Post Hoc and Real-World Analyses Explore Benefit of Lenvatinib in DTC

Lori J. Wirth, MD

Medical Director, Center for Head and Neck Cancers

Massachusetts General Hospital

Professor of Medicine

Harvard Medical School

Boston, MA

Targeted Oncology:Could you describe the post hoc analyses from the SELECT trial (NCT01321554) of lenvatinib (Lenvima) in differentiated thyroid cancer (DTC)?

Lori Wirth, MD: In terms of overall survival [OS]…and the difficulty in looking at it because this is a randomized crossover design, when we looked at the overall survival based on objective response, patients who were responders to lenvatinib did have improved OS compared with patients who didn't respond [median, 52.2 months vs 19.0 months; HR, 0.32; 95% CI, 0.23-0.46]. But that's not a surprise.¹

What was perhaps a little bit more interesting is the analysis that was done looking at OS based on baseline tumor burden, and I thought that this was food for thought. When we did that, what we found was that patients who were randomly assigned to lenvatinib vs placebo who had a lower tumor burden had a significant improvement in OS when they had RECIST measurement of 4 cm or less compared with patients who had a higher volume of disease [median OS, not estimable for lenvatinib vs 41.0 months for placebo; HR, 0.39; 95% CI, 0.21-0.73]. I felt that that was interesting because what it seems to imply is that patients will do better with lenvatinib when they have a lower tumor burden at the time of initiating therapy, suggesting that you might not want to wait as long as possible before initiating therapy.

We also took a look at how patients with lung metastases do, and in this analysis, the Kaplan Meier curves show OS for patients on lenvatinib compared with those receiving placebo who had lung metastases that were 1 cm in size or larger. Even though a vast majority of patients randomly assigned to placebo crossed over and received lenvatinib, in these patients with lung metastases, they still have OS benefit that's statistically significant, even though the majority of those patients given placebo did cross over and receive lenvatinib [HR, 0.63; 95% CI, 0.47-0.85; log-rank P = .0025].²

The forest plot shows that the OS benefit holds up when we looked at larger lung metastases as well. So in my mind, the take-home of this analysis was that patients with lung metastases, which are very common in metastatic DTC, can have an OS benefit with lenvatinib when they have lung metastases even as small as 1 cm in size.

What real-world data support the use of lenvatinib in DTC?

There was recently a real-world evidence analysis with lenvatinib that was published by Francis P. Worden, MD.³ What this study did was capture up to 5 cases from physicians across the country and received data on patients with radioactive iodine–refractory DTC who were treated with lenvatinib. More than 300 patients were analyzed here. The patient characteristics in this real-world patient population were very similar to the patients who were enrolled in the SELECT trial.

What was a bit of a surprise to me in the real-world data was that most of the patients did start at the 24-mg starting dose, though there were 38% of patients that started at a lower starting dose. What we saw in this real-world evidence analysis was that many of the patients were able to be maintained at their initial starting dose, and perhaps even a higher percentage than expected. Overall, the median duration of treatment with lenvatinib was 17.5 months in this real-world analysis.

In terms of response, a response was not all per RECIST 1.1; it was investigator determined, but the response rates were quite high, with an overall response rate of 72% in the real-world analysis. In terms of disease control, almost 91% of patients had disease control on lenvatinib.³

There was a PFS rate in this real-world patient population [of greater than 50%]. That was surprising at 48 months, which is even a little bit longer than was seen in the SELECT trial, and the median OS had not yet been reached.

How did mutations affect outcomes in the real-world population?

One question is whether BRAF V600E mutations are the most common mutation in papillary thyroid cancer. Papillary thyroid cancers are the most common advanced DTC that we see. So should we be using lenvatinib in the first line in these patients who harbor BRAF V600E mutations, or should we be using dabrafenib [Tafinlar] and trametinib [Mekinist]? A real-world database took a look at how patients in the real-world group of patients who had BRAF V600E mutations did on lenvatinib. The BRAF-mutant patient population was similar to the BRAF wild-type or BRAF-unknown patients [in terms of staging and other baseline characteristics].⁴

The BRAF-mutated patients did better in terms of PFS as well as OS than the BRAF wild-type patients. This [analysis] shows the numbers for patients with BRAF-mutated disease vs BRAF wild-type disease in terms of median PFS and median OS, [also showing slight benefit for the BRAF-mutated group].

_References:

_{1. Kiyota N, Tahara M, Robinson B, et al. Impact of baseline tumor burden on overall survival in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib in the SELECT global phase 3 trial. Cancer. 2022;128(12):2281-2287. doi:10.1002/cncr.34181}

_{2. Tahara M, Kiyota N, Hoff AO, et al. Impact of lung metastases on overall survival in the phase 3 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}

_{3. Worden F, Rajkovic-Hooley O, Reynolds N, Milligan G, Zhang J. Real-world treatment patterns and clinical outcomes in patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) treated with first line lenvatinib monotherapy in the United States. Endocrine. 2024;84(2):663-669. doi:10.1007/s12020-023-03638-7}

_{4. Worden FP, Wirth LJ, Reynolds N, et al. Patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) with BRAF V600E and/or K601E mutation status: A real-world view of effectiveness of lenvatinib monotherapy. J Clin Oncol. 2024;42(suppl 16):6098. doi:10.1200/JCO.2024.42.16_suppl.6098}