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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:Could you describe the post hoc analyses from the SELECT trial (NCT01321554) of lenvatinib (Lenvima) in differentiated thyroid cancer (DTC)?

In terms of overall survival [OS]…and the difficulty in looking at it because this is a randomized crossover design, when we looked at the overall survival based on objective response, patients who were responders to lenvatinib did have improved OS compared with patients who didn't respond [median, 52.2 months vs 19.0 months; HR, 0.32; 95% CI, 0.23-0.46]. But that's not a surprise.

What was perhaps a little bit more interesting is the analysis that was done looking at OS based on baseline tumor burden, and I thought that this was food for thought. When we did that, what we found was that patients who were randomly assigned to lenvatinib vs placebo who had a lower tumor burden had a significant improvement in OS when they had RECIST measurement of 4 cm or less compared with patients who had a higher volume of disease [median OS, not estimable for lenvatinib vs 41.0 months for placebo; HR, 0.39; 95% CI, 0.21-0.73]. I felt that that was interesting because what it seems to imply is that patients will do better with lenvatinib when they have a lower tumor burden at the time of initiating therapy, suggesting that you might not want to wait as long as possible before initiating therapy.

We also took a look at how patients with lung metastases do, and in this analysis, the Kaplan Meier curves show OS for patients on lenvatinib compared with those receiving placebo who had lung metastases that were 1 cm in size or larger. Even though a vast majority of patients randomly assigned to placebo crossed over and received lenvatinib, in these patients with lung metastases, they still have OS benefit that's statistically significant, even though the majority of those patients given placebo did cross over and receive lenvatinib [HR, 0.63; 95% CI, 0.47-0.85; log-rank 

The forest plot shows that the OS benefit holds up when we looked at larger lung metastases as well. So in my mind, the take-home of this analysis was that patients with lung metastases, which are very common in metastatic DTC, can have an OS benefit with lenvatinib when they have lung metastases even as small as 1 cm in size.

What real-world data support the use of lenvatinib in DTC?

There was recently a real-world evidence analysis with lenvatinib that was published by Francis P. Worden, MD.

 What this study did was capture up to 5 cases from physicians across the country and received data on patients with radioactive iodine–refractory DTC who were treated with lenvatinib. More than 300 patients were analyzed here. The patient characteristics in this real-world patient population were very similar to the patients who were enrolled in the SELECT trial.

What was a bit of a surprise to me in the real-world data was that most of the patients did start at the 24-mg starting dose, though there were 38% of patients that started at a lower starting dose. What we saw in this real-world evidence analysis was that many of the patients were able to be maintained at their initial starting dose, and perhaps even a higher percentage than expected. Overall, the median duration of treatment with lenvatinib was 17.5 months in this real-world analysis.

In terms of response, a response was not all per RECIST 1.1; it was investigator determined, but the response rates were quite high, with an overall response rate of 72% in the real-world analysis. In terms of disease control, almost 91% of patients had disease control on lenvatinib.

There was a PFS rate in this real-world patient population [of greater than 50%]. That was surprising at 48 months, which is even a little bit longer than was seen in the SELECT trial, and the median OS had not yet been reached.

How did mutations affect outcomes in the real-world population?

 V600E mutations are the most common mutation in papillary thyroid cancer. Papillary thyroid cancers are the most common advanced DTC that we see. So should we be using lenvatinib in the first line in these patients who harbor 

 V600E mutations, or should we be using dabrafenib [Tafinlar] and trametinib [Mekinist]? A real-world database took a look at how patients in the real-world group of patients who had 

-mutant patient population was similar to the 

-unknown patients [in terms of staging and other baseline characteristics].

-mutated patients did better in terms of PFS as well as OS than the 

 wild-type patients. This [analysis] shows the numbers for patients with 

 wild-type disease in terms of median PFS and median OS, [also showing slight benefit for the 

1. Kiyota N, Tahara M, Robinson B, et al. Impact of baseline tumor burden on overall survival in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib in the SELECT global phase 3 trial. 

. 2022;128(12):2281-2287. doi:10.1002/cncr.34181

2. Tahara M, Kiyota N, Hoff AO, et al. Impact of lung metastases on overall survival in the phase 3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer. Eur J 

. 2021;147:51-57. doi:10.1016/j.ejca.2020.12.032

3. Worden F, Rajkovic-Hooley O, Reynolds N, Milligan G, Zhang J. Real-world treatment patterns and clinical outcomes in patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) treated with first line lenvatinib monotherapy in the United States. 

. 2024;84(2):663-669. doi:10.1007/s12020-023-03638-7

4. Worden FP, Wirth LJ, Reynolds N, et al. Patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) with BRAF V600E and/or K601E mutation status: A real-world view of effectiveness of lenvatinib monotherapy. 

. 2024;42(suppl 16):6098. doi:10.1200/JCO.2024.42.16_suppl.6098

During a Case-Based Roundtable® event, Lori J. Wirth, discussed recent analyses that have developed a better understanding of the outcomes with lenvatinib in differentiated thyroid cancer in the second article of a 2-part series.

Post Hoc and Real-World Analyses Explore Benefit of Lenvatinib in DTC

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.