COMMENTARY

New Targeted Treatments for Differentiated Thyroid Cancer

Kartik Sehgal, MD; Lori J. Wirth, MD

Disclosures

November 04, 2022

This transcript has been edited for clarity.

Kartik Sehgal, MD: Hello, everyone. I'm Kartik Sehgal. I'm the director of the Thyroid Cancer Center at Dana-Farber Cancer Institute and Brigham and Women's Hospital. I'm very excited today to be joined by my illustrious colleague, Dr Wirth.

Dr Wirth, would you like to introduce yourself?

Lori J. Wirth, MD: Hi, everyone. I'm Lori Wirth. I'm the Elizabeth and Michael Ruane Chair of Endocrine Oncology at Massachusetts General Hospital.

Sehgal: Thanks. Lori. Today, we'll be talking about new targeted treatments for differentiated thyroid cancer. I think it's an exciting time to be working in the field of thyroid cancer with new molecular targets, which have emerged over the course of, approximately, the last decade. When we are talking about differentiated thyroid cancer, we are referring to papillary, follicular, Hürthle or oncocytic, and poorly differentiated thyroid cancer.

The targets that we're hoping to touch upon include the BRAF V600E mutation, seen in about 40%-60% of patients with thyroid cancer. Other targets that we will be talking about include rearrangements or fusions in RET genes, NTRK, and alterations in some other genes, which may provide future prospects.

Dr Wirth, would you like to add to that introduction?

Wirth: I think that it's fair to say that thyroid cancer really has emerged as a poster child for precision oncology in the field. Most of our patients have potentially druggable alterations when they present with advanced thyroid cancer, so the topic is really pertinent to what we do in clinic with our patients every day.

Sehgal: Do you recommend upfront molecular profiling for patients, especially those with radioactive iodine–refractory differentiated thyroid cancer, especially when they are seen in the medical oncology clinic?

Wirth: Absolutely. I think that now, each and every patient should have biomarker testing done when they have advanced iodine-refractory differentiated thyroid cancer. Hopefully it can be done prior to initiating the first-line therapy for patients.

I think there's also an emerging role for doing biomarker testing in patients who have very high-risk disease for recurrence as well in the newly diagnosed, surgical setting.

Sehgal: I would completely agree with that. I have tried my best to incorporate that into our clinical practice by utilizing either the research studies that we have at our institution or through commercially available sequencing platforms. As I'm sure you also see, when we do see patients from some of the other centers, which are, for instance, non-teaching hospitals or private practices, I think we still have some work to do to disseminate that information.

Wirth: Kartik, one thing that I think is worth mentioning along those lines is that it's a difficult decision to know which test to use. Because these gene fusions are seen in so many patients, I think it is important to make sure that when people are ordering biomarker testing that they do just a little bit of homework to make sure that they're using a test that can identify all of the gene fusions that we see in thyroid cancer, including NTRK1, NTRK2, NTRK3, RET fusions, and ALK fusions.

Sehgal: I think you highlighted a very important point about RNA sequencing, especially, because the regular DNA sequencing sometimes can miss some of these important alterations for which we have great therapies.

I think that's a perfect segue into talking about the BRAF V600E mutation. I know you've done a large amount of work in that field, and I would love to hear your perspective on patients whose tumors harbor the BRAF V600E mutation.

Wirth: BRAF V600E is the most common potentially druggable alteration that we see in patients with advanced thyroid cancer. What's very interesting is that BRAF-targeted therapy in iodine-refractory BRAF-mutant papillary thyroid cancer doesn't seem to work quite as well as our standard multikinase inhibitor therapies, particularly lenvatinib.

I think the most important trial was a National Comprehensive Cancer Network (NCCN) multicenter trial that took a look at dabrafenib plus or minus trametinib in these patients, many of whom had received prior therapy, but some patients didn't have any prior therapy. We saw that, whether it was with dabrafenib alone or dabrafenib and trametinib, the response rates weren't nearly as high as what we saw with lenvatinib as first- or second-line therapy.

My take on this is that, even though dabrafenib and trametinib now have a tumor-agnostic approval by the US Food and Drug Administration (FDA) for BRAF V600E–mutant disease, for the most part, we should reserve dabrafenib and trametinib for the second-line setting in patients with BRAF-mutant, progressive, iodine-refractory papillary thyroid cancer because I think that lenvatinib seems to work better.

Sehgal: One of the questions as a follow-up to that, which has often come up in discussion with other colleagues as well, is if we have a patient who is older, relatively frail, not with absolute contraindications to lenvatinib — I think in that case, the answer is a little easier — if it's an older, frail person with multiple comorbidities, but still a candidate for systemic therapy with the BRAF V600E mutation, what's been your practice in terms of starting with lenvatinib? The standard dose is 24 mg. Do you start with a lower dose, or take the targeted therapy approach directed toward BRAF V600E?

Wirth: That has to be a case-by-case decision for sure. There was the analysis that took a look at the older patients in the SELECT trial with lenvatinib that showed that there was an overall survival benefit in patients age 65 years or older, despite the fact that there was crossover from the placebo arm to lenvatinib at the time of progression. That overall survival benefit, I think, is important to keep in mind when we're thinking about older patients.

If the patient doesn't have a definite contraindication to lenvatinib, I would still try to use it. I do think that the data looking at the higher dose vs the lower dose, which show that the lower dose is not noninferior, that the standard 24-mg starting dose is the right dose to use. But you have to use your judgment.

In an older, frail person, of course I'll start with a lower dose than the 24-mg dose to be judicious. I think it is a reasonable approach in patients who are not good candidates for lenvatinib therapy who have a BRAF V600E mutation to use dabrafenib and trametinib in the first line.

Sehgal: That has been my personal approach as well. Any other thoughts in terms of the toxicities for BRAF/MEK-targeted therapy?

Wirth: It's tricky because, often, patients do quite well. Some patients don't really have any treatment-related adverse events at all, as far as I've experienced. But sometimes people really do have trouble, particularly with the syndrome of fever, myalgias, and flu-like symptoms. That's a difficult syndrome to manage. I think it ends up being manageable in most circumstances.

Sehgal: Moving on to targets that are not as common, RET rearrangement is one of the other actionable targets that we look for in patients with thyroid cancer. I can talk about some of the data, and I know you worked on one of the papers published, specifically looking at selpercatinib and another selective RET inhibitor being pralsetinib.

The data for both those selective RET inhibitors come from phase 1 and 2 studies, LIBRETTO-001 and ARROW, respectively, for selpercatinib and pralsetinib, with such impressive response rates. It's so heartening when we see response rates like those. In addition to those response rates, which vary somewhere between [65% and 90%], I would like to highlight the lesser adverse events, relatively speaking.

Between selpercatinib and pralsetinib, Dr Wirth, do you use a guideline or how do you select between those two options? I know there are some adverse event profile differences, pneumonitis being relatively more common with pralsetinib (but again, at ranges of about 5%), and maybe more QTc prolongation being seen with selpercatinib. I would love to hear your thoughts between those two agents if we had to select.

Wirth: Well, of course, we have absolutely no head-to-head comparison between the two, so it's really very difficult to know if one drug is better than the other drug in this setting. I think you highlighted a couple of differences. Another minor difference between the two agents is that you see a little bit more bone-marrow suppression with pralsetinib than is seen with selpercatinib. But I've found that to be very manageable as well.

I think that both drugs really are very good options for patients with progressive RET fusion–positive iodine-refractory differentiated thyroid cancer. Certainly, also in the first line setting. Instead of reserving one of those two drugs and using lenvatinib, cabozantinib, or sorafenib first, I think that the response rates, progression-free survival, and tolerability are really so good that we should not be saving them for second-line therapy.

Sehgal: I would absolutely agree with you. That's been my practice as well. Our other target, NTRK gene fusion, I know you commented on that earlier. I would love to hear your thinking about those targets.

Wirth: I actually like to talk about NTRK in the setting of thyroid cancer often because in the larotrectinib series, for example, the most common adult solid tumor enrolled was thyroid cancer tied with soft-tissue sarcoma. There was a study done with more than 11,000 genotype tumors that [were profiled by] Caris Life Sciences that showed that the highest frequency of NTRK fusions found in solid tumors was in patients with thyroid cancer.

So if you're thinking about NTRK fusion–driven disease, top in your mind, you want to be thinking about thyroid cancer. Both larotrectinib and entrectinib have good activity. The updated data for entrectinib had about [16 patients] with thyroid cancer enrolled.

The response rates with entrectinib are pretty high. The response rates in NTRK fusion–positive differentiated thyroid cancer with larotrectinib are very high, approximately 89%. Both drugs are very well tolerated, and we see quite durable responses. Again, I think that NTRK-specific therapy really should be first-line therapy for these patients.

Sehgal: I absolutely agree with you. The response rates are astounding, and we don't see that often in the field of oncology, where we see such great response rates and relatively well-tolerated drugs.

Between larotrectinib and entrectinib, I'm curious: Because larotrectinib may be a bit more selective inhibitor compared with entrectinib, do you have a preference between the two? I can share my preference. If I see a new patient — and again, I have patients on both these drugs who are doing well — I may tend to favor larotrectinib, given its selectivity for NTRK. I'm curious to hear your thoughts.

Wirth: I agree with you. I came to the same conclusion. Also, in the larotrectinib series, there were more patients treated with thyroid cancer. We just have a bit of a tighter confidence interval around the response rates, for example.

Sehgal: I know we've talked about the targets for which we have approved therapies. Are there other targets that you are excited about for the future, and for the targets that we talked about, for future trials?

Wirth: Well, you mentioned in the introduction [that we would be discussing alterations in some genes, which provide future prospects, such as] the PI3 kinase/mTOR pathway. I think we should touch on that very briefly. I want you to do that.

Sehgal: We have had phase 2 studies with everolimus, which is an mTOR inhibitor, and seen mostly stable disease. The response rates, unfortunately, if you define by RECIST, were 0%-6%.

The stability was seen in up to 60%-70% of the patients, so I have used it in an off-label manner, even though it's not FDA-approved for treatment of thyroid cancer, when there are no other options available, including clinical trials.

Hopefully we can harness this pathway. I think there are many possibilities to explore, including PI3K inhibitors or combinations with some of the targeted therapies with mTOR inhibitors, which is something that I look forward to working on with our colleagues in the field.

Wirth: I agree with you. I think there is something to exploit there. We need to figure that piece out a little bit better in the future.

Sehgal: Thank you so much, Dr Wirth.

Wirth: Thank you so much, Kartik. This was great.

Follow Dr Sehgal on Twitter: @KartikSehgal_MD

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