Lori J. Wirth, MD: Let me share this case with you. This is a patient of mine who I met when she was 69 years old. When she was an infant she was treated with radiation for an enlarged thymus. She was followed as an adult for many years for Hashimoto thyroiditis. She had a multinodular goiter. She was also treated for anal cancer in 2010. She noted a new neck mass in 2018. It had an FNA [fine-needle aspiration] that was suspicious for follicular neoplasm. She took an Afirma [gene expression test], which was suspicious for malignancy. She underwent a thyroidectomy, and the pathology showed another poorly differentiated thyroid cancer, at 2.8 cm. It was an insular type that was widely invasive. There was marked vascular invasion, including invasion of large vessels, and significant extrathyroidal extension. It was a nasty-looking tumor. She did get a treatment dose of radioactive iodine [RAI] of 125 mCi. The whole-body scan showed evidence of uptake in a thyroid remnant only.

In June 2020, her thyroglobulin was rising. That prompted a neck and chest CT scan. In the images here, [do you] see that enhancing necrotic mass in the right supraclavicular region? It looks as if it might be embedded in the sternocleidomastoid muscle. She also had small lung nodules. This was consistent with RAI-refractory disease because she had recently had RAI, and there was no uptake in these sites. She underwent a revision neck surgery because that tumor in the neck looked so scary. The pathology confirmed an intramuscular poorly differentiated thyroid cancer with 7 nodes that were also taken being negative.

We did molecular diagnostics at this point. She had a TERT promoter mutation, and she harbored this THADA-IGF2BP3 fusion, which hadn’t been previously described in the oncology literature that we could find. It was classified as of unknown significance but predicted to increase IGF2 protein expression. It could be a driver. It makes a lot of sense in this patient who received radiation therapy in infancy. Lo and behold, she had disease progression in the right neck and the lung nodules, but it was out of proportion, with the neck disease looking a lot worse. She had another revision neck surgery at that point to get that stuff out of there.

At that point, when she recovered from her surgery, we started her on lenvatinib at 24 mg a day. She did develop treatment-emergent hypertension. I started lisinopril, my favorite antihypertensive therapy. She developed treatment-emergent diarrhea with lenvatinib as well. We dose reduced her. She had chemoradiotherapy because of her anal cancer and had a terrible time with proctitis, which was quite difficult to manage. I got GI [gastrointestinal] specialists to help me manage her symptoms. She achieved a partial response on her restaging scans with a decrease in the lung nodules. Her thyroglobulin went down as well. That was in April 2021. However, in August 2021, just a few months later, she experienced disease progression. Unlike most patients on lenvatinib, while she responded, it was a very short duration of response. She was on lenvatinib for only 6 months. She had another revision neck surgery. She then had IMRT [intensity-modulated radiation therapy] to the neck to get control of that threatening locoregional disease.

After she recovered from her radiation therapy, by March 2022, she had a progression of disease in lung nodules as well as in mediastinal and hilar adenopathy. We started her on cabozantinib at 40 mg a day. I started her at 40 mg rather than the 60-mg FDA-approved dose based on the COSMIC-311 study because of the severe proctitis that she had earlier on lenvatinib. She did have mild treatment-emergent diarrhea and mild hand-foot syndrome. She did not develop hypertension on cabozantinib. You can see on her scans that she had a beautiful response, with a decrease in the mediastinal nodes from February to August 2022. She also had a beautiful decrease in thyroglobulin, measuring from 500 to just 7 ng/mL. As of my last visit with her, she remains responding to cabozantinib at 40 mg per day and is tolerating it well. Interestingly, she had a much better response to second-line cabozantinib than she did to first-line lenvatinib, and it has lasted longer as well.

Marcia S. Brose, MD, PhD: You have to wonder if that has to do with the IGF genetic abnormality. You’re probably hitting some of those downstream pathways a little better with cabozantinib, whereas lenvatinib was a little more specific. It’s interesting.

Lori J. Wirth, MD: I’m glad you made that point. I’ve wondered that. We haven’t shown it. We haven’t proved it.

Marcia S. Brose, MD, PhD: Interesting.

Lori J. Wirth, MD: Marcia, thanks for making that point. Ezra, any thoughts about the case?

Ezra Cohen, MD, FRCPSC, FASCO: Yes. I was going to say the same thing.

Marcia S. Brose, MD, PhD: Sorry.

Lori J. Wirth, MD: She stole your good point.

Ezra Cohen, MD, FRCPSC, FASCO: While you were talking about the case, Lori, I searched for cabozantinib and IGF-receptor blockade. There is some evidence that cabozantinib might hit that receptor. The promiscuity of the drug might serve the patient quite well.

Marcia S. Brose, MD, PhD: That’s what I love most about it.

Ezra Cohen, MD, FRCPSC, FASCO: In general, this is an aggressive disease in a patient who requires therapy. No doubt about it. You went through the sequence of therapies exactly as I would have. Using cabozantinib, you’ve gotten a nice response. I hope that response turns out to be durable. But judging from her prior experience with lenvatinib, I suspect she’s going to eventually progress and you’re going to need to think about the next line of therapy. Unfortunately, we don’t have approval for that next line of therapy. Hopefully, you’ll be able to [enroll her in] clinical trials.

Lori J. Wirth, MD: Exactly. But hopefully not for a long time.

Ezra Cohen, MD, FRCPSC, FASCO: The other thing that’s worth pointing out in this patient is the use of external beam radiation to control different parts of the disease. Sometimes with thyroid cancer, we forget that external beam radiation can be quite effective and can treat symptomatic disease, certainly bone disease—not in this case, but in general. I utilize our radiation oncologists in patients like this.

Marcia S. Brose, MD, PhD: The 1 caveat is that I don’t tend to do the full-neck radiation that we’ve done in the past because there’s definitely higher morbidity, probably related to the breakdown of the scar tissue when you start them on cabozantinib later. We saw that a lot with the medullary patients. I’ve had a patient who had a very sad situation with an esophageal cutaneous fistula. It was devastating. Her disease shrank away beautifully, but she ended up dying of the fistula.

With IMRT, you can localize it when you go to the neck. But I try to stay away from radiation to the neck when I can. Of course, local therapy is also a good way to extend the clinical benefit of any of these agents. Whether it’s first-line lenvatinib or second-line cabozantinib, we’ve all had patients who start to progress with only 1 lesion, not the entire disease. We have data from DECISION, SELECT, and other [trials] that if you radiate that disease, you can almost double your progression-free survival [PFS] or get another equal PFS by managing that 1 site. I consider it like my kinase extender. We have a certain number of drugs. This extends or doubles the amount of time I can get clinical benefit.

Lori J. Wirth, MD: I love that point about using radiation for oligoprogressive disease so you can keep the treatment that’s working everywhere else on board as long as possible.

Transcript edited for clarity.