Roundtable Discussion: Nadler Discusses Decision- Making in Thyroid Cancer

Eric Nadler, MD, MPP

Eric Nadler, MD, MPP, medical director of US Oncology Health Informatics and Internet Technology, Texas Oncology-Baylor Charles A. Sammons Cancer Center, led a Case-Based Roundtable discussion on treating a 58-year-old man with thyroid cancer.

LUU: I don’t see much thyroid, but I think I would go to the NCCN guidelines, and if they recommended additional body imaging, then that’s what I would do.

NADLER: Any way you’d image in particular?

LUU: Yes, I think a CT scan for the body.

NADLER: Anybody else? Would you do a neck, chest, abdomen, pelvis, or maybe bone scan?

MAZHARUDDIN: I do remember with a papillary thyroid case, it wasn’t medullary, but we did say, “Just get a chest x-ray.” I think that was partly to avoid the iodine with the contrast.

NADLER: That’s what I was trying to get at with this case. What you’re really trying to work around in MTC—you’re not playing in the iodine cascade like you would be in differentiated thyroid malignancies. Therefore, there is no wrong answer in what the appropriate staging evaluation is. Those tumor markers are excellent. If you said PET, that would not be incorrect, and CT imaging is typically what I do, but you can see bony lesions. So if you get CTs, and you can’t find anything, checking for either a bone scan or other osseous approach would be reasonable. Anybody have a favorite way of thinking through this, for patients with MTC?

GU: I haven’t seen [this case before], so yes, I guess I would go to the NCCN guidelines.

NADLER: What would you do in terms of genetic screening? We know these are famous for having familial endocrinopathies.

MAZHARUDDIN: I believe you have to screen for the multiple endocrine neoplasia syndromes automatically.

NADLER: Often there’s a germline mutation, but this patient had no family history of it. In patients with that, you can have de novo, so they could potentially be carriers of this for their children, so that would be 1 potential reason. You’re never wrong genetically screening a patient. I would feel less strongly if the patient had a very strong family history [and I] would lean toward that a little bit more. Anybody feel compelled to screen the children, or the patient, in this case? Would you refer to genetic counseling?

RAZAQ: I would send for next-generation sequencing [NGS] molecular testing, with FoundationOne. Circling back to your staging, even if they have a metastatic disease, NCCN recommends these patients have thyroidectomy done. I also had one of these patients with a metastatic disease, sent back to otolaryngologist, but he refused it. He said he had a metastatic disease, why should we remove this thyroid? So, I don’t know what’s the right answer.

MANDANAS: It won’t affect the RET mutation in these patients. This genetically moderated RET mutation should be positive in those cases, at least more than 96% of cases.

NADLER: Certainly, the majority of patients with MTC are RET-positive with both [tumors] mutated, more commonly than fused, but you can see occasionally 1 of each. The other thing is, now with these drugs over past 15 years of the treatment of RET malignancies, we’ve had multiple generations of advancement in the efficacy and selectivity of these drugs. I think you raise an interesting point, Mohammad, of maybe now with the selectivity of these drugs, the idea that you have to take out the thyroid in these cancers may be something that we should discuss with our endocrine colleagues.

AGARWAL: We have enough tissue, so we’ll send the tissue [for testing].

NADLER: We have de novo mutations, as this patient has. You can see those as mutations, and most commonly with MTC, there will be mutations, unlike RET mutations in lung cancer, which is fusion. Papillary, and even other differentiated thyroid cancers will have fusions and mutations as well. You do have to test broadly amongst these, and as you can see, somewhere between 60% and 90%, depending on which case series you’re looking at, of MTC cases will be RET-positive.

[This patient] was tested, and it did show a primary somatic mutation. So, this was a de novo mutation, and the tumor mutational burden was low. We all agreed, it’s time to do something, and the question is what do you use: vandetanib [Caprelsa] or cabozantinib [Cabometyx]? The original agent, as I mentioned, was sorafenib [Nexavar]. That was the first 1 we had in these diseases, and the first FDA approval. Then, vandetanib and cabozantinib, and now the more recent ones: selpercatinib [Retevmo] and pralsetinib.²

NADLER: For those people who decided to sequence, what was the reason for sequencing? What would be some arguments for sequencing, starting with vandetanib or cabozantinib?

GU: I just have to relate to my experience in lung cancer. I don’t treat this as often. I think we were more playing into sequencing, maybe saving some good options for down the road, but we know that some patients don’t have that. If they progress, they could be in bad shape where they wouldn’t have a chance to benefit from the next line of therapy. So, I think if we have a specific, selective and potent treatment option, we really ought to use it in the first-line setting, at least in the EGFR-positive disease in lung, like osimertinib now in first-line.

NADLER: Would you not have that same kind of idea for [patients with RET-mutated tumors]?

GU: That’s what I would apply here, where I would use the same kind of thinking and try to use my best agent up front.

MANDANAS: I think, sometimes, if we didn’t have the possibility of getting the mutation tested, these 2 older drugs, you can use them without having to prove that it’s RET-positive, whereas the newer drugs, we may have to prove that they have a RET mutation, or fusion for that matter. So sometimes we don’t have that luxury; you have no choice but probably to use these older drugs first.

HUANG: I guess, in general, you can argue for sequencing when a certain agent has much more toxicity. For example, I think for ALK of rearranged non–small cell lung cancer, I think most people would still do alectinib, and then lorlatinib, rather than frontline lorlatinib.

NADLER: I agree wholeheartedly. Well, I think we’re all saying the same thing. It was just 4 participants who voted on the first 2, so I was just curious. I think we all agree that it’s time to start therapy.

AGARWAL: Obviously, it’s a very effective treatment. Very few things in oncology will have 100% clinical benefit.

NADLER: Exquisitely sensitive drug for MTC, exquisitely more sensitive than even lung.

RAZAQ: I think it’s related to vandetanib and cabozantinib; they’re not fun. Give it to patients, you always end up having some trouble: hypertension, diarrhea, fatigue.

NADLER: As you mentioned, it was nearly a 60% dose reduction, and over a 50% secondary dose reduction on some of those initial agents. I agree, their targets hadn’t given them very frequently, but they were more challenging to give; I agree with you.

NADLER: The ARROW trial is the same trial [as LIBRETTO-001 in that] once-a-day dosing with 400 mg is the same.1 It had patients with RET-mutation positive MTC with prior treatment with either agent, then you had RET-mutation MTC with no prior treatment. There were other RET-altered tumors that were allowed in, and it did have a very small arm in under-accrued, they tried to have more for patients who had had other therapies beyond TKI [tyrosine kinase inhibitor]. So they did have that, and it was presented, so we’ll discuss it a little bit.

The first patients who had had either of the prior TKIs [had a similar] balance as regarding age, except there’s a much stronger male predilection to MTC than you’d see in lung. There were some patients who had up to 7 prior therapies. When you’re looking at [treatment-naive patients], they did lump in some of those patients who had some of the non–TKI-related drugs. So you did have some of those in that; it wasn’t quite as clean.

In the patients who had had either of the prior TKIs, you can see a response rate of 60%, a complete response [CR] of 1.8%, and the remaining being a partial response, and the median duration of response just under 80%. If they had not had 1 of the TKIs the response rate bumped up a little bit to 66%, with a CR of 10%. Now, we did have a higher CR rate, and the partial response of 55%, and the duration of response was a little bit higher at 84%. In this subgroup, the patients who [had a mutation in their tumor and] who were untreated did have slightly higher response rates and durations of response.

[There was] hypertension, but in this case, 20% had grade 3-4, a bit higher than you’d see in some of the other trials and 5% had diarrhea. [Pralsetinib was] FDA-approved specifically in patients who we talked about, in lung, who had RET gene fusion and alterations, and specifically for MTC, and dedifferentiated when they were RET mutated.

[Pralsetinib was] seen in lung or differentiated thyroid cancers, and it was seen in medullary. I think there were 2 instances, but it was only seen in medullary thyroids. Well, pralsetinib had the tumor lysis syndrome.

Is there something that would make you lean in 1 direction or another, or think about this drug, its efficacy, or its toxicity, in a different way?

GHABACH: This is like the early days of EGFR inhibitors where it’s too early to make a distinction and have a preferred agent yet.

NADLER: Would tumor lysis syndrome in an oral drug scare anybody, particularly, if in a patient with MTC? Again, it wasn’t really seen in lung, or differentiated thyroids with this drug, but it was seen in MTC.

GHABACH: Yes, I probably would.

NADLER: I probably would, too. If I started this agent in a patient with MTC, I’d probably bring them back 2 or 3 days later. It’s probably highly effective for that reason, but I would check their labs a few days later. Is there something about 1 of these agents? At least in MTC, a very selective disease, that would point you in 1 direction or another?

GU: When I was going through this case presentation, I was just thinking, “I wish they were doing adjuvant trials.” You look at this particular case, it’s high risk for recurrent disease. So, we have such an effective treatment option, I think. I know it’s hard to run the trial with this rare disease, but it would be best if we could prevent this from getting metastatic and having to deal with it later.

NADLER: I couldn’t agree more. In lung, these trials are ongoing. It’s a great thought, and 1 that I think that we have such effective agents, 1 that should really be explored. That’s a great thought.

KONDURI: Primary disease, from what I know, the place where resection happens for thyroid cancers is the primary area of resection happens for thyroid cancers. Even if the disease is metastatic, you’re looking for a treatment with radioactive iodine. If you have the primary tumor sitting in the neck, then it acts as a sump. It sucks the radioactive iodine in, and therefore you want to have that removed so that it can go off into the metastatic areas and treat. I was not aware of a medullary thyroid carcinoma consideration for resection.

NADLER: I’ve never seen one not resected. The 2 possibilities I could come up with and I can ask our [ear, nose, and throat] colleagues for clarification. The first is, it’s not uncommon for mixed histology, for all of these. I’ve seen differentiated thyroid cancers in medullaries before, where it had different subsets. The second thing that I would toss out is, regarding patients with MTC, you’re really trying to follow the tumor and the level of the tumor marker burden. It’s by far the best way of classifying these. Even if you had an osseous lesion, or 2, or 3, you’d potentially try to resect the bulk of the disease in the neck, maybe irradiate the 1 or 2 spots, and then follow. But, I agree, I had been taught that often you go after the in situ disease.

RAZAQ: I have tried to search that issue when I had that patient, and what I realized is the recommendation is more based on historical data that the majority of metastatic medullary thyroid, when they are diagnosed by that, and their tumor has already been resected. One process could be that many a times with the metastatic MTC, we will observe patients rather than starting treatment right away. If you resect the primary tumor your level will go down, and you can follow that level.

NADLER: I’ve seen metastatic disease where they’ve resected, and I’m not sure. It’s really a phenomenal point, but I’m not sure if with these new selective agents, if that really should be the way we proceed. Our drugs were just very poor, before, and now they’re far, far more effective.

MANDANAS: I have a question. In terms of detecting the RET fusion or mutation, how sensitive is the [circulating tumor] DNA or plasma testing?

KONDURI: From the lung cancer perspective, generally the consideration depends on the burden of the disease. The feeling is that there’s about an 80% sensitivity and specificity, maybe even higher. But the problem is that if you have a localized volume of disease it doesn’t shed into the peripheral blood; you have a problem where you come out with a negative result. Frankly, that is 1 of the main reasons I just don’t jump in and do peripheral blood for a lot of these circumstances. That’s my personal opinion; you can certainly do it both ways, but many a time what you will get out of tissue will be more or less adequate for figuring it out. Now, it’s in the rarer circumstances that you don’t see it. That’s when you fall back on the blood.

The take on the largest of these trials, not just in RET but in consideration for the others, if there is a presence in the blood, you will pick it up. That’s not a problem if there is a presence. The usual presence of a positive finding is generally very specific: You will be able to pick it up and put it.

The problem is when the thing doesn’t shed into the blood. I don’t know if that answers your question, but, relatively, the efficacy of the blood for testing, it is not the problem. In my opinion, it is more the problem that the stuff doesn’t come through.

MANDANAS: For the fusion, what do they use? Do they use FISH [fluorescence in situ hybridization]?

KONDURI: For example, in NGS it’s not a FISH. In NGS they are just going through that fusion, that whole genome, and they’re looking for the various partners. It just goes down the line, just like ALK, just like ROS. So, there’s not FISH.

NADLER: They’re just looking at the primers, exactly. You’d have to use a lot of primers, then.

_REFERENCES

_{1. Hu M, Subbiah V, Wirth LJ, et al. Results from the registrational phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET mutation-positive medullary thyroid cancer (RET+ MTC). Abstract presented at: 2020 European Society of Medical Oncology; September 20-22; virtual. Abstract 19130.}

_{2. FDA approves pralsetinib for RET-altered thyroid cancers. Press release. FDA. December 1, 2020. Accessed August 5, 2021. https://bit. ly/2TVj5t8}