Future Directions and Unmet Needs in Treating DTC
Marcia S. Brose, MD, PhD, concludes by listing some future directions she’d like to see within the treatment landscape, as well unmet needs that she hopes will be considered.
Marcia S. Brose, MD, PhD: In summary, we’ve made tremendous progress, especially in the last decade, on the treatment of radioactive iodine-refractory differentiated thyroid cancer. We’ve had approvals of 3 agents for all comers: sorafenib [Nexavar], lenvatinib [Lenvima], and most recently cabozantinib [Cabometyx]. We have at least 4 agents: 2 for TRK-fusion cancers and 2 for RET-fusion cancers. Entrectinib [Rozlytrek] and larotrectinib [Vitrakvi], for TRK fusions, and pralsetinib [Gavreto] and selpercatinib [Retevmo], for RET fusions.
The question is where we go next. We’re doing a good job at exhausting and targeting a lot of the mutations. However, there are definitely additional markers associated with poor prognosis, and it would be great if we could target those as well. We haven’t been successful at targeting patients who have NRAS mutations. That area would be great with some of the new RAS inhibitors. If we could find some that actually target NRAS, those patients are an unmet need because they tend to do worse on the multikinase inhibitors.
We’re going to continue to make progress on targeting based on molecular profiles. I’d like to see as much progress made with immunotherapy as with targeted therapy. But unfortunately, in thyroid cancer, immunotherapy has been only an incremental increase. In patients who have no other options, however, adding in immunotherapy, if they have the right criteria, is something we might consider.
Overall, at the end of the day, patients will progress through all the therapies I’ve just described. We’re going to have to consider other options. In the case of TRK-fusion and RET-fusion differentiated thyroid cancer, we have ongoing clinical trials for patients who develop the solvent-front mutations, which confer resistance. Many patients progress after developing those secondary mutations. We may see some progress in having second-line selectively targeted therapies as well.
Those are going forward, but no matter what we have, it’s never enough until all our patients survive their disease and die of something else because they’re so healthy and are living good-quality lives following treatment or during treatment of thyroid cancer.
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
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