Clinical Benefit Achieved With Lenvatinib/Pembrolizumab in Anaplastic Thyroid Carcinoma

Christine Dierks, MD

Lenvatinib (Lenvima) in combination with pembrolizumab (Keytruda) was found to be effective in patients with anaplastic thyroid carcinoma (ATC), according to interim results from the phase 2 ATLEP trial (NCT02973997) presented during the 2021 Annual Meeting of the American Thyroid Association.¹

However, Christine Dierks, MD, noted that in this patient population there were concerns with adverse events (AEs) of aspergillus pneumonia, fistula development, and bleeding complications.

ATCs are typically associated with aggressive tumor growth, increased neoangiogenesis, high PD-L1 levels, and high tumor mutational burden. Thus, ATCs are associated with a poor prognosis.

In a small cohort from the study (n = 8), long-lasting remissions were seen in 50% of the patients treated with lenvatinib and pembrolizumab,² showing a possibly effective option for patients with ATC.

The ATLEP study explored the combination of lenvatinib and pembrolizumab in patients with ATC and poorly differentiated thyroid cancer (PDTC). The trial was expecting to enroll 40 adult patients with blood pressure up to 160/90 mmHg and no prior therapy with lenvatinib for more than 10 days or prior immune checkpoint inhibition. Patients with BRAF V600E mutations were excluded from the study. Those with brain metastasis had to be stable for at least 2 weeks and must have been treated with radiation or surgery. Patients needed to be free of thrombotic events or bleeding complications for 4 weeks prior to treatment.

Participants were treated with 3 different dose levels of daily lenvatinib: 20, 14, and 10 mg, plus 200 mg pembrolizumab in 21-day cycles. Treatment continued until disease progression by immune-related RESPONSE criteria.

The primary end point was objective response rate (ORR) at 3 months and secondary end points included progression-free survival (PFS), disease control rate (DCR), best overall response (BOR), overall survival (OS), and safety.

Thirty-nine patients were screened, including 32 with ATC and 7 with PDTC. However, 3 patients were not evaluable due to no target lesion, removed consent, or an abscess observed before treatment. Dierks noted that the PDTC cohort is being increased.

Among the 36 evaluable patients, the median age was 63.75 (range, 39-82), and 58.3% were men. About one-third of patients had an ECOG performance status of 0 (36.1%) or 1 (38.9%) and 25% had a score of 2. The majority of patients had ATC (80.6%) and stage IVC (97.2%) disease at baseline; the remaining patients had PDTC (19.4%) and stage IVB disease (2.8%). All patients had undergone prior surgery and 83% had also undergone prior cervical radiation therapy and chemotherapy. Additionally, 19.4% received prior radioiodine therapy.

The ORR after 3 months of treatment was 38.5% among the first 26 patients, which comprised all partial responses. Additionally, 57.6% patients achieved stable disease. One patient had progressive disease.

Within 2 years, the BOR included 68.5% among 16 patients with ATC. With 5 additional patients with ATC achieving stable disease (31.5%), the clinical benefit rate was 100%. “All patients here profit from the treatment,” commented Dierks, of the Department of Hematology and Oncology, University of Halle, Germany.

Nearly all patients respond to treatment, Dierks noted, with some degree of tumor reduction from baseline recorded in the majority of patients and about half of the patients achieved 40% or more tumor reduction.

The median PFS was 10 months and the median OS was 11 months in patients with ATC. A quarter of patients had remissions over 20 months. Among patients with PDTC, neither the median PFS nor the median OS was reached at the time of data cutoff.

Of 20 patients, treatment was ongoing in 6 patients; 7 patients had progressive disease and the remaining patients died of other causes. Dierks noted that patients were more commonly first developing complications, such as fistula and cervical bleeding, with progressive disease presenting later after around 8 to 10 months and leading to death.

Grade 3 or 4 AEs were reported in 53% of all 36 patients, including fistula development, arterial hemorrhage, and aspergillus pneumonia in 4 patients each; sepsis, thrombosis, and diarrhea in 3 patients each; lung embolia and autoimmune hepatitis in 2 patients each; and pneumonia and posterior reversible encephalopathy syndrome in 1 patient each.

Dierks commented that aspergillus pneumonia is not typically seen with the lenvatinib/pembrolizumab combination in other indications.

She concluded that a treatment group is being added to the trial to explore lenvatinib at 24 mg daily in combination with standard pembrolizumab.

_References

_{1. Dierks C, Miething C, Klein C, et al. Lenvatinib/pembrolizumab in metastasized anaplastic thyroid carcinoma (ATC): interim results of the ATLEP trial. Presented at: 2021 Annual Meeting of the American Thyroid Association; September 30-October 3, 2021; virtual. Oral abstract 4.}

_{2. Dierks C, Seufert J, Aumann K, et al. Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. Thyroid. 2021;31(7):1076-1085. doi:10.1089/thy.2020.0322}