Clinical trials propel new standards of care for thyroid cancer

Alan L. Ho, MD, PhD discusses targeted therapies such as TKIs that have shown promising efficacy in multiple patient populations as well as the agents lenvatinib and pembrolizumab.

According to Alan L. Ho, MD, PhD, multidisciplinary approaches remain crucial because treatment options rely on expert knowledge to cover the wide range of thyroid cancer subgroups. The broader the scope of contributions, the better the chances of expanding and delivering clinical trials tailored to patients with unmet needs.

“More than a decade ago, there were few treatment options for these diseases,” Ho said. “We now have several targeted agent-driven therapy options that have been studied in trials biologically rational clinics and targeted agents. Thyroid cancer, even more than other diseases, has [been privy to] the fruits of the genomic era [and] advances in drug development, but much remains to be done to better understand tumor biology and develop better therapies for patients.

Ho, a medical oncologist and chair of the Geoffrey Beene Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York, is moderating the session on head, neck and thyroid cancer. On Friday, November 11, he gave a lecture entitled “Therapeutics for Thyroid Cancer” at the 40th Annual Chemotherapy Foundation Symposium® (CFS®).

In an interview with Live® Ho discussed targeted therapies such as tyrosine kinase (TKI) inhibitors which have shown promising efficacy in multiple patient populations as well as the agents lenvatinib (Lenvima) and pembrolizumab (Keytruda).

What updates in the head and neck space have been shared at CFS®?

[With the meeting,] the audience had the opportunity to learn about new standards of care and new developments in all the different types of solid malignancies outside of their specialty. In the head and neck session in particular, we had some great speakers and discussions on HPV-induced head and neck squamous cell carcinoma, which is an important topic right now given that [histology] accounts for most head and neck cancer patients in the United States. We don’t tailor our therapies well enough to the HPV status of tumors, and there are exciting new areas that can [help] define how we should do it.

another conversation [highlighted the role of] immunotherapy in squamous cell carcinomas where there have been major advances and changes in the standard of care for these patients. Beyond my own specialty, it’s always instructive to learn more about disease advances.

[In head and neck cancer] we reviewed many recent advances in developmental therapeutics for different types of thyroid cancer. It was an exciting time when we [seen the] development of numerous agents targeted against specific genetic alterations in different types of thyroid cancer histology. We reviewed the updated data [and how it affects] standards of care.

Some of the interesting biological knowledge from these trials is that a few of the same regimens will have different efficacy profiles, whether [for] non-anaplastic or anaplastic thyroid cancers. [For example,] lenvatinib and pembrolizumab have been evaluated in both anaplastic and non-anaplastic populations. Very promising response data have been published in trials involving patients with anaplastic thyroid cancer. Although toxicity, morbidity and complications remain a problem that we must pay attention to.

The landscape of non-anaplastic thyroid cancers is a bit different, but there is some interesting data regarding the role of pembrolizumab [and how it] may prolong the benefit of lenvatinib in patients who have already become resistant to it. There are different potential roles or clinical uses for these combinations depending on what [type of] thyroid cancer suffered by a patient.

What did the COSMIC-311 trial (NCT03690388) show about the survival benefits of cabozantinib monotherapy in radioiodine refractory differentiated thyroid cancer? (Table 1)1

COSMIC-311 is the third phase 3 trial that has been formed for radioactive iodine refractory thyroid cancer. This trial demonstrates for the first time PFS [progression-free survival] benefit of cabozantinib (Cabometyx) compared to placebo in patients who have already received TKI treatments, i.e. 1 or 2 previous lines, and established the efficacy of cabozantinib in the context.

You recently published a pilot clinical trial looking for patients with BRAF– mutant thyroid cancers refractory to radioactive iodine (NCT02456701). What was the rationale for this trial and what key data emerged regarding the effectiveness of the combination? (Table 2)2

My colleagues and I have demonstrated that in BRAF-mutant thyroid cancers, [first-generation] BRAF inhibitors can be quite effective for a subset of patients where you can take tumors that are no longer hungry for radioactive iodine and make them hungry for that radioactive iodine, again making it an effective treatment. But like all approaches, it was fine in that it only involved a subset of patients.

The idea behind evaluating different combinations is to see if we could increase efficiency and expand [the] use [of the available agents] to more patients with BRAF– mutant thyroid cancer. CDX-3379 targets HER3 and we have preclinical data showing that when you treat BRAF– mutant thyroid cancers with BRAF inhibitors, you can achieve upregulation of HER3 signaling. If you could repeal that, you might get more potent inhibition of the very pathways we want to inhibit to restore iodine avidity.

This trial was a very small pilot trial, 6 patients with BRAF-mutants [disease]and we were able to demonstrate that the combination [of vemurafenib and CDX-3379] was safe and that we had good efficacy in terms of restoring redifferentiation. What is needed in this area are larger studies and randomized trials to demonstrate the effectiveness of redifferentiation in refractory patients, as well as randomized comparisons to know that these combinations are better than single agents.

What is the importance of multidisciplinary management in this disease? Who else but medical oncologists can be involved in the treatment of patients?

Multidisciplinary care is essential for patients with advanced thyroid cancers. First and foremost, it is the surgeons who are, of course, important for the initial control of locally advanced disease. Even for patients with tumors in dangerous locations, surgical procedures can sometimes be considered.

The endocrinologist also helps manage TSH [thyroid stimulating hormone] deletion [and] nuclear medicine physicians [handle] radioactive iodine treatments. Radiation oncologists often [consider] palliative radiotherapy or more definitive radiotherapy for these patients. Next, medical oncologists are [handling] systemic therapeutic options, traditionally relegated to [either] radioactive iodine refractory disease, anaplastic disease, mastoid disease or recurrent metastatic disease.

There are now new paradigms where clinical trials are being evaluated with the neoadjuvant use of drugs to see if we can improve surgical outcomes for patients. With the development of better drugs [and] better approaches, it has become more and more [necessary for] multidisciplinary patient care.

What challenges remain to be met in order to develop treatments for thyroid cancer?

Metastatic differentiated thyroid cancer, refractory to radioactive iodine; anaplastic thyroid cancer; these remain incurable diseases with limited FDA-approved options. There is a need and a push to develop better, safer and more effective treatments for these patients and there is an ongoing push to better understand the biology, develop therapies and conduct clinical trials.

More and more, [thyroid cancers have] have gone from rare diseases to diseases that we can assess well in clinical trials. In settings where randomized trials may be needed, we can now do those randomized trials in settings where we need to conduct larger phase 2 trials to re-explore drug signals. We need to pursue more definitive trials to understand the effectiveness of the drugs we are developing.


  1. Brose MS, Robinson BG, Sherman SI, et al. Cabozantinib for previously treated radioactive iodine refractory differentiated thyroid cancer: updated results from the COSMIC-311 phase 3 trial. Cancer. Published online October 19, 2022. doi:10.1002/cncr.34493
  2. Chekmedyian V, Dunn L, Sherman E, et al. Enhancement of radioiodine uptake in BRAF-Mutant, radioiodine-refractory thyroid cancers with vemurafenib and the anti-ErbB3 monoclonal antibody CDX-3379: results of a pilot clinical trial. Thyroid. 2022;32(3):273-282. doi:10.1089/thy.2021.0565

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