Perspectives on the use of lenvatinib therapy to manage a patient with radioiodine-refractory DTC, preceding broader considerations for sequencing kinase inhibitor therapy.
Marcia Brose, MD: Some people have asked why I start people at a 24-mg dose, and in general, I'm conservative, and I always try to repeat the doses that were used in clinical trials. However, after that, subsequently, a lot of patients were started at lower doses because people felt that that might be better tolerated. Interestingly, following that, another trial was designed where it was a double-blinded study where we randomized patients to start at either 24 mg a day or 18 mg a day. Now, this was done after this patient, of course, was being treated with lenvatinib. The study design is shown here: patients with radioactive iodine-refractory DTC [differentiated thyroid cancer] who are progressing were then randomized to either start at 24 mg a day or 18 mg a day. I'll note that this was a blinded study, so the investigators double blinded. Neither the investigators nor the patients knew what dose they were starting on, but everybody was treated the same. And if they had issues, they were dose adjusted and treated identically, until they found a dose, obviously, that they could tolerate, and adverse effects were all managed uniformly. The primary end points of this study were overall response rate as of week 24 and the safety as shown by treatment-emergent adverse events that were greater to or equal to [grade] 3 as of week 24, the idea being that we wanted to know whether it was as effective and as safe to start at 24 mg as with 18 mg. In addition, secondary end points we looked at [were] PFS [progressive free survival] and overall safety. And a third end point, which I will not be able to have time to present here, was also looking at patients’ quality of life. And the overall response rate as of week 24 was 57.3% in the lenvatinib 24-mg-per-day arm, and 40.3% in the lenvatinib 18-mg-per-day starting-dose arm. Therefore, these report results failed to demonstrate noninferiority of the lenvatinib 18-mg-day starting dose when compared with the lenvatinib 24-mg-per-day starting dose. In other words, it was better to start patients at 24 mg than it was at 18 mg. The question then becomes, maybe the efficacy is better at 24 mg, but what about the safety? The safety events are shown here, and what the hypothesis was, is that possibly 18 mg would have less grade 3 treatment-emergent adverse events. However, what we saw was the opposite. It turned out that they had almost equivalent grade 3 or higher adverse events, implying that starting patients at 18 mg a day was not any more superior safety wise than the 24-mg-per-day arm that was our second end point. In summary, going back to our patient, they started at 24 mg per day arm, and even though he had a BRAF mutation, he was still treated with a multi-kinase inhibitor. I'll point out that just because we have inhibitors for BRAF does not mean that lenvatinib and sorafenib were not active in the BRAF-positive population. He was started on my cynical 20 mg a day prior to starting lenvatinib because he had elevated blood pressure, and amlodipine 5 mg a day was added in the afternoon subsequently, and subsequently increased to 10 mg a day in order to control his blood pressure. In March of 2020, he had increasing bowel movements and he was treated with Imodium, but despite aggressive therapy, it became too much, [and] he was eventually reduced to 20 mg a day for this reason. He did well until September of 2020, when he had ongoing weight loss and he was decreased once again to 14 mg a day. At this point, my current sequencing of kinase inhibitor therapy for patients with radioactive iodine-refractory differentiated thyroid cancer is the following: I do check patients to see if they have TRAK fusions or RET fusions because I tend to use the specific inhibitors for those 2 genes. First, if I identify these fusions, but then first- and second-line, I'll tend to use lenvatinib and then sorafenib, but since these were proven in large international phase 3 studies. Recently, there's been new data showing that cabozantinib is active in the second line after lenvatinib or sorafenib. For those patients, I've now added that into my algorithm, and then if for some reason they have to go off of the VEGF inhibitors for toxicity, sometimes I might treat them with a BRAF mutation inhibitor first. But usually, if they haven't had a BRAF inhibitor yet, following cabozantinib, I will shoot with a BRAF inhibitor. Occasionally though, I've had patients who've had a lot of trouble with adverse effects from lenvatinib, for instance, that are overlapping with cabozantinib. And if I feel that they need a break from that toxicity profile, I will occasionally move the BRAF inhibitor up to second-line. But in general, I use cabozantinib because it's the only 1 that's been proven to be active following lenvatinib.
Transcript edited for clarity.