Applying Guideline Recommendations for Advanced Thyroid Cancer

The management of advanced thyroid cancer requires careful consideration of histology, molecular profiling, and treatment tolerability. At a Case-Based Roundtable event in Scottsdale, Arizona, Lori Wirth, MD, a professor of medicine at Harvard Medical School and medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, discussed options for patients with radioactive iodine-refractory differentiated thyroid cancer (DTC) with and without actionable gene fusions. Wirth emphasized that management of treatment-related adverse events (AEs) is crucial for maintaining therapy and achieving long-term benefit.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: What are the recommendations for a patient with DTC who doesn’t have an actionable gene mutation?

Lori Wirth, MD: For patients with radioactive iodine-refractory disease without an actionable biomarker-linked, FDA-approved first-line therapy, multikinase inhibitor [MKI] therapy with either lenvatinib [Lenvima] or sorafenib [Nexavar] is recommended. In most cases, lenvatinib is the preferred first-line MKI. That basically says if your patient doesn't have a RET, NTRK, or ALK fusion, and they need systemic therapy, you want to give them an MKI. Lenvatinib is the preferred MKI unless the patient has a contraindication to lenvatinib.¹

In adults with DTC, the rate of oncogenic kinase fusions is [approximately 25%], and RET fusions are more common than NTRK fusions.² If you only might see 1 or 2 patients a year [with DTC], you might not ever see a RET fusion. But if you don't test for it, then you're never going to see it, and we have a great drug for that rare patient population. The interesting thing about the kinase fusions is that they're seen more frequently in pediatric patients and young adults.

Are there adjuvant therapy clinical trials for these young patients with thyroid cancer?

No, we tried to do an adjuvant therapy trial with selpercatinib [Retevmo] in medullary thyroid cancer [MTC]. In MTC, you can predict the patients who are going to recur because of rising calcitonin. We wanted to do an adjuvant trial, and it was impossible to do just because of the small numbers of patients and the expense of doing a clinical trial like that. I launched a redifferentiation trial with selpercatinib, not in an adjuvant setting, but in patients with small-volume disease; that was also impossible to enroll. It is a rare patient population, so it's exceedingly challenging to do clinical trials in these patients.

What to the American Thyroid Association (ATA) guidelines suggest for patients with a gene mutation?

The ATA guidelines do recommend first-line NTRK, RET, or ALK targeted therapy for patients that harbor those fusions when they need systemic therapy….

The BRAF V600E mutation is the most common mutation in papillary thyroid cancer, and that's the most common thyroid cancer that we see. BRAF V600E mutation are common, and the new ATA guidelines do recommend that BRAF-directed therapy can be considered in the first line for patients who are not good candidates for lenvatinib, but otherwise, if patients are a candidate for lenvatinib, then BRAF-directed therapy should be reserved for second line. That is consistent with the tissue-agnostic approval for dabrafenib [Tafinlar] and trametinib [Mekinist], which is for patients who don't have other alternatives for therapy.

For other actionable targets, still first-line lenvatinib or participation in a clinical trial is recommended.

What are the NCCN guideline considerations for kinase inhibitors in thyroid cancer?

The NCCN guidelines are a little bit more medical oncology–user friendly.³ One of the principles is that not all patients with advanced thyroid cancer need to be started on therapy right away. We do have patients with metastatic MTC or radioactive iodine-refractory DTC who have low-volume, asymptomatic, slow-growing disease, and in the days of having cabozantinib [Cabometyx], vandetanib [Caprelsa], lenvatinib, and sorafenib, we often would not initiate therapy right away if people have really slow-growing disease. I do think that with other treatments that have a different AE profile and great efficacy, then there may not be as good a reason to hold off on initiating therapy if you're dealing with a patient with RET fusion–positive disease, for example. But I think it is very helpful to know the flavor of the disease if you have that luxury to hold off on starting therapy.

How do AEs play a role in selecting these treatments for thyroid cancer?

These drugs are not curative; however, there is a strong contrast benefit, but the therapies can affect the quality of life. Then the other principle that's highlighted, which I think is important, and I'm sure others spend a lot of time on, is that optimal management of patients on treatment is key.

For example, with lenvatinib, one of the early patients who I saw who was referred to me had been started on lenvatinib and had a beautiful response, but had treatment-emergent hypertension, and it was [difficult] hypertension, so that lenvatinib had been stopped. But we did an analysis of patients on the SELECT trial [NCT01321554] who had treatment-emergent hypertension vs those who didn't. There was an overall survival benefit in the patients who had treatment-emergent hypertension compared with the placebo arm, even though almost everybody on the placebo arm crossed over to receive lenvatinib.⁴

It's a good pharmacodynamic marker of benefit from therapy, so the last thing you want to do is stop lenvatinib as soon as a patient gets hypertension, because that patient is much more likely to benefit from it. With many of these therapies, patients take them every day, and patients can take them for a number of years, so we need to optimally manage their AEs.

What are the principles of systemic therapy per the NCCN guidelines in DTC?

Both lenvatinib and sorafenib were studied in randomized phase 3 trials, showing a progression-free survival benefit [PFS], and both are FDA approved. The NCCN guidelines do put lenvatinib in a separate box as the preferred regimen, because the PFS benefit with lenvatinib was so much bigger than the PFS benefit compared with placebo with the sorafenib trial; the overall response rate was a lot higher too.^5,6 So that's why the NCCN feels quite comfortable supporting lenvatinib.

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_{DISCLOSURES: Wirth previously reported a consulting or advisory role with Merck, Eisai, Lilly, Bayer, Exelixis, Coherus Biosciences, METIS Precision Medicine, Tome Biosciences, EMD Serono, Ellipses Pharma, Illumina, and Nested.}

_References:

_{1. Ringel MD, Sosa JA, Baloch Z, et al. 2025 American Thyroid Association management guidelines for adult patients with differentiated thyroid cancer. Thyroid. 2025;35(8):841-985.}

_{2. Ju G, Sun Y, Wang H, et al. Fusion oncogenes in patients with locally advanced or distant metastatic differentiated thyroid cancer. J Clin Endocrinol Metab. 2024;109(2):505-515. doi:10.1210/clinem/dgad500}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Thyroid carcinoma; version 1.2025. Accessed November 5, 2025. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf}

_{4. Wirth LJ, Tahara M, Robinson B, et al. Treatment-emergent hypertension and efficacy in the phase 3 study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT). Cancer. 2018;124(11):2365-2372. doi:10.1002/cncr.31344}

_{5. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630. doi:10.1056/NEJMoa1406470}

_{6. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319-328. doi:10.1016/S0140-6736(14)60421-9}