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Spotlight

This roundtable series explores therapies available for patients with differentiated thyroid cancer after they have radioactive iodine-refractory disease, as discussed by key opinion leaders at virtual live events and interviews.

Differentiated Thyroid Cancer Treated After Radioactive Iodine Therapy

Targeted Oncology: What treatments do the NCCN guidelines recommend for patients with unresectable recurrent differentiated thyroid cancer (DTC)?

In the NCCN guidelines for radioactive iodine [RAI]-refractory progressive papillary thyroid cancer systemic therapy is appropriate when patients have systemic disease rather than 1 focal, receptable lesion or 1 focal lesion that might be treated with an oligometastatic approach.

 The preferred regimen is lenvatinib [Lenvima] with a category 1 recommendation, and sorafenib [Nexavar] is included as another alternative regimen based on the randomized phase 3 DECISION trial [NCT00984282] that showed sorafenib improved progression-free survival [PFS] over placebo. However, the NCCN guidelines show preference for lenvatinib over sorafenib because of the strength of the evidence in the SELECT trial [NCT01321554]. There are alternatives, particularly for patients who have 

 fusion–positive disease with larotrectinib [Vitrakvi] or entrectinib [Rozlytrek], and then also selpercatinib [Retevmo] or pralsetinib [Gavreto] for patients who have 

What are the targets of lenvatinib and other kinase inhibitors?

Lenvatinib is a multikinase inhibitor that targets VEGFR1, 2, and 3 in the vascular compartment, as well as FGFR, which is expressed in both the vascular compartment and the tumor compartment.

 activity, as well as inhibiting several other kinases. There are multiple other multikinase inhibitors that have been studied in the thyroid cancer space. There's a lot of overlap in terms of the kinases that are inhibited, but there are slightly different flavors that are dialed in with the different multikinase inhibitors as well, such as cabozantinib [Cabometyx] that has some anti-

Could you describe the study design and patient population of the SELECT trial of lenvatinib?

The SELECT trial was a randomized phase 3 trial studying lenvatinib in patients with progressive RAI- refractory DTC. They had to have disease progression within 13 months prior to randomization based on a prior set of imaging, and they were allowed to have 1 prior VEGF targeted therapy. Patients were randomly assigned in a 2:1 fashion to lenvatinib at 24 mg per day vs placebo. And then when patients were found to have disease progression on blinded independent review, they were unblinded, and those patients that were found to be on placebo at the time of progression were allowed to cross over and receive open-label lenvatinib. The primary end point of this trial was PFS, with important secondary end points including objective response rate [ORR] and overall survival [OS].

Approximately one-quarter of patients had received 1 prior tyrosine kinase inhibitor, mostly sorafenib, but there were a couple of other treatments as well.

 More patients had papillary thyroid cancer than poorly differentiated follicular and Hürthle cell thyroid cancers, as would be expected with the frequency of papillary thyroid cancer. A majority of patients had lung metastases, but almost 40% of patients had bone metastases as well. Most patients had a good ECOG performance status of 0 or 1.

What were the efficacy outcomes of this trial?

[Looking at] the PFS Kaplan-Meier curves, there was a wide separation between lenvatinib vs placebo with a more than 14-month improvement in PFS from placebo to lenvatinib that was highly statistically significant [HR, 0.21; 99% CI, 0.14-0.31; 

In terms of the objective responses, we saw an ORR of 65% in patients with treated with lenvatinib [vs 2% with placebo]. Most of the responses were partial responses, but there was a handful of patients who had complete responses as well [4% vs 0% with placebo]. When you look at the patients who had progressive disease, it was only 7% of patients initially randomly assigned to lenvatinib who experienced disease progression as their best overall response [vs 39.7% with placebo], so most of the patients enrolled and randomly assigned to lenvatinib derived clinical benefit with lenvatinib.

When you have these [patients receiving] placebo who crossed over to open label study designs, it is difficult to evaluate OS. Not only do these patients have thyroid cancer and they're going to live for a little while, but also almost all the patients ultimately are going to receive the study drug. To detect an OS benefit can be challenging with this study design. You can do a RPSFT [Rank-Preserving Structural Failure Time] analysis that adjusts or corrects for the open-label lenvatinib treatment in the patients that were initially randomly assigned to the placebo arm. In that RPSFT OS analysis, it does look like there may be an improvement in OS with lenvatinib compared with placebo, but that is with a biostatistical correction [HR, 0.62; 95% CI, 0.40-1.00].

What was the safety profile of lenvatinib in this trial?

In terms of adverse events [AEs], lenvatinib and the other VEGFR multikinase inhibitors carry AEs that can impact on how patients feel. We see hypertension, diarrhea, fatigue, decreased appetite and weight, nausea, stomatitis and palmar-plantar erythrodysesthesia in patients treated with lenvatinib. Overall with lenvatinib, 76% of patients had grade 3 or higher AEs. There were a couple of patients [n = 6, 2.3%] who were enrolled in the SELECT trial who had a grade 5 AE that was considered treatment related.

We think that the hypertension is in part due to nitric oxide, which causes vasoconstriction. That brings us to another common AE, which is proteinuria. The vasoconstriction in the renal tubule then leads to protein loss in the urine. You do want to monitor for proteinuria as well for patients when they're initiating lenvatinib. The package insert has careful dose modification guidelines for hypertension, and hypertension is something that we you want to be aggressive in managing. I train the nursing group who answers the patient gateway messages and phone calls on hypertension to make sure that if they're holding the drug, we do something about all of the blood pressure medicines that we've ramped up, because the half-life of lenvatinib is very short. If you keep patients on their 3-drug hypertension regimen when you're holding lenvatinib, [their blood pressure drops] pretty quickly.

1. NCCN. Clinical Practice Guidelines in Oncology. Thyroid carcinoma, version 4.2024. Accessed November 11, 2024. 

https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf

2. Cabanillas ME, Habra MA. Lenvatinib: Role in thyroid cancer and other solid tumors. 

. 2016;42:47-55. doi:10.1016/j.ctrv.2015.11.003

3. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. 

. 2015;372(7):621-630. doi:10.1056/NEJMoa1406470

During a Case-Based Roundtable® event, Lori J. Wirth, discussed the SELECT trial and the role of multikinase inhibitors in differentiated thyroid cancer in the first article of a 2-part series.

SELECT Trial Outcomes Support Lenvatinib as RAI-Refractory DTC Therapy