MSK Head and Neck Cancer: Thyroid Cancer Research Update

Clinicians and scientists at Memorial Sloan Kettering Cancer Center (MSK) continue to investigate new ways to improve outcomes for patients with thyroid cancer.

Recent research insights from MSK thyroid cancer experts include:

• the safety and feasibility of active surveillance for patients with low-risk papillary thyroid cancer,
• the identification of mutation profiles of subgroups of the newly-defined high-grade follicular cell-derived nonanaplastic thyroid carcinoma (HGFCTC),
• recommendations for future clinical trials of redifferentiation therapy for patients with radioactive iodine refractory (RAIR) disease, and
• study results showing that larotrectinib may be beneficial for treatment-naïve patients with NTRK fusion-positive thyroid cancer.

Active Surveillance is Safe and Feasible for Low-Risk Papillary Thyroid Cancer

The rising incidence of differentiated thyroid cancer globally is largely due to the increasing detection of micropapillary thyroid carcinomas. As mortality rates have not changed, many of these cases are likely overtreated. ^{(1) (2) (3)}

Low-risk papillary thyroid cancer is defined as lacking radiographic nodal metastasis, distant metastasis, and significant extrathyroid extension. Active surveillance of low-risk disease was pioneered in Japan in the mid-1990s and integrated into the American Thyroid Association clinical guidelines in 2015 based on favorable outcomes, including low rates of tumor enlargement and lymph node involvement.  ⁽⁴⁾

However, there is limited data describing outcomes of the 10% to 20% of patients with low-risk disease who undergo delayed surgery after a period of active surveillance. The most recent report from Japan showed that patients who eventually had conversion surgery exhibited low rates of lymph node metastasis and experienced favorable survival outcomes.  ^(5) (6)

A recent retrospective study by MSK found that conversion surgery for suspected disease progression was associated with surgical and oncologic outcomes similar to immediate surgery, supporting the safety and feasibility of active surveillance in patients with low-risk papillary thyroid cancer. 

R. Michael Tuttle, MD, Chief of the Endocrinology Service at MSK, was the senior author of the study published in JAMA Otolaryngology-Head & Neck Surgery.  ⁽⁷⁾ The eligibility criteria for active surveillance were previously described by Dr. Tuttle and colleagues at MSK. ⁽⁸⁾

Among 550 patients managed with active surveillance between January 2004 and December 2022, 55 or 10% had conversion surgery, of whom 39 had surgery due to suspected disease progression and 16 chose surgery for other reasons, including patient preference (50%) and imminent changes in insurance status (13%).  ⁽⁷⁾

The five-year overall survival rate was 100% in both the disease-progression conversion surgery and a propensity-matched immediate surgery cohort from the MSK database of 8,599 patients with differentiated thyroid cancer treated between January 1985 and December 2020.  ⁽⁹⁾

Although the cohort of patients undergoing conversion surgery for disease progression represented a subset of more aggressive disease, there were no clinically meaningful differences in rates of regional recurrence, local recurrence, distant metastasis, or disease-specific mortality compared with the matched immediate surgery group.  ⁽⁷⁾

Five-year recurrence-free survival rates were 86% for the conversion surgery group overall and 100% for the immediate surgery group.  ⁽⁷⁾

These findings provide additional support to previous observational evidence that patients with low-risk papillary thyroid cancer experiencing disease progression during active surveillance have similar outcomes as patients with no progression. Undergoing conversion surgery did not result in upstaging compared with immediate surgery and was associated with excellent survival and low recurrence rates. 

MSK-IMPACT® Insights: Subgroups of High-Grade Follicular Cell-Derived Nonanaplastic Thyroid Carcinoma

The 2022 World Health Organization classification of thyroid cancer introduced the term HGFCTC to describe invasive/infiltrative nonanaplastic thyroid cancer with high-grade features, including poorly differentiated and high-grade differentiated thyroid cancer. ^(10) (11)

A team of surgeons, pathologists and an endocrinologist at MSK conducted a retrospective cohort study to compare clinicopathologic characteristics, outcomes, and mutation profiles among HGFCTC subgroups. Head and neck surgeon Ian Ganly, MD, PhD, was the senior author of the study published in Thyroid  ⁽¹²⁾ in February 2025.

The researchers categorized a retrospective cohort of 252 patients who underwent surgery for HGFCTC at MSK between 1986 and 2020 into five subgroups based on increasingly aggressive tumor features as follows:  ⁽¹²⁾

Overall, 50% of patients had infiltrative, 33% had encapsulated angioinvasive, and 18% had encapsulated noninvasive/minimally invasive tumors. Patients with infiltrative tumors were significantly more likely to have T3/T4 disease (71%), regional metastases (55%), and distant metastases (25%).  ⁽¹²⁾

Five-year disease-specific survival was worse in patients with infiltrative disease (68%) compared with those in the encapsulated angioinvasive focal VI (90%), encapsulated angioinvasive extensive VI (88%), and encapsulated noninvasive/minimally invasive (100%) subgroups.  ⁽¹²⁾

All MSK patients with advanced thyroid cancer have their tumors sequenced with the MSK-IMPACT® assay, which looks for mutations in more than 500 cancer-related genes. For the present study, MSK-IMPACT results were available for 117 patients.

Differences in oncologic profiles were reflected in the mutational landscape of the five subgroups.

The most common mutations were TERT (42%), BRAF^V600E (29%), NRAS (27%), EIF1AX (11%), and TP53 (9%). Altered pathways included RTK/RAS/RAF/MAPK (69%), PI3K/AKT/MTOR (14%), histone methyltransferases (9%), and SWI/SNF chromatin remodeling complex (8%). ⁽¹²⁾

Subgroup analysis revealed that tumors in the infiltrative subgroup were mainly driven by BRAF^V600E mutations, whereas tumors in the encapsulated angioinvasive and minimally invasive subgroups were driven by NRAS mutations. Encapsulated noninvasive tumors had a unique mutation profile driven mainly by DICER1 mutations. ⁽¹²⁾

Most patients with angioinvasive or infiltrative tumors underwent total thyroidectomy and adjuvant radioactive iodine (RAI) therapy, and more than 81% achieved RAI uptake in at least one metastatic lesion.  ⁽¹²⁾

Stratifying patients with HGFCTC by clinicopathologic characteristics and mutation profiles will help clinicians predict outcomes and thereby optimize treatment strategies. These categories will likely be incorporated into the next American Thyroid Association clinical practice guidelines.

Redifferentiation Therapy in Advanced Radioactive Iodine Refractory Disease

Two-thirds of patients with metastatic thyroid lesions become radioactive iodine refractory (RAIR), primarily due to loss of cell differentiation, which leads to impaired iodine uptake and retention, or intrinsic radioresistance.  ⁽¹³⁾

Redifferentiation therapy restores tumoral uptake of high-activity radioiodine (¹³¹I). Alan Ho, MD, PhD, Chief of the MSK Head and Neck Oncology Service and MSK colleagues led the first successful study to show a benefit for redifferentiation in 2013. In that trial, the small molecule MAPK kinase MEK1 and MEK2 inhibitor selumetinib restored or enhanced RAI uptake in 60% of patients. ⁽¹⁴⁾The U.S. Food and Drug Administration granted the drug Orphan Drug Designation for treating patients with stage 3 or 4 differentiated thyroid cancer in the adjuvant setting in May 2016. ⁽¹⁵⁾

Since then, several additional prospective phase 2 studies with small numbers of patients and varying study designs have continued to demonstrate efficacy with this approach for some patients, but evidence regarding how this strategy impacts survival or quality of life is still lacking. In the meantime, it has become a more accepted palliative strategy in patients with RAIR thyroid cancer with select targetable mutations.  ⁽¹³⁾

As Correlative Sciences Chair for the Executive Committee of the International Thyroid Oncology Group (ITOG), Dr. Ho recently led a review of the latest evidence and outstanding questions regarding redifferentiation therapy for patients with unresectable or metastatic RAIR thyroid cancer. MSK endocrinologist Laura Boucai, MD, and endocrinologist James Fagin, MD, Head of the Division of Subspecialty Medicine, were co-authors of the ITOG statement, which was published in the June 2025 issue of The Lancet Diabetes and Endocrinology.  ⁽¹³⁾

Overall, the ITOG statement calls for more evidence of the efficacy and long-term benefits of redifferentiation therapy. The authors provided the following recommendations for future clinical trials:  ⁽¹³⁾

• Evaluate the proportion of patients with increased iodine uptake after MAPK inhibitor treatment, the three-month and six-month response rate after the combination of MAPK inhibition with radioactive iodine therapy, and progression-free survival
• While time to retreatment may be a clinically helpful endpoint for future trials, keep in mind that validation of its utility and definition are important questions that still need to be addressed.
• Recognize that the optimal time to initiate redifferentiation remains controversial.

Larotrectinib May Be Beneficial in the First-Line Setting for NTRK Gene-Fusion-Positive Tumors

In April 2025, the U.S. Food and Drug Administration granted full approval to the first-in-class TRK-inhibitor larotrectinib for treating adult and pediatric patients with solid tumors that have an NTRK gene fusion without an acquired resistance mutation, are metastatic or inoperable, or have no satisfactory treatment options or have progressed on prior treatment.  ⁽¹⁶⁾

MSK helped lead the latter two of these three multicenter, open-label, single-arm clinical trials: NCT02122913, NCT02637687 (SCOUT), and NCT02576431 (NAVIGATE), which included patients with thyroid cancer.

Overall, larotrectinib achieved exceptionally durable responses and extended survival with a favorable safety profile for all cancer types with NTRK gene fusions. Across the three trials, the efficacy rate was 60%, the complete response rate was 24%, the partial response rate was 36%, and the median duration of response was 43 months. ⁽¹⁶⁾

MSK thoracic medical oncologist and early drug development specialist Alexander Drilon, MD, was the senior author of a new study evaluating outcomes from these three trials for treatment-naïve patients who achieved a clinical benefit or who discontinued the drug after surgery. Among the 101 patients enrolled with 14 different tumor types, 17 patients had thyroid cancer.  ⁽¹⁷⁾

For thyroid cancer participants, the objective rate of response was 89%, the median duration of response was not reached, the median progression-free survival was not reached, and the five-year overall survival rate was 76%.  ⁽¹⁷⁾

These results, published in June 2025 in ESMO OPEN, suggest that larotrectinib is beneficial in the treatment-naïve setting. 

MSK Clinical Trials for Patients with Thyroid Cancer

MSK is currently conducting these clinical trials for patients with thyroid cancer:

• An MSK-exclusive phase 2 study of avutometinib and defactinib for patients with advanced differentiated thyroid cancer or anaplastic thyroid cancer with a RAF-dimer-driven RAIR differentiated and anaplastic thyroid cancer. Avutometinib is a RAF and MEK inhibitor, and defactinib is a focal adhesion kinase (FAK) inhibitor. The study (NCT06007924) seeks to enroll 30 patients. Learn more.
• A phase 1 study of TILT-123 (an oncolytic adenovirus) plus avelumab in people with advanced solid tumors, including thyroid. The study (NCT05222932) is sponsored by TILT Biotherapeutics Ltd. and is recruiting participants at MSK and the Docrates Cancer Center in Helsinki, Finland. Learn more.
• A phase 2 master protocol study of FORE8394, an inhibitor of BRAF class 1 and class 2 alterations, in participants with advanced solid tumors harboring BRAF alterations. Subprotocol D includes patients 10 years of age and older with thyroid cancer harboring a BRAF V600E mutation. Sponsored by Fore Biotherapeutics, the international study (NCT05503797) is recruiting patients at MSK and other centers. Learn more.