Patient Scenario 3: Treating RR DTC With an Identified RET Fusion


Centering discussion on the final clinical scenario of RR DTC, Francis Worden, MD, highlights the management of a patient with an identified RET rearrangement.


Francis P. Worden, MD: This is a case that interests me. We’re talking about the sequencing of some of the more targeted agents when we have nice responses to agents. They weren’t on the market or even developed when I started seeing this patient. We could perhaps talk about that as well. This is a 51-year-old woman who was previously treated for papillary thyroid carcinoma—a columnar variant—with thyroidectomy. She had a bilateral neck dissection, which was followed by RAI [radioactive iodine]. Upon follow-up, she developed disease progression. She had another iodine scan and was found to be without uptake, so she was deemed to be refractory.

In November 2015, she had a recurrence in her neck and had SBRT [stereotactic body radiation therapy] to 1 particular node in her neck that was causing her a lot of pain. She did well for a while, until July 2017, when she received further treatment with a palliative course of radiation to her mediastinum. She presented with conglomerate lymph nodes, a superior vena cava syndrome, and scattered pulmonary nodules. She had some response to that, but not a complete response. In September 2018, unfortunately, she developed multiple brain metastases and was treated with whole-brain radiation therapy. She did OK until the first part of 2019, when she developed a wrist soft-tissue mass. Because I was concerned that this was probably her disease, I ordered a biopsy. This showed some transformation to this poorly differentiated component of her papillary thyroid carcinoma.

In February of that year, she was enrolled in the ITOG [International Thyroid Oncology Group] study, which Lori and I both participated in. Patients [in the study] were treated with a combination of lenvatinib and pembrolizumab. She was on the arm we treated with both drugs up front. She completed 14 cycles of therapy, during which she had disease progression, primarily in the brain and some in the hilum. With the brain lesions, she was seen by a neurosurgeon and 1 of our radiation oncology specialists and was given SBRT with control of her disease.

In September 2019—at that time we weren’t necessarily getting the NGS [next-generation sequencing] testing or robust RNA sequencing, but they were coming into vogue—we did testing on her and we found that she had a RET gene rearrangement. You can see here the FISH [fluorescence in situ hybridization] RETfusion that is noted, the NCOA4. She was put on selpercatinib 160 mg twice daily. After 4 months of treatment, she developed symptoms of hypertension and had edema in her eyes, which were swollen, and in her lower extremities. The drug was stopped and the doses of selpercatinib were decreased to 80 mg twice daily. Her adverse effects of the drug massively improved, and she was able to tolerate the medication. Today she continues the medication. She had a nice response. All her symptoms of her superior vena cava syndrome have diminished, and she continues on therapy.

Lori J. Wirth, MD: What about in the CNS [central nervous system]? Did she have lesions in the CNS that hadn’t been treated? Did you see a response there? Because in this study there were patients with CNS disease and response scenes, we know that there’s some CNS activity.

Francis P. Worden, MD: That’s a good point. I have a patient with lung cancer who I treated in the LIBRETTO-001 study. I did see that. In this patient, radiation oncologists and neurosurgeons followed her extremely closely. Her disease was primarily treated with stereotactic radiosurgery. Perhaps there was some benefit because we didn’t see growing lesions. But did we see a response to a brain lesion? I’m not so sure.

Marcia S. Brose, MD, PhD: That’s interesting because later on, when we were doing this study, I had a patient who had some small lesions. We didn’t treat them, and they did respond. You make a good point: many of our patients have been around forever before we even knew to do the testing. I have several patients in whom I discovered NTRK fusions or RET fusions after they had first- or second-line therapy. I wouldn’t give it in that order now. But the CNS is another area because we would radiate those all the time.

Francis P. Worden, MD: Absolutely. Had I known what I know now about this patient and if the drugs available, to be perfectly honest, I would have treated her totally differently. I don’t think I even had to entertain the idea of radiation to her brain. It’s amazing what these drugs have done and how patients in the past could have benefited if they were only available when they were alive.

Lori J. Wirth, MD: I’m glad that you had a case with CNS metastases because that’s something that we haven’t paid enough attention to in this patient population. Marcia, when you said these patients are living long enough now, I thought you were going to say that many patients later in the course of their illness—after they’ve been heavily pretreated—will develop CNS metastases. In the LIBRETTO-001 trial, for example, and other studies of advanced thyroid cancer, we see about 10% of patients enrolling with CNS metastases. I used to think that we don’t see brain metastases at all, and we only need to look for brain metastases in select cases. But now I have incorporated ruling out CNS metastases in most of my patients with iodine-refractory advanced thyroid cancer. I do the same for medullary thyroid cancer.

Francis P. Worden, MD: I do too. In fact, before I consider starting a TKI [tyrosine kinase inhibitor], I’ll make sure we have imaging of the brain.

Lori J. Wirth, MD: Yes.

Transcript edited for clarity.

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