Clinical trials drive new standards of care for thyroid cancer

Clinical trials drive new standards of care for thyroid cancer

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

Multidisciplinary approaches remain crucial, as treatment options rely on expert knowledge to cover the wide range of thyroid cancer subgroups, according to Alan L. Ho, MD, PhD. The broader the scope of contributions, the greater the chances of scaling up and offering suitable clinical trials for patients with unmet needs.

“More than a decade ago there were few therapeutic options for these diseases,” Ho said. “We now have multiple targeted therapy options powered by targeted agents, which have been studied in biologically sound clinical trials 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 more needs to be done to better understand the biology of tumors and develop better therapies for patients.”

Ho, a medical oncologist and Geoffrey Beene Junior Faculty Chair 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 talk entitled “Therapeutics for thyroid cancer” during the 40th Annual Chemotherapy Foundation Symposium® (CFS®).

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

What head and neck space updates were shared on CFS®?

[With the meeting,] the audience had the opportunity to become familiar with new standards of care and new developments in all the different types of solid malignancies outside of the specialty. Specifically in the head and neck session, we had excellent speakers and talks on squamous cell carcinoma of the head and neck caused by HPV, which is an important topic right now given that [histology] represents the majority of head and neck cancer patients in the US We don’t tailor our therapies as well enough to the HPV status of tumors as we can and there are new and exciting areas that can [help] define how we should do that.

another talk [highlighted the role of] immunotherapy in squamous cell carcinomas where there have been great advances and changes in the standard of care for these patients. Beyond my own specialty, it is always educational to hear more about advances in disease.

[In head and neck cancer] we review many of the recent advances in developing therapies for different types of thyroid cancer. It has been an exciting time in which we have [seen the] development of many agents directed against specific genetic alterations in different histological types of thyroid cancer. We review the updated data [and how it affects] standards of care.

Some of the interesting biological insights from these trials are that some of the same regimens will have different efficacy profiles, either [for] non-anaplastic or anaplastic thyroid cancers. [For example,] Lenvatinib and pembrolizumab have been evaluated in both anaplastic and non-anaplastic populations. There are some very promising response data that have emerged in trials enrolling patients with anaplastic thyroid cancer. Although toxicity, morbidity and complications continue to be an issue that we must be aware of.

The picture in non-anaplastic thyroid cancers is a bit different, but there are interesting data on the role of pembrolizumab [and how it] may extend the benefit of lenvatinib in patients who have already become resistant to it. There are different potential roles or clinical use of these combinations depending on what [type of] thyroid cancer that a patient has.

What did the COSMIC-311 (NCT03690388) trial 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 to be formed for thyroid cancer refractory to radioactive iodine. This trial demonstrates for the first time the PFS [progression-free survival] benefit of cabozantinib (Cabometyx) over placebo in patients who have received prior TKI therapy, either 1 or 2 prior lines, and established the efficacy of cabozantinib in the setting.

He 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 efficacy of the combination? (Table 2)two

My colleagues and I showed 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 radioactive iodine avid and make them radioactive iodine avid, making it an effective treatment again. But like all approaches, it was perfect because it’s only a subset of patients.

The idea behind evaluating different combinations is to see if we can increase the effectiveness 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 it treats BRAF-mutant thyroid cancers with BRAF inhibitors, can elicit upregulation of HER3 signaling. If you could override that, you can 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-mutant [disease]and we were able to show that the combination [of vemurafenib and CDX-3379] it was safe and that we had good efficiency in terms of restoring redifferentiation. What is needed in that field are larger studies and randomized trials to demonstrate the efficacy of redifferentiation for refractory patients, as well as randomized comparisons to learn that these combinations are better than single agents.

What is the importance of multidisciplinary management in this disease? Who else may be involved in the patient’s treatment besides medical oncologists?

Multidisciplinary management is essential for patients with advanced thyroid cancers. First of all, it is the surgeons who, of course, are important for the initial control of locally advanced diseases. Even for patients with tumors in dangerous locations, surgeries can sometimes be considered.

The endocrinologist also helps monitor TSH [thyroid stimulating hormone] suppression [and] nuclear medicine doctors [handle] radioactive iodine treatments. Radiation oncologists often [consider] palliative radiation or more definitive radiation for these patients. So medical oncologists are [handling] systemic therapy options, which have traditionally been relegated to [either] disease refractory to radioactive iodine, anaplastic disease, mastoid disease, or recurrent metastatic disease.

There are now new paradigms in which clinical trials using neoadjuvant drugs are being evaluated to see if we can improve surgical outcomes for patients. With the development of better medicines [and] better approaches has become increasingly [necessary for] Multidisciplinary patient management.

What challenges lie ahead for the development of treatments for thyroid cancer?

Radioiodine Refractory Recurrent Metastatic Differentiated Thyroid Cancer; anaplastic thyroid cancer; these remain incurable diseases with limited FDA-approved options. There is a need and a drive to develop better, safer, and more effective treatments for those patients and there is a continuing drive to better understand the biology, develop therapies, and conduct clinical trials.

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

References

  1. Brose MS, Robinson BG, Sherman SI, et al. Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: updated results from the phase 3 COSMIC-311 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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