Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma

Abstract

Background: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. Patients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14-24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1-90%). Results: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with longterm (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%.

FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale

“…In a recent series of metastatic ATC and PDTC negative for the BRAF V600E mutation, 8 patients received a combination therapy of LEN and PEM for a maximum of 40 months after failing chemotherapy, radiation or radioiodine therapy. The combination treatment was not only well tolerated with 50% (3/6) of ATC patients still on therapy at data cutoff but also led to complete response (CR) in 66% (4/6) of ATC patients after 7, 10 and 12 months and PR in 75% of patients after three to four months of treatment ( 28 ). Range of PD-L1 expression was 1%-90% and patients with a PD-L1 expression greater than 50% (5/8) responded best to combination therapy ( 28 ).…”

“…The combination treatment was not only well tolerated with 50% (3/6) of ATC patients still on therapy at data cutoff but also led to complete response (CR) in 66% (4/6) of ATC patients after 7, 10 and 12 months and PR in 75% of patients after three to four months of treatment ( 28 ). Range of PD-L1 expression was 1%-90% and patients with a PD-L1 expression greater than 50% (5/8) responded best to combination therapy ( 28 ). There was no association of PD-1 expression or frequency of tumor infiltrating lymphocytes (TILs) with treatment response ( 28 ).…”

“…Range of PD-L1 expression was 1%-90% and patients with a PD-L1 expression greater than 50% (5/8) responded best to combination therapy ( 28 ). There was no association of PD-1 expression or frequency of tumor infiltrating lymphocytes (TILs) with treatment response ( 28 ).…”

Poorly Differentiated and Anaplastic Thyroid Cancer: Insights into Genomics, Microenvironment and New Drugs

“…In this series, fatigue, anemia and hypertension were the most common AEs associated with this combination and drug-induced rash and altered mental status (likely related to PD) induced drug interruption [152]. Similarly, Dierks et al showed interesting results about lenvatinib and pembrolizumab combined treatment both in ATC and PDTC: 5/6 patients with ATC reached CR/PR and 2/2 with PDTC obtained PR [153]. Similarly, nivolumab (anti-PD1 antibody) was added to vemurafenib in patients affected by metastatic ATC, obtaining a prolonged response (more than 20 months) [154].…”

PRKAR1A and Thyroid Tumors

“…In addition, multiple clinical trials with VEGF and/or VEGF inhibitor and immune checkpoint inhibitors have been designed. Pemproblizumab plus lenvatinib was investigated in a phase 2 trial for unresectable ATC (NCT04171622) as well as in a randomized study in a small group of advanced ATC and PDTC [162]. The same combination is under study in DTC and PDTC naïve or progressing after lenvatinib patients (NCT02973997).…”