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. 2018 Jul 11;6(1):68.
doi: 10.1186/s40425-018-0378-y.

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

Priyanka C Iyer  1 , Ramona Dadu  1 , Maria Gule-Monroe  2 , Naifa L Busaidy  1 , Renata Ferrarotto  3 , Mouhammed Amir Habra  1 , Mark Zafereo  4 , Michelle D Williams  5 , G Brandon Gunn  6 , Horiana Grosu  7 , Heath D Skinner  6 , Erich M Sturgis  4 , Neil Gross  4 , Maria E Cabanillas  8
Affiliations

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

Priyanka C Iyer et al. J Immunother Cancer. .

Abstract

Background: Anaplastic 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.

Methods: We 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.

Results: Twelve 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.

Conclusion: In 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.

Keywords: Anaplastic thyroid cancer; Dabrafenib; Immunotherapy; Lenvatinib; Salvage; Thyroid cancer; Trametinib; Undifferentiated.

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Conflict of interest statement

Ethics approval and consent to participate

Approved under IRB protocol PA13–0246.

Consent for publication

IRB approved waiver of consent.

Competing interests

Ramona Dadu is on the advisory board of BMS. MEC has received research funding from Eisai and Genentech. NLB has received research funding from Novartis and consulting fees from Eisai. Other authors have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Waterfall plot demonstrating response to combination of kinase inhibitor therapy and pembrolizumab: A partial response was observed in 5/12 (42%), stable disease in 4/12 (33%) and progressive disease in 3/12 (25%). The box below the patient number describes the PD-L1 status on the tumor tissue
Fig. 2
Fig. 2
Swim lane plot demonstrating time on combination of kinase inhibitor therapy and pembrolizumab: The figure below describes the timeline on combination of kinase inhibitor therapy and pembrolizumab. Patient no. 11 was on trametinib with pembrolizumab. She developed Grade 3 rash on this combination and was switched to everolimus as a single agent. Seven patients (58%) died while on this therapy. Of these, four patients discontinued treatment due to adverse events and opted for hospice. The figure below shows that these patients continued to derive some survival benefit from exposure to this combination therapy and lived for a median of 4.25 months (range 2.29–5.4 months) after discontinuing all treatment for their cancer
Fig. 3
Fig. 3
Overall survival (OS) from start of kinase inhibitor therapy. The figures below describe the median OS from the start of kinase inhibitor (KI) therapy. From the start of KI, the median OS was 10.43 months (95% CI = 6.02, 14.83) for the entire cohort (a). On the basis of type of KI (b), median OS was 7.4 months from the start of dabrafenib plus trametinib (95% CI = 0.43, 14.3), 10.4 months from the start of lenvatinib (95% CI = 7.1, 13.8). The patient on trametinib and pembrolizumab (Patient 11) was alive at the time of data analysis 6.7 months from the start of trametinib
Fig. 4
Fig. 4
Overall survival (OS) after the addition of pembrolizumab. The figures below describe the median OS from the start of pembrolizumab added to their respective kinase inhibitor (KI) therapy. From the date of addition of pembrolizumab, the median OS was 6.93 months (95% CI = 1.7, 12.15) (a). In the patients who were on dabrafenib plus trametinib while on pembrolizumab, the median OS was 3.8 months (95% CI = 2.5, 5.1). Similarly the median OS of the patients who were on the combination of lenvatinib plus pembrolizumab was 8.25 months (95% CI = 5.4, 11.1), from the start of pembrolizumab (b). The patient on trametinib is alive 4.9 months after starting pembrolizumab in addition to her trametinib
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