Frontline Treatment Options in RR-DTC
Dr Brose reviews frontline treatment options for radioiodine-refractory differentiated thyroid cancer (RR-DTC).
Marcia S. Brose, MD, PhD: When we talk about first-line treatment options for RAI [radioactive iodine]-refractory differentiated thyroid cancer, we really have seen a big change in this area just in the last couple of years. Starting almost 10 years ago, we had the approval of the first multikinase inhibitors. The first was sorafenib [Nexavar], which was approved as the starting dose of 400 milligrams twice daily, and then about a year, a year and a half later, lenvatinib [Lenvima] was approved in this setting with a starting dose of 24 milligrams once a day. The interesting thing is, and I’ll talk about which ones I would use and in which order, but those 2 agents, I would say really ruled the therapeutic options for these patients for years. Along the way, more recently, 2 other agents have been approved for RAI refractory based on whether they have either a RET fusion or a track fusion. For RET fusions, 2 agents target RET. One of them is called selpercatinib [Retevmo] and the other one’s called pralsetinib [Gavreto]. If they have a track fusion, we have larotrectinib [Vitrakvi] and entrectinib [Rozlytrek]. I think there are some other ones coming down the pipeline. Those are FDA [Food and Drug Administration]–approved. There are also BRAF inhibitors, which are not FDA approved. In my opinion, those are a little bit further down on the list. The other agent that was recently approved is cabozantinib [Cabometyx], which was approved also for all comers. Now we have 3 agents that are approved for all comers. We have sorafenib and lenvatinib approved in the first-line setting. We have cabozantinib approved in the second-line setting after either lenvatinib or sorafenib. And then we have the handful of other inhibitors that are specific for differentiated thyroid cancers that harbor a particular fusion.
The first thing that you need to know is the fact that sorafenib and lenvatinib are approved for all patients. Even if they have a mutation, if they have a gene fusion, sorafenib and lenvatinib are still indicated for those patients. If you don’t have access to those highly selective inhibitors, you can still treat them with sorafenib and lenvatinib. Now, while we can’t say exactly which one’s better between lenvatinib and sorafenib, we do know that the response rate for the lenvatinib study was quite high and higher than what we were seeing in the DECISION study. Now, this wasn’t a head-to-head, so we can’t say directly that they’re comparable. But the fact that they were a much greater response rate, closer to 60% instead of 20% or actually even 15% or 12%, which was what was seen in the DECISION study tells me that there is a higher response rate with lenvatinib. I think based on this, most patients are started on lenvatinib as the first-line therapy of choice. Some patients for various reasons might be started on sorafenib because of tolerance issues or because of concern over extremely high blood pressure. They might be started on sorafenib because they have an invasive lesion, and we want to shrink it more slowly to try to minimize the risk of fistula formation. Sorafenib still can be used in certain circumstances. But I think, when given most of our patients, I tend to use lenvatinib first. Then in patients who progress on lenvatinib, I would normally go to cabozantinib next because that’s the 1 randomized control trial we have showing activity and responses in patients who have progressed on lenvatinib. We don’t have that same data for sorafenib. And so, unfortunately, sorafenib may be used a little bit less at this point. As I said, in other countries where some of these agents aren’t available, there might be other roles for sorafenib. As far as lenvatinib goes, I would say it’s really the most suitable for the general RAI-refractory patient who’s otherwise healthy, who has maybe 1 or 2 blood pressure medicines, but it’s well-controlled and they’re otherwise doing well. Also, interestingly, we have very good data that says that patients, regardless of their age, do well. Being frail is not by itself a reason to not give lenvatinib, so I would say it depends a little bit on why they’re frail or why you would consider them frail. But I will say I also sometimes can’t predict who will tolerate lenvatinib well, or even sorafenib or cabozantinib for that matter. Sometimes I see somebody, I think, “Oh, you’ll tolerate this just fine.” And they have more trouble. Whereas my frail 70-year-old patient does quite well. What that does say to me is that we need to personalize this. We try to start them on the highest dose that they’ll tolerate, but then we need to watch and see what happens and make sure we stay in close contact with the patient so that we can actually adjust as needed.
This transcript has been edited for clarity.
Case: A 70-Year-Old Woman With Differentiated Thyroid Cancer
Initial presentation
- A 70-year-old woman presents with a painless “lump on her neck.”
- PMH: unremarkable
- PE: palpable, non-tender solitary right-of-the midline neck mass; otherwise unremarkable
Clinical workup and initial treatment
- Labs: TSH WNL
- Ultrasound of the neck revealed a 3.4 cm suspicious right mass arising from the right thyroid; 4 suspicious supraclavicular lymph nodes (LNs), largest 2.2 cm in size.
- Ultrasound-guided FNAB of the thyroid mass and the largest LN confirmed papillary thyroid carcinoma.
- Patient underwent total thyroidectomy with central compartment and right selective neck dissection.
- Pathology: 3.4 cm papillary thyroid cancer arising in the right lobe of thyroid, tall-cell features; extrathyroidal extension present;
- 2 of 6 positive central compartment lymph nodes, largest 1.8 cm
- 4 of 13 right lateral compartment involved nodes largest 2.2 cm in size, positive extra nodal extension.
- StageT2N1aMX; ECOG PS 0
Subsequent treatment and follow-up - She was treated with radioactive iodine 150 millicuries
- Whole body scan showed uptake in the neck, consistent with thyroid remnant but no uptake in the lungs
- Follow-up at 3 months
- TSH 0.2 µU/mL, thyroglobulin 28 ng/mL (negative anti-thyroglobulin antibodies)
- Chest CT scan showed 8 small bilateral lung nodules largest 1.3 cm
- Follow-up CT neck and chest scan 3 months later was notable for 1-2mm growth in several lung nodules and 3 new distinct 9.5 mm lung nodules
- Next-generation sequencing was negative for mutations, rearrangements
- Lenvatinib 24mg po qd was initiated
Case 2: A 57 Year-Old Man With Differentiated Thyroid Cancer
Initial presentation
- A 57-year-old man presents with a solitary nodule on the neck and occasional shortness of breath and intermittent excessive fatigue
- PMH: unremarkable
- PE: palpable, hard and fixed solitary nodule in the anterior neck
Clinical workup and initial treatment
- Labs: TSH 10.3 µU/mL; all others WNL
- Ultrasound of the neck revealed a 2 cm mass near the isthmus of the thyroid; several suspicious lymph nodes ranging from 0.3-2.4 cm in size
- Ultrasound-guided FNAB: confirmed papillary thyroid carcinoma; with nuclear enlargement and nuclear grooves, no colloid seen
- Patient underwent total thyroidectomy with bilateral central neck dissection
- Pathology: 2.1 cm papillary thyroid cancer arising in isthmus of the thyroid, 3 of 7 positive central compartment lymph nodes, largest 1.8 cm, positive extra nodal extension
- StageT2N1MX; ECOG PS 1
Subsequent treatment and follow-up
- He was treated with radioactive iodine 150 millicuries
- Whole body scan showed uptake in the neck; indicative of thyroid remnant
- Follow-up at 3 months TSH 0.2 µU/mL, thyroglobulin 68 ng/mL
- Neck US showed no evidence of residual disease in thyroid bed, no suspicious neck nodes. Chest CT was done: 4 lung lesions that were 0.3 and 0.6 cm in size
- The physician recommended not initiating systemic therapy and putting the patient on active surveillance
Anticipating Novel Options for the RAI-Refractory DTC Armamentarium
May 15th 2023In season 4, episode 6 of Targeted Talks, Warren Swegal, MD, takes a multidisciplinary look at the RAI-refractory differentiated thyroid cancer treatment landscape, including the research behind 2 promising systemic therapy options.
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