Off-Label Treatment Offers Hope for Patients With Rare Medullary Thyroid Cancer

Oncologists at Massachusetts General Hospital are the first in the country to use a proven lung cancer treatment off-label to help patients with advanced medullary thyroid cancer, a type of thyroid cancer that can be difficult to treat. Since the fall of 2024, five Mass General patients with advanced MTC have undergone treatment with tarlatamab, a first-of-its-class immunotherapy. The drug significantly shrunk the tumor in several cases and stabilized disease progression in the other patients.

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“MTC can be aggressive with high rates of recurrence and metastatic disease,” says Thomas Roberts, MD, MBA, an oncologist in the Center for Head and Neck Cancers at Massachusetts General Hospital. “Because the cancer originates in parafollicular cells, common thyroid cancer treatments like radioiodine don’t help.”

This fall, Dr. Roberts, along with other thyroid cancer experts, presented their treatment findings at the American Thyroid Association (ATA) annual meeting. While the medication shows promise, its high toxicity is a concern. Using the knowledge gleaned over the past year, Dr. Roberts spearheaded efforts at Mass General to develop a treatment protocol that has the potential to be safer while still offering patients the best chance of progression-free survival.

Treating a rare, aggressive thyroid cancer

MTC is a rare thyroid cancer, occurring in approximately 1,200 Americans every year. The parafollicular cells where the cancer starts are cells in the thyroid that secrete calcitonin, a hormone that regulates calcium and phosphate levels. At the time of an MTC diagnosis, many patients already have metastatic disease to nearby lymph nodes. The cancer commonly spreads to distant sites, such as the bones, lungs, and liver.

“More than half of patients with MTC have a mutation in the RET gene,” says Dr. Roberts. Located on chromosome 10, the REarranged during Transfection (RET) gene encodes a protein that aids the development of the nervous system and is important for signaling in cells.

An estimated 1 in 4 people with MTC have a familial type stemming from an inherited RET gene mutation that causes multiple endocrine neoplasia types 2A (MEN2A) and 2B (MEN2B), conditions that carry a high chance of developing MTC. The majority of all MTC diagnoses — 75% — occur in patients with no family history of MTC. A sporadic RET gene mutation causes 40% to 70% of those cases.

Selpercatinib is an FDA-approved targeted therapy for patients with advanced MTC who have a RET mutation. This selective kinase inhibitor attacks the abnormal RET kinase protein that spurs the growth of cancer cells. The development of selpercatinib was led by Lori Wirth, MD, medical director for the Center for Head and Neck Cancers at Mass General Brigham Cancer Institute. Other FDA-approved treatments for patients with MTC include multikinase kinase inhibitors (MKIs), cabozantinib, and vandetanib.

“Once of the challenges with MTC is that the cancer has a high rate of returning after initial treatment,” says Dr. Roberts. Because of its high metastatic and recurrence rates, MTC accounts for up to 20% of all thyroid cancer-related deaths. While selpercatinib is a highly effective medication for patients with RET mutations, “patients’ tumors inevitably develop a resistance to selpercatinib. After developing resistance, patients have no established treatment options.”

Novel bispecific T-cell engager (BiTE) drug targets cancer cell proteins

Tarlatamab is a new type of targeted immunotherapy drug known as a bispecific T-cell engager (BiTE). The first-of-its-class drug received FDA approval in May 2024 for patients with advanced small cell lung cancer that has progressed on standard treatments.

The drug targets DLL3 proteins found on the surface of lung cancer cells. Those proteins are also found on the surface of MTC cells, making tarlatamab a promising option for patients whose disease progresses with selpercatinib. One arm of the drug binds to DLL3 proteins on cancer cells, while the other arm attaches to cancer-fighting T cells. The drug helps T cells find and destroy cancer cells.

In the fall of 2024, Dr. Roberts and his team began treating four patients with advanced MTC who developed resistance to targeted therapies and weren’t candidates for clinical trials. All patients showed evidence that their tumor responded to tarlatamab — their tumor either shrunk on restaging scans or their levels of calcitonin and carcinoembryonic antigen (CEA), two biomarkers commonly followed in MTC, decreased. However, all of the patients developed severe complications from the drug, including two patients that required hospitalized intensive care and one patient who succumbed to a perforated bowel.

“From earlier studies, we knew the drug posed a high risk of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS),” says Dr. Roberts. “But we didn’t expect that patients with MTC would have more severe complications than those treated for lung cancer.”

Although the treatment seemed effective, the team felt that level of toxicity was too high to continue offering the treatment to new patients using the dose used to treat lung cancer. The rarity of MTC makes it more challenging to initiate clinical trials. “But we felt we were on to something. We needed to find a way to make the treatment safer,” says Dr. Roberts. With this goal in mind, Dr. Roberts engaged a team of Mass General oncologists, pharmacists, and ethicists to review the pattens of the adverse events they saw, draw from lesson learned at MGH from using other immunotherapies and cellular therapies, and develop a modified dosing regimen.

In May 2025, Robb Jutton, a 51-year-old New Hampshire resident with advanced MTC, became the first person to receive tarlatamab at Mass General using the new treatment protocol. “We’re using a slower step-up protocol when administering the medication, keeping patients in the hospital longer after dosing, and monitoring vitals more closely, even when patients have no symptoms or mild ones,” says Dr. Roberts. “We’re using different medications to counteract tarlatamab side effects and have a lower threshold to start those medications.”

At the start of treatment, Jutton was experiencing severe pain from metastatic cancer in his bones that left him unable to walk. Dr. Roberts gave him 50-50 odds of living just a few more weeks to attend his daughter’s graduation. But Jutton’s response to tarlatamab exceeded everyone’s expectations. He experienced mild neurotoxic effects that responded quickly to treatment.

“His pain is gone. He’s walking again and back to work — and he saw his daughter graduate,” says Dr. Roberts. “His imaging tests show no evidence of disease, and his biomarkers have returned to the normal ranges. It’s still early in the treatment process, but we’re very encouraged by what we’ve seen.”

In the meantime, Dr. Roberts advised caution to other MTC specialists nationwide. “We are still learning about this treatment in patients with MTC, and the risks are significant. This treatment needs to take place in a carefully controlled environment with teams who know the protocols and are experienced in managing these kinds of toxicities,” he says. “It’s also important that patients understand that this drug is not an approved treatment for MTC, and the potential risks, including death, are very real.”

Dr. Roberts acknowledges that the initial results — while encouraging — are limited to a very small patient population. “We don’t yet know how effective this treatment will be,” he says. “But it has potential to become a new standard of care for advanced MTC.”

Learn more about The Center for Head and Neck Cancers

Learn more about Mass General Brigham Cancer Institute