Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma

Abstract

BackgroundAnaplastic thyroid carcinoma (ATC) is a rare but deadly form of thyroid cancer. Kinase inhibitors kinase inhibitors have shown clinical efficacy in the management of ATC, however, eventually these tumors acquire resistance to KI and patients succumb to their disease. Salvage therapy in this setting is limited. As ATC tumors diffusely express the programmed cell death protein ligand (PD-L1), anti- programmed cell death protein (PD-1) drugs such as pembrolizumab offer therapeutic potential. We sought to explore the efficacy of adding pembrolizumab to kinase inhibitors at progression in ATC.MethodsWe retrospectively reviewed the charts of ATC patients initiated on pembrolizumab in combination with KI at the time of progression on kinase inhibitors at MD Anderson Cancer Center between August 2016 and August 2017. Efficacy was evaluated with best overall response (BOR) using RECISTv1.1 criteria. Progression free survival (PFS) from the start of pembrolizumab and overall survival (OS) from the start of kinase inhibitors, as well as from the time of addition of pembrolizumab were calculated.ResultsTwelve patients were treated with combination kinase inhibitors plus pembrolizumab at the time of progression on their KI therapy. Median age at initiation of pembrolizumab was 60 years (range 47–84 years). BOR was as follows: 5/12 (42%) had partial response, 4/12 (33%) had stable disease and 3/12 (25%) had progressive disease. Median OS from the start of kinase inhibitor was 10.43 months (95% CI = 6.02, 14.83, range 5.4–40 months). Median OS and PFS from the addition of pembrolizumab were 6.93 months (95% CI = 1.7, 12.15, range 3–15.9 months) and 2.96 months (95% CI = 2.2, 3.7, range 0.57–13.14 months), respectively. Fatigue, anemia and hypertension were the most common AEs encountered on these combinations. Therapy had to be discontinued in 2 patients due to drug induced rash and altered mental status likely from progression of disease.ConclusionIn a subset of ATC patients, pembrolizumab may be an effective salvage therapy added to kinase inhibitors at the time of progression on these drugs. However, better treatment strategies aimed at incorporating immunotherapy in patients with ATC should be explored. Frontline combination of KI with immunotherapy should be studied in prospective clinical trials.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0378-y) contains supplementary material, which is available to authorized users.

Do we need PD‐L1 as a biomarker for thyroid cytologic and histologic specimens?

“…Therefore, there is a need for new treatment modalities, including targeted therapies and/or immunotherapies, mostly for patients who have advanced and/or poorly differentiated/undifferentiated cancers. More treatment options are available since the approval of kinase inhibitors; however, despite being effective, the duration of response to kinase inhibitors is limited, and disease ultimately progresses . To date, fine‐needle aspiration (FNA) cytology (FNAC) represents the main diagnostic tool for the evaluation of thyroid nodules.…”

“…In a retrospective study from The University of Texas MD Anderson Cancer Center, 12 patients with ATC received pembrolizumab in combination with kinase inhibitors at the time of disease progression. Of these patients, 5 had a partial response, 4 had stable disease, and 3 had progressive disease . A recent phase 1b study of pembrolizumab monotherapy in 22 patients with PD‐L1–positive, advanced differentiated thyroid cancer showed that only 2 patients had confirmed partial responses lasting 8 and 20 months, respectively .…”

“…1,21 Preclinical studies have PD-L1 Biomarker for Thyroid Specimens/Pusztaszeri et al demonstrated the efficacy of PD-1/PD-L1 axis blockade in limiting the growth of ATC-derived cell lines injected into mice, 1 but data from clinical trials with anti-PD-1/PD-L1 drugs for aggressive thyroid cancers have been limited and rather disappointing. 1,[6][7][8] In a retrospective study from The University of Texas MD Anderson Cancer Center, 12 patients with ATC received pembrolizumab in combination with kinase inhibitors at the time of disease progression. Of these patients, 5 had a partial response, 4 had stable disease, and 3 had progressive disease.…”

“…Of these patients, 5 had a partial response, 4 had stable disease, and 3 had progressive disease. 8 A recent phase 1b study of pembrolizumab monotherapy in 22 patients with PD-L1positive, advanced differentiated thyroid cancer showed that only 2 patients had confirmed partial responses lasting 8 and 20 months, respectively. 6 Finally, the results from a phase 2 study of pembrolizumab combined with chemoradiotherapy as initial treatment for ATC were published in October 2019.…”

“…More treatment options are available since the approval of kinase inhibitors; however, despite being effective, the duration of response to kinase inhibitors is limited, and disease ultimately progresses. 8 To date, fine-needle aspiration (FNA) cytology (FNAC) represents the main diagnostic tool for the evaluation of thyroid nodules. However, from 20% to 30% of thyroid FNACs are cytologically indeterminate.…”