Biological Insights Fuel Novel Treatments for Rare Head and Neck Cancers (Part 2: Rare Thyroid Cancers)

Biological Insights Fuel Novel Treatments for Rare Head and Neck Cancers

Part 2: Rare Thyroid Cancers

This article is Part 2 of our three-part series on MSK-led advances for improving outcomes for patients with rare head and neck cancers. Part 2 summarizes MSK’s leadership and expertise in developing new therapeutic options for patients with rare thyroid cancers based on scientific and clinical research insights. Part 1 covers rare salivary gland cancers and Part 3 covers rare non-melanoma skin and oral cavity cancers.

“MSK has a legacy of expertise in pioneering new treatment approaches and conducting investigator-initiated clinical trials for patients with rare thyroid cancers, said head and neck oncologist Eric Sherman, MD, MSK. “Collaborations with colleagues at other centers have also been valuable for advancing the field.”

Dr. Sherman works with MSK scientists on translational insights and also leads the design of multicenter studies conducted through the NCI National Clinical Trials Network for patients with rare thyroid cancers. The NCI National Clinical Trials Network recently reported results for its first clinical trial for patients with anaplastic thyroid cancer.

Pioneering Work in Redifferentiation Strategy for Radioactive Iodine-Refractory Thyroid Cancers Continues

About 90% of thyroid tumors are well-differentiated and can be treated with radioactive iodine (RAI). However, a minority become refractory, leading to poor outcomes. More than a decade ago, MSK pioneered redifferentiation as an effective strategy for treating RAI-refractory metastatic thyroid cancers. MSK endocrinologist James Fagin, MD and members of the James Fagin Lab discovered selective MEK and BRAF kinase inhibitors effectively redifferentiated refractory tumors and restored their ability to take up radioactive iodine in transgenic mouse models. (1)

The discovery led to a landmark MSK clinical trial led by head and neck oncologist Alan Ho, MD, PhD. The results, published in the The New England Journal of Medicine in 2013, showed that selumetinib produced clinically meaningful increases in iodine uptake and retention in a subgroup of patients, especially those with RAS-mutant disease. (2) Today, MSK continues to explore redifferentiation together with targeted therapies based on biological findings from tumors collected in clinical trials.

Clinical Trials of Targeted Therapies for Rare Thyroid Cancers

Medullary thyroid cancer is the rarest of all thyroid cancers, making up 3% to 4%. About 25% of cases are inherited through a RET gene mutation.  (3)

MSK’s Early Drug Development group, led by thoracic oncologist Alexander Drilon, MD, pioneered the preclinical investigation of LOXO-292, a highly selective RET inhibitor, and published their findings in the Annals of Oncology in 2018. (4) This work led to the LIBRETTO series of trials testing selpercatinib, a selective RET inhibitor. The FDA granted accelerated approval to selpercatinib in May 2020 for adults and adolescents with advanced or metastatic RET-mutant medullary thyroid cancer based on results from the LIBRETTO-001 trial. (5)

Most recently, Dr. Sherman led the design of LIBRETTO-531, an international multicenter, open-label, randomized controlled phase 3 study comparing selpercatinib to cabozantinib or vandetanib in patients with advanced, multikinase inhibitor-naïve RET-mutant medullary thyroid cancer. Primary study completion was achieved in May 2023, with full completion anticipated in 2026 (NCT04211337).

The trial results were published in The New England Journal of Medicine in November 2023. (6)

The BRAF V600E mutation accounts for about 60% of all thyroid cancer mutations. It plays a role in MAPK (ERK) signaling, through activating transcription factors essential for directing cell cycle and survival. (7)

Dr. Sherman initiated and is currently conducting a pilot study adding cemiplimab immunotherapy to dabrafenib and trametinib, the standard treatment for patients with BRAF V600E-mutant anaplastic thyroid cancer. Cemiplimab is already FDA-approved for treating skin cancer and is considered investigational in this MSK-exclusive trial (NCT04238624).

MSK is also participating in a multisite,  phase 2 master protocol to assess the efficacy and safety of FORE8394 in people with BRAF-mutated solid tumors, including thyroid malignancies (NCT05503797). FORE8394 is an investigational inhibitor of class 1 (v600) and class 2 (activating non-V600) BRAF-mutated tumors. This trial builds on results from the phase 1/2a trial (NCT0248712) in which monotherapy FORE8364 demonstrated antitumor activity in various BRAF-altered tumors. (8)

Results from the First Anaplastic Thyroid Cancer Clinical Trial

Last but not least, MSK recently led the design and participated in the first randomized clinical trial for patients with anaplastic thyroid cancer, a rare indication with a poor prognosis. Anaplastic thyroid cancer is characterized by a rapidly growing neck mass that can cause asphyxiation, requiring swift local disease control with surgery, chemotherapy, and radiotherapy. (9)

In the multisite phase 2 trial conducted by the NCI Clinical Trials Network Group in collaboration with NRG Oncology (NCT01236547), 89 patients received intensity-modulated radiation therapy and paclitaxel plus the pazopanib, a multiple protein tyrosine kinase inhibitor, or a placebo.

The primary endpoint of overall survival was not met. However, an additional analysis showed that any potential benefit would only be found in patients without distant metastasis at diagnosis, a departure from the belief that local control improves survival. Interestingly, patients with stage M0 cancer in the pazopanib group showed encouraging survival rates starting around six months from randomization. The trial results were published recently in The Lancet Oncology(10)

“Collaboration within the NCI Natinonal Clinical Trials Network made it possible to conduct the first randomized controlled trial in this rare thyroid cancer,” said Dr. Sherman, lead author of the paper and the NCI–NRG Oncology trial design. “While the endpoint was not met in this first study, encouraging evidence is informing the design of our next trial.”

Explore MSK clinical trials for patients with thyroid cancers, including the following:

Access disclosures for Dr. ShermanDr. FaginDr. Ho, and Dr. Drilon

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  1. Chakravarty D, Santos E, Ryder M, et al. Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J Clin Invest. 2011;121(12):4700-4711.
  2. Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013;368(7):623-632.
  3. National Cancer Institute. Medullary Thyroid Cancer. Accessed at
  4. Subbiah V, Velcheti V, Tuch BB, et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol. 2018;29(8):1869-1876.
  5. U.S. Food and Drug Administration. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. May 8, 2020. Accessed at
  6. Hadoux J, Elisei R, Brose MS, et al. Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer. N Engl J Med. 2023;389(20):1851-1861.
  7. Al-Masri M, Al-Shobaki T, Al-Najjar H, et al. BRAF V600E mutation in papillary thyroid carcinoma: it’s relation to clinical features and oncologic outcomes in a single cancer centre experience. Endocr Connect. 2021;10(12):1531-1537.
  8. Macarena IDLF, Ahnert JR, Yaeger R, et al. Safety and efficacy of the novel BRAF inhibitor FORE8394 in patients with advanced solid and CNS tumors: Results from a phase 1/2a study. J Clin Oncol. 2023:41.16_suppl.3006.
  9. Foote RL, Molina JR, Kasperbauer JL, et al. Enhanced survival in locoregionally confined anaplastic thyroid carcinoma: a single institution experience using aggressive multimodal therapy. Thyroid. 2011;21(1):25-30.
  10. Sherman EJ, Harris J, Bible KC, et al. Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial. Lancet Oncol. 2023;24(2):175-186.