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Treating Advanced and Radioactive Iodine-Refractory Thyroid Cancer With Jochen Lorch, MD

Dr. Jochen Lorch, MD, MSc, is a Professor of Medicine and Medical Oncologist specializing in head, neck, and thyroid cancers at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University. Dr. Lorch discusses the challenges of selecting treatment for advanced thyroid cancers, the importance of molecular testing for selection of kinase inhibitors in thyroid cancers, and future directions of research in thyroid cancer treatment selection and sequencing.  

Oncology Data Advisor: Welcome to Oncology Data Advisor. I'm here today with Dr. Jochen Lorch. Dr. Lorch, would you tell us a little about what you do?

Jochen Lorch, MD, MSc: I'm a Medical Oncologist and I am directing the head, neck, and thyroid center here at Northwestern University in Chicago.

Oncology Data Advisor: What are some of the most challenging aspects of managing patients with thyroid cancer?

Dr. Lorch: As a medical oncologist, I usually see patients with fairly advanced thyroid cancer. So I can't really comment much on the management of thyroid nodules or anything like that. What I usually deal with are patients with iodine-refractory differentiated thyroid cancer or poorly differentiated thyroid cancer, and also with anaplastic thyroid cancer, as well as medullary thyroid cancer that has not responded to the standard treatment, which is typically surgery, followed by radioactive iodine in many cases, for differentiated thyroid cancer, at least. We're talking really about a minority of patients because most patients with thyroid cancer undergo surgery and the standard that I was just describing and are cured. For the majority of these patients their cancer never comes back. Out of 100 patients, there's a handful of them where the cancer comes back, at least among differentiated thyroid cancers, and then eventually the cancer becomes iodine-refractory.

Anaplastic thyroid cancer, which I think of as a totally different disease, is extremely aggressive. Prognosis is usually still quite poor, although this has been changing, and radioactive iodine plays absolutely no role in treatment.

Medullary thyroid cancer is also typically operated on and if it does come back, which happens in 10% to 20% of cases, then they may also be referred to me. What I'm trying to say is I'm essentially dealing with a very small fraction of all the thyroid cancer patients that are out there because, as I said, most of them are treated and cured.

Now, I should specify that, among patients with differentiated thyroid cancer, that became iodine-refractory, the greatest challenge in my opinion is to find the optimal time to actually start treatment. If you look, for example, at the American Thyroid Association Cancer Guidelines, then you'll see that they recommend treatment essentially when patients become symptomatic.

Now that, in my opinion, is certainly a reasonable standard, but in my practice, I often start patients sooner than that. I also know that many, if not most of my colleagues would do the same. Now that depends on many things though.

When to start—one issue is, how well are these patients doing? Are they otherwise relatively healthy? Are they young or old? How much toxicity are they able to tolerate? The second question is how quickly does their tumor progress? As you probably know, suppression of thyroid stimulating hormone, TSH, is essential in the long-term treatment of thyroid cancer, at least the more advanced thyroid cancers. And with a fully suppressed TSH, often people don't have much, if any, progression for extended periods of time, which can be years, if not longer. So, if on the other hand, cancer is progressing relatively quickly, that will also be something that could more push you towards starting treatment sooner rather than later. And then lastly—and that's one area where we really don't have many good answers yet—what's the influence of their molecular profile on this decision?

We know, for example, that patients who are BRAF—usually BRAF V600E-mutated—have a higher risk of eventually falling in this high-risk category. Their risk is about twice as high to develop metastatic and eventually radioiodine-refractory disease. But now, if we have somebody with iodine-refractory disease, it's not so clear if BRAF mutations should push us more towards treating sooner or not. One could also make a case for the opposite.

But how about, for example, people with TERT promoter mutations, which usually indicate a very aggressive biology, or those with a TERT and BRAF mutation combined, where these two mutations often enhance each other and lead to a very aggressive biology. If we know about these things, I feel that it does influence the decision to treat versus continuing to wait. On the other hand, in my opinion, it's still the x-rays, the computed tomography (CT) scans, and the evidence for radiographic progression that is the strongest determinant of whether or not we're starting treatment.

And speaking of molecular profiles, ultimately also important is the question of whether they have any other mutations or fusions such as RET fusions or NTRK fusions. ALK fusions can sometimes occur in anaplastic thyroid cancer and drugs that target these mutations compared to these more general drugs, such as lenvatinib, which target vascular endothelial growth factor (VEGF), but also many other tyrosine kinases. Those more specific drugs that target TERT, NTRK, ALK are a lot better tolerated. Now, how does that influence our decision to start treatment? Should it be sooner, or could we wait even more because these drugs actually tend to be very effective for the most part?

And for example, with NTRK fusions, but also with RET fusions in differentiated thyroid cancer, the disease control rate is very, very high. It's approaching 100%. So having a well-tolerated treatment option, should that then lead you to treating sooner? Or, with the opposite argument, you could say, 'well, this is a highly effective treatment. Why start it right away?' When you could likely induce a really good response at a later point and get people out of trouble and let them enjoy life without having to deal with the hassle of taking pills once or twice a day, and the potential side effects that come with it. We don't have the good guidance on that. We also do not know if starting sooner versus later leads to any improvement in overall survival.

For example, if you look at the data from the large phase three studies, the DECISION study or the SELECT study which were done with sorafenib and lenvatinib, the tyrosine kinase inhibitors, you see that the primary end point for both of these studies is actually progression-free survival, which is different from overall survival. And to this day, there has not been shown any difference in overall survival between the treatment arm and the placebo arm. So, to make the long story short, we do not know whether it's favorable to start treatment sooner rather than later, because we don't know whether either approach is associated with better survival.

Oncology Data Advisor:

Thank you so much for that. When you're talking about these advanced and anaplastic thyroid cancers, what are the considerations you make when you're selecting multi-kinase inhibitors?

Dr. Lorch: This day and age, I get molecular testing on all of the cases, and molecular testing these days is usually next-generation sequencing. Now with anaplastic thyroid cancer, as I mentioned, which is a very aggressive type of thyroid cancer, time is usually of the essence. Untreated anaplastic thyroid cancer can lead to death within days and weeks, usually not months. So, the first thing you want to make sure if you have somebody with anaplastic thyroid cancer, is whether or not they have BRAF mutation. And that for the most part can actually be determined with a simple immunohistochemistry stain. So that is always the first thing that you should reach for and make sure that the BRAF mutation does not go unrecognized in anaplastic thyroid cancer.

Next-generation sequencing typically takes anywhere between one and three weeks and it's become increasingly cheap—or if not cheap, less expensive. Next generation sequencing usually provides a whole host of mutational data. Most of these panels that are around and commercially available test between 500 and 800 tumor-related—cancer-related genes, and include everything that's relevant for thyroid cancer, including the fusions and translocations.

So, if you find, for example, in a differentiated thyroid cancer case, that the tumor is BRAF-mutant, then you could consider starting a RAF inhibitor such as vemurafinib, but there's several others out there that are equally effective. But again, the question then goes back to, when do you really start? And that goes back to the first question that you were asking, but it's good to have that information. Now, if somebody has a RET or an NTRK fusion, then you would also consider those specific inhibitors, RET inhibitors, such as selpercatinib and pralsetinib, which are FDA-approved, and NTRK inhibitors, and there's also two of them that are FDA-approved.

Now, the overall chances of finding one of these mutations or fusions for BRAF is about 40% or so for differentiated thyroid cancer. And well, more like 50-60% for differentiated thyroid cancer, but about 40% in anaplastic thyroid cancer. And for RET and NTRK fusions, that's somewhere a little bit north of 10%. These are relatively rare, but because there are specific inhibitors, you don't want to miss them. So, I get molecular information fairly early on, usually when they're becoming iodine-refractory for differentiated thyroid cancer and definitely for anaplastic thyroid cancer. Because as I said, time is of the essence, and you don't want to miss any one of those fusions.

Oncology Data Advisor: And has the recent approval of cabozantinib had an impact on thyroid cancer treatment?

Dr. Lorch: Yes. The FDA approved cabozantinib as second-line agent for iodine-refractory thyroid cancer. And, I think, we're all grateful that this trial was done. It did not come as a shock that it was positive. We all knew that—it's been known and done for a long time—that you can actually go from one tyrosine kinase inhibitor to the next and from there onto the next and the next. You often get very similar efficacy also in terms of duration of response, you end up with something that's really not very different whether you'd treat with first- or second-line tyrosine kinase inhibition. And therefore, again, it wasn't a complete surprise that this trial was positive. I think the way I look at it, it's great to have FDA approval because it means that for the most part, you can just prescribe these drugs and they will be delivered to patients' homes and, there's usually not much hassle around ordering them.

Is cabozantinib as second-line better than, for example, any one of the other tyrosine kinase inhibitors that are also targeting primarily VEGF? No, I think we don't know if cabozantinib is better. It's entirely possible that results with a different tyrosine kinase inhibitor would be very similar to the data with cabozantinib, but they did the study, and they get the FDA approval. And so I think in that sense, it makes life a little bit easier. What does not make life easier necessarily is that it's still a pretty toxic drug, just like all the other tyrosine kinase inhibitors and you have to, of course, educate patients about potential side effects and be ready to treat these patients aggressively if they do develop side effects from their treatment. But it's definitely an effective drug.

Now, the question that always comes up is what about a patient who has one of these mutations, like BRAF or NTRK or RET? What would you use then as second-line after failing multi-tyrosine kinase inhibitors, such as lenvatinib or sorafenib first-line? And I am not sure if I would then use cabozantinib if somebody presented with, say, a RET fusion or an NTRK fusion. In fact, if I knew about one of those fusions being present, I would consider starting them first-line on the more specific inhibitor. Now, of course, there's no data that compared one of the more specific inhibitors with, say, cabozantinib as second-line treatment. And some of these studies are going to be done now in medullary thyroid cancer, for example, with RET-mutated medullary thyroid cancer, comparing cabozantinib, which is also FDA-approved for medullary thyroid cancer, with one of the newer RET inhibitors.

And we won't have these data for a while, but in the meantime, the difference between the specific inhibitors versus the broader tyrosine kinase inhibitors is just in terms of side effects. It's just so strong that I usually start patients on those specific inhibitors right away if I know about their molecular profile. And if that's suggested, it's a good idea.

Oncology Data Advisor: Of the agents currently in clinical trials for thyroid cancer, which do you think are the most promising right now?

Dr. Lorch: I think it's a little hard to say that there's any specific ones. I mean, there are a few, for example, the second-generation RET inhibitors. The background here is of course, that even as good as these specific inhibitors, such as pralsetinib and sorafenib are, eventually patients will develop resistance to these drugs. And the question then is what to do with them? There's a number of second-generation inhibitors that are currently under development, targeting different types of resistance mutations, and we'll have to see in the next couple of years. We will find out how effective these really are, and also how well tolerated they are, because they may not be quite as well tolerated as some of the first generation of RET inhibitors, for example, and the same for NTRK inhibitors. We don't know whether it's second generation, which are often these rationally designed tyrosine kinase inhibitors, whether there will be as well tolerated as the first generation, but we'll see. I think that is definitely an area of research that is exciting, and that will offer new possibilities or new treatment options for patients with thyroid cancer, both in the differentiated thyroid cancer field, but also medullary thyroid cancer, for example.

Now with anaplastic thyroid cancer, again, I think the anaplastic thyroid cancer is really a pretty much a different disease and in terms of molecular profile, it's very different. It's just extremely aggressive and genomically, it just has a lot more going on. I think the breakthrough for anaplastic thyroid cancer has been the advent of immunotherapy. It tends to respond quite well to that. We will have to conduct larger studies to show that how effective they really are. It seems that responses to PD1 inhibitors alone, for example, are in the order of anywhere between 15% and 20%, perhaps combination treatments between PD1 and CTLA-4, such as nivolumab plus ipilimumab may be doing better, but we do not know. But what is clear is that this is a very immune sensitive disease among the newer developments in the immunotherapy space.

I find that for example, bispecific antibodies, which are antibodies that actually target not just one epitope, not one target only, but actually two within the same molecule that there is certainly a lot of promise. I think given the immune sensitivity of anaplastic thyroid cancer, there may be room for cell-based therapies, although while that's explored, there are no results available. Also related to that potentially, this could be a disease that may be amenable to things like vaccinations, rationally designed vaccines, nanotechnology-based, for example. And there's definitely a lot of research going on in that space. I find that it's exciting now just with research, in general, not everything pans out quite the way it's intended, and there are always surprises good and bad, but I think it's an exciting time right now in oncology.

It's horrible to have cancer, but perhaps for thyroid cancer it's the best time to have cancer so far, because if you look back 15 years ago, there was virtually nothing we could do, and now we have treatment options that are very tolerable for a whole host of thyroid cancer types. That list is getting longer, not quite every day, but getting longer, very quickly.

About Dr. Lorch

Dr. Jochen Lorch is a Medical Oncologist with the head and neck cancers group at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University and an expert on the treatment of advanced thyroid cancers. He has over 50 publications on targeted therapies for head, neck, and thyroid cancers.

For more information:

Brose MS, Nutting CM, Jarzab B, et al (2014). Sorafenib in locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet, 384(9940):319-328. DOI:10.1016/S0140-6736(14)60421-9

Schlumberger M, Tahara, M, Wirth LJ, et al (2015). Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med, 372:621-630. DOI:10.1056/NEJMoa1406470

Clinicaltrials.gov (2022a). A study of selpercatinib (LY3527723) in participants with RET-mutant medullary thyroid cancer (LIBRETTO-531). NLM identifier: NCT04211337.

Clinicaltrials.gov (2022b). A study of pralsetinib versus standard of care (SOC) for treatment of RET-mutated medullary thyroid cancer (MTC). (AcceleRET-MTC). NLM identifier: NCT04760288.

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor. 


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