Dr. Nabil Saba shares the first evidence-based guideline on thyroid cancer from ASCO. He highlights recommendations on first- and subsequent-line systemic treatment – including multikinase inhibitors (MKIs), genomically targeted therapies, immunotherapy, and cytotoxic chemotherapy across four subtypes of thyroid cancer: well-differentiated, differentiated high-grade or poorly differentiated, anaplastic, and medullary thyroid cancer. He dives into the evidence supporting each recommendation and explains the importance of shared decision-making on the risks and benefits of each treatment option. Dr. Saba also touches on outstanding questions including sequencing of agents, addressing resistance, emerging biomarker targets, and management of toxicities. Read the full guideline, "Systemic Treatment of Thyroid Cancer: ASCO Guideline." TRANSCRIPT This guideline, clinical tools and resources are available at https://ascopubs.org/topics/asco-guidelines/head-neck-cancer. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Nabil Saba from Emory University, lead author on "Systemic Treatment of Thyroid Cancer: ASCO Guideline." Thank you for being here today, Dr. Saba. Dr. Nabil Saba: Pleasure to be here. Brittany Harvey: And then just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Saba, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then to dive into what we're here today to talk about, Dr. Saba, could you start us off by providing a general overview of the scope and purpose of this first ASCO guideline for thyroid cancer? Dr. Nabil Saba: So thyroid cancer is a complex disease, and the complexity has been added with the advent of multiple systemic therapeutic agents that have recently come on as part of the standard of care for treating this disease. The guidelines have lagged behind, I believe, in terms of being able to clearly delineate how to use these agents and what clinical settings to use them. And so this guideline, I think, is a much-needed and much-awaited guideline for clinicians to allow them to understand better the use of systemic agents in the treatment of thyroid cancer. And when we talk about systemic agents, what we want to specify is this applies mostly for patients with recurrent metastatic disease, patients who have failed the standard initial treatment, which continues to be surgical resection for these patients if surgery is possible, in addition to radioiodine therapy for the right clinical setting. Brittany Harvey: Absolutely. It's a good point that this patient population for this guideline focuses mainly on recurrent disease and patients who have already received surgery and radioactive iodine therapy. So then this guideline covers four subtypes of thyroid cancer, including well-differentiated, differentiated high-grade or poorly differentiated, anaplastic, and medullary thyroid cancer. As you mentioned, you address clinical questions on systemic therapies, including multikinase inhibitors, genomically targeted therapies, immunotherapy, and cytotoxic chemotherapy in both the first-line and subsequent lines for each of these subtypes. So I'd like to review the key recommendations by subtype. So first, what are the key points for systemic therapy for well-differentiated thyroid cancer? Dr. Nabil Saba: It's important to also stress the point that we have these different subtypes of thyroid cancer. So when we talk about radioiodine refractory, those are for patients who are candidates for radioiodine therapy, of course. This usually encompasses the well-differentiated thyroid cancer. So for this group of patients, the guideline focuses on whether the use of multikinase inhibitors compared to placebo or observation impacts the survival in the first-line setting, whether the use of targeted therapies compared to placebo impacts also the survival in the first-line setting, all in the radioiodine refractory setting, of course. And then we tackle the issue of immunotherapy because this also is a topic that has entered the realm, if you like, of thyroid cancer and is being used in some subtypes of thyroid cancer. So we thought it would be important to raise the question of the role of immunotherapy compared to targeted agents or multikinase inhibitors, in addition to the role of cytotoxic therapy or chemotherapy, as we say, in this patient population. So the guideline goes through all of these questions and then makes specific recommendations as to the use of some of the agents in the first-line setting and second-line setting in case these patients progress after first-line setting. So, for example, it's clear that for patients who are radioiodine refractory and who have well-differentiated thyroid cancer, multikinase inhibitors are centerpiece of the first-line treatment option. And for this patient population, the recommendation essentially is to use lenvatinib or sorafenib, even though lenvatinib is considered to be the first choice in this patient population in the first-line setting. For the subsequent line settings, patients should be offered cabozantinib, which has been also proven in randomized trials. As far as genomically targeted therapy, there is always the contention of whether these agents should be initiated first in case the patient has a genomically altered disease. And so, for example, if the patient has a RET alteration or NTRK alteration, the recommendation here is in favor of using RET-targeted therapies such as selpercatinib or NTRK-targeted therapies such as larotrectinib or entrectinib for these patients as a first-line setting. If they do have the BRAF alteration, which is a commonly seen alteration in these settings, the guideline essentially indicates that this may be offered initially prior to treatment with multikinase inhibitors as well, even though the quality of the evidence here is rather lower, and the strength of the recommendation is conditional. And so it's clear that multikinase inhibitors, in the absence of any of these genomic alterations, is really the first line, and then the question becomes when do we use these genomically targeted approaches in patients who have genomically altered disease? Which basically introduces also the complexity of the question here because we have multiple agents depending on these genomic findings. And then it is sometimes confusing for practitioners which one to use or what do we use first? And so I think the guideline provides clarity in terms of what is acceptable, what is rather not acceptable, what is based on a strong recommendation, what is based on a rather weaker recommendation. I think that's part of the value of such a guideline. And then finally we have the question of radioiodine well-differentiated and the question of immunotherapy as a first line. And here we do not recommend using immunotherapy for this patient population. For patients with subsequent line settings, potentially adding pembrolizumab to a multikinase inhibitor is mentioned, however the evidence is low, and the strength of the recommendation is also conditional here. As far as chemotherapy, this is not recommended in this day and age for this patient population, however it may be considered also in patients who fail or progress on genomically targeted therapy and/or multikinase inhibitors. So this is the summary of the recommendations for well-differentiated thyroid cancer, but certainly, for details, I would refer you to the actual guideline since there are many nuances that cannot be covered during just this discussion. Brittany Harvey: Certainly. The full guideline will be available for listeners in our show notes, and there are many recommendation tables and figures that can help folks as they think through these recommendations. A lot of those key points are really important as clinicians think through which systemic therapies to offer and sequencing of these agents, as you mentioned. Following those recommendations for well-differentiated thyroid cancer, what are the recommendation highlights for systemic therapy for differentiated high-grade or poorly differentiated thyroid carcinoma? Dr. Nabil Saba: This entity is rather a rare entity. It's important to stress the fact that this entity has not really been very well represented in clinical trials, and so when we talk about differentiated high-grade or poorly differentiated, the information here is limited. However, the guideline infers on the recommendations to this subtype of thyroid cancer based on what we know for other subtypes. And I think because of the strength of evidence we have in the well-differentiated and the anaplastic thyroid cancer, this guideline for this subgroup of patients draws from these two guidelines and sort of makes recommendations based on this. So in the first-line setting, of course, if patients don't have a genomically altered disease, we certainly would recommend lenvatinib or sorafenib like we do in the well-differentiated disease. For patients with genomically altered diseases, we follow sort of the same guideline as we have followed for the well-differentiated setting, with the caveat that the quality is rather lower here and the stren
