Differentiated Thyroid Cancer: Initial Management

Lori Wirth, MD: In terms of the initial management of iodine-refractory DTC [differentiated thyroid cancer], we have several options. One option that is FDA approved is sorafenib, which was first shown in a randomized stage III trial to improve progression-free survival in this patient population compared with placebo. The second drug that was approved by the FDA was lenvatinib based on the SELECT trial, which showed that progression-free survival is improved with lenvatinib compared with placebo.

One of the difficult questions is about which drug should be used first because we don’t have a head-to-head comparison. When we think about the overall response rate and progression-free survival benefit with sorafenib, the overall response rate was 12%, and the median progression-free survival with sorafenib was 11 months.

In the SELECT trial with lenvatinib, the overall response rate was 65%, and the progression-free survival was 18 months. If I had to pick a winner based on those 2 different phase 3 trials with different patient populations, I would pick lenvatinib. That is usually the drug that I use first with the principle that we always like to put the best drug first in oncology.

What about when patients progress on first-line therapy? We have some data that show that patients can have responses and benefit in terms of survival with second-line therapy in DTC with various TKIs [tyrosine kinase inhibitors]. For example, there was a second-line and third-line small study that was done investigating cabozantinib. We saw that cabozantinib has responses in the second-line setting or even in the third-line setting for patients with iodine-refractory disease.

We also have real-world data showing that, if you use lenvatinib second following progression on sorafenib, then you can see an overall response rate of 20% and probably a survival benefit as well. That’s based on a Korean real-world trial.

The other thing we know about lenvatinib in the second-line setting is from the SELECT trial: Patients who were previously treated with a TKI such as sorafenib were allowed to enroll. That included approximately 25% of patients who were in the study, and those patients also had a progression-free survival benefit with second-line lenvatinib. We have good data indicating that we have benefit in the appropriate patients with second-line therapy once they progress on a first-line MKI [multikinase inhibitor].

What is the optimal time to initiate MKI therapy in patients with iodine-refractory DTC? We often follow patients on active surveillance for some time. If patients have a low burden of disease that’s entirely asymptomatic and growing very slowly, those patients are sometimes followed on active surveillance, which many people think is quite reasonable to do. In this case, the patient had a fairly large burden of disease, particularly with multiple lung metastases at initial presentation, and the decision was made to initiate lenvatinib without a long active surveillance period first.

We have data now that indicate that this is a reasonable decision. For example, an analysis was done of the SELECT trial participants to determine if patients did better when they had a better performance status vs a worse performance status. We analyzed patients with an ECOG fperformance status of 0 vs 1, and we analyzed how they did when treated with lenvatinib vs placebo. We saw that patients with a performance status of 0 had a better response rate, and they even had a better overall survival with lenvatinib compared with placebo or compared with patients with a performance status of 1, which indicates that you don’t want to wait until patients have symptoms that impact performance status to get the most benefit out of lenvatinib.

We also did an analysis to determine the benefits of lenvatinib compared with placebo in the SELECT trial patients who had lung metastases. We found that, even when patients have small lung metastases of 1 cm or larger, they had an overall survival benefit compared with the patients who received placebo and then crossed over to lenvatinib at the time of progression when they had lung metastases that were 1 cm in size or larger, which indicates that, in this patient population, you don’t need to withhold lenvatinib if there are small lung nodules that are just 1 cm or so in size.

Transcript edited for clarity.

Case Information: A 64-Year-Old Man With Differentiated Thyroid Cancer

Initial Presentation

• A 64-year-old man presents with a solitary nodule on the neck and occasional shortness of breath and intermittent excessive fatigue
• PMH: unremarkable
• PE: palpable, hard and fixed solitary nodule

Clinical Workup and Initial Treatment

• Labs: TSH 10.3 µU/mL; all others WNL
• Ultrasound of the neck revealed a 2.2 cm mass near the isthmus of the thyroid; several suspicious lymph nodes ranging from 0.3-2.2 cm in size
• Ultrasound-guided FNAB: confirmed papillary thyroid carcinoma; with nuclear enlargement and nuclear grooves, no colloid seen
• Patient underwent total thyroidectomy with bilateral central neck dissection
• Pathology: 2.1 cm papillary thyroid cancer arising in isthmus of the thyroid, 3 of 7 positive central compartment lymph nodes, largest 1.8 cm, positive extra nodal extension
• StageT2N1MX; ECOG PS 1

Subsequent Treatment and Follow-up

• He was treated with radioactive iodine 150 millicuries
  • Whole body scan showed uptake in the neck; indicative of thyroid remnant
• Follow-up at 3 months TSH 0.2 µU/mL, thyroglobulin 68 ng/mL
• Neck US showed no evidence of residual disease in thyroid bed, no suspicious neck nodes. Chest CT was done: > 15 lung lesions, largest 1.4 cm in size
• Lenvatinib 24 mg PO qDay was initiated