TKIs Continue to Improve the Treatment Paradigm for RAI-Refractory DTC

Warren C. Swegal, MD

With the availability of lenvatinib (Lenvima) and the promise being shown with cabozantinib (Cabometyx), the future of treatment for radioactive iodine-refectory (RAI) differentiatedthyroid cancer (DTC) looks promising, according to Warren C. Swegal, MD.

The findings supporting the use of the tyrosine kinase inhibitor (TKI) lenvatinib come from the SELECT trial (NCT01321554).¹ In SELECT, lenvatinib was compared with placebo, and showed a progression-free survival (PFS) advantage along with good responses. The median PFS was 18.3 months with lenvatinib vs 3.6 months with placebo (HR, 0.21; 99% CI, 0.14-0.31; P <.001). The response rate observed with lenvatinib was 64.8% compared with 1.5% among patients who received placebo (P <.001). Safety wise, the toxicities associated with lenvatinib were considerable, but manageable with either dose modification or adding another medicine.

Cabozantinib is not FDA-approved, but has demonstrated promise in the COSMIC-311 trial (NCT03690388) of cabozantinib vs placebo.² This study also showed a PFS advantage for the TKI, with the median PFS being not reached (96% CI, 5.7–not estimable [NE]) with cabozantinib vs 1.9 months (1.8–3.6) with placebo (HR, 0.22 (96% CI, 0.13-0.36; P <.0001). The safety findings from COSMIC-311 showed that there were serious treatment-related adverse events in 16% of patients vs only 2% who received placebo.

The belief is that one day, these TKIs will be interchangeable in patients with RAI-refractory DTC who are heavily-treated. Swegal of Allegheny Health Network (AHN) said, “the sense I get is that it's clinician dependent. It's up to the medical oncologist when you dig into, which drug is better.”

In the interview, Swegal, a head and neck cancer surgeon at AHN, takes a deep dive into the RAI-refractory DTC treatment armamentarium, and predicts the role of key agents in the near future.

TARGETED ONCOLOGY: What update can you give of therapies available to treat RAI-refractory thyroid cancer?

SWEGAL: Of the vast numbers of papers out there looking at thyroid cancer, only a small set are truly related to radioactive iodine-refractory, and out of those, first-line treatment as designated by the NCCN is really surgery if it’s local disease or regional disease. That tends to be the first option. If surgery isn't an option, you can always consider external beam radiation in order to slow down disease progression, or other ablative techniques, such as alcohol ablation or radiofrequency ablation all to get rid of that regional or local disease.

However, for disease that is non-resectable, or metastatic, where surgery is not an option, and radioactive iodine isn't an option, [we use] systemic therapies. The NCCN says to consider thyrotropin suppression using high doses of levothyroxine. That can slow down disease progression. Then, that's where some of the other systemic options become available, and these are things like lenvatinib.

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How would you define the role of lenvatinib right now in RAI-refractory disease? What are the most recent data showing?

This is a newer therapy. I can say when I was in med school, it was not around yet, or at least it was being developed. As of right now, for those patients with radioactive iodine-refractory differentiated thyroid cancer and systemic disease, lenvatinib is the preferred or category-1 level of evidence recommended by the NCCN. This is the first tool in the bag for a lot of medical oncologists. Much of that is based on the recent trials, specifically the SELECT trial, which was done a couple of years ago.

SELECT is a phase 3 trial, placebo-controlled trial where they compared lenvatinib [with] placebo. It showed that for younger patients, there was better progression-free survival, and for older patients, there was better overall survival compared with placebo. Follow-up studies to that looking at a kind of retrospective use of the drug have shown similar, somewhat variable progression-free survival compared [with] that. But again, the results confirmed what the SELECT trial showed.

Cabozantinib is also a drug used often in the RAI disease setting. Can you discuss the promising data with this drug in the COSMIC-311 study?

This is second-line when you consider systemic therapies. This is for patients who have failed sorafenib [Nexavar]. The COSMIC-311 study was another phase 3, placebo-controlled trial, which looked at patients who have failed at first-line treatment, and then we're given either cabozantinib or placebo. Again, for those patients, the patients receiving the drug had a better overall and progression-free survival than those who received placebo. For those who have failed that first-line, it is a good second-line option.

Considering the newly available options, do you think that sorafenib still has a role in this space?

The sense I get is that it's clinician dependent. It's up to the medical oncologist when you dig into which drug is better. The studies are overall very close. There aren't many head-to-head studies, but there was recently 1 which showed that lenvatinib may have a slightly higher progression-free survival rate than sorafenib, but may potentially have increased toxicity rates. While I think a lot of people feel more comfortable using lenvatinib, I think it's still a little bit of a clinician preference.

Cabozantinib has been granted a breakthrough therapy designation by the FDA for RAI-refractory DTC. What could be the impact of a future FDA approval of cabozantinib for this indication?

This designation already means it's a promising drug. Usually, drugs that don't have a lot of promise or a lot of excitement behind them usually don't get this explanation. Already, that kind of labeled it as, hey, this is the next thing. I think 1 thing is that it'll hopefully help speed up the process of an FDA approval to it also does mean there's probably some increased scrutiny around it. We want drugs to be well-tested.

But it also means that once there is clear FDA approval, it may bump it up in that treatment line. Now, we’re going to start looking at it as maybe a first-line treatment or using it in combination with other drugs. It opens the door for it to be used in a wider range of disease in patients.

As you alluded to, the safety of TKIs is an important topic. What can you say about these safety profile of some of the TKIs available for RAI-refractory DTC?

In general, TKIs are considered safer than standard chemotherapy drugs, which can have a lot of significant toxicities. There are some important things to think about with regard to TKIs. Gastrointestinal [adverse] effects are pretty common. For example, things like diarrhea are seen often. Hypertension is also very common. Sometimes up to 70%-75% of patients experience hypertension on a TKI, depending on the study. Things like weight loss secondary to anorexia can be seen in a significant portion of patients, and then you can also have some hand, foot, and skin reactions with some of these medications that that can vary with regard to grade. I do also have to say alopecia and mucositis can occur.

What are some of the unmet needs for the treatment of RAI-refractory DTC?

The lucky thing about RAI-refractory disease is that this is a small portion of patients. Most patients are treated with surgery or radioactive iodine after surgery. That being said, these are often patients are in their fourth- or fifth-line treatment and who are still dealing with the disease. Yes, it's not terribly aggressive, or in some cases can be, we’re kind of running out of options. That is why all of these new systemic therapies, while they are new, have a lot of excitement and promise. These are patients who have kind of run out of options. A magic bullet is always what we need, but those are always hard to find. I think right now what we need for radioactive iodine-refractory cancer is either a single or combination medicine that can treat that entire range of patients or something that can, in a sense, turn back the clock and reset that iodine sensitivity.

_REFERENCES:

_{1. Tahara M, Kiyota N, Hoff AO, et al. Impact of lung metastases on overall survival in the phase3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer. 2021;147:51-57. doi:10.1016/j.ejca.2020.12.032}

_{2, Brose M, Robinson B, Sherman SI, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):P1126-1138. doi:10.1016/S1470-2045(21)00332-6.}