PK [pharmacokinetic] peak of lenvatinib is about 10 hours after they take the medicine. So we added amlodipine at about 8 hours after the lenvatinib dosing, and that helped to bring down that peak that was happening for her in the late afternoon just before dinnertime.

If you had a patient who is already on blood pressure medicine, they often are with a cardiologist, and I always let them know that we’re going to be doing this so that they can do some close follow-up, within a week. In fact, these blood pressures change within 24 to 48 hours. So you have to be prepared at least with something so you can address it, at least to get them started, even if they are not going to go in for a doctor’s appointment. So she did restart, she started at 14 mg a day in October with the amlodipine added. She did well until June 2021 when she started having trouble with more bowel movements.

Now the bowel movement problem is 2-fold. One, of course, it’s not pleasant for the patients. But in addition to this, they will not absorb their thyroid hormone replacement if they need it. They will not absorb the lenvatinib that they might need. They certainly don’t absorb their blood pressure medicine as well. So, it’s really important to control it. It also leads to sarcopenia and significant weight loss. I find that if I do a really good job at preventing that and keeping them to 1 bowel movement a day, many other issues can be avoided. We showed her how to take Imodium not just in response to a loose bowel movement, but to try to titrate it up so she would get to a point where she only had 1 a day. It took her about 3 tablets up to twice a day, or 6 tablets a day, sometimes she broke it up into 3 doses, in order to have a regular bowel movement. And that did a lot to decrease other issues that she had because she had also been having some trouble with fatigue. Both of those did better, she felt better because she also wasn’t losing all of her nutrients and getting dehydrated. [We] had to be aggressive on the bowel movements. Again, that’s very common, and tends to come up a little later, it does not always come up right away, but is really common with lenvatinib. [It is] also common with cabozantinib in the second line, so we have to do that with both.

She did well. Her fatigue started to increase a bit in January 2022, and she was getting scans about every 3 months. What we started to do was, every time she had a scan, she would have a week off after the scan was done, like a planned holiday. That really helped her with her fatigue. That started in about the second year, which started becoming an issue. She remains on lenvatinib to this day at 14 mg. She’s tolerating it beautifully, comes in, and now it’s almost like a well visit. She comes in, she feels great, and happily has done really well. On the bottom, you can see her CT scan from when she started, and where it is now with no symptoms at all of the dysphasia or difficulties.

I will add one point that may come up, which is the fact that I started her at 24 mg, and I know that will raise some eyebrows in a lot of people because there are people who are nervous about blood pressure and managing it. However, there are good data, there was a randomized, double-blind, controlled trial that compared people who started at 24 mg to 18 mg. When we did that study, we anticipated that the 18 mg would be better for the patients, they would be happier, they would do just as well, and they wouldn’t have as many grade 3 and 4 toxicities. And we were wrong on all 3 counts. It was less effective, they had just as many grade 3s and 4s, and their patient-reported outcomes were identical. So I no longer start at a low dose because I have very good, high-quality data that tell me I’m not doing the patient any favor by doing that. So I start with 24 mg; I do watch them like a hawk those first months though because I have to watch out for these other issues.

Transcript edited for clarity.