PD-1 Blockade in Anaplastic Thyroid Carcinoma

Abstract

Purpose: Anaplastic thyroid carcinoma is an aggressive malignancy that is almost always fatal and lacks effective systemic treatment options for patients with BRAF-wild type disease. As part of a phase I/II study in patients with advanced/metastatic solid tumors, patients with anaplastic thyroid carcinoma were treated with spartalizumab, a humanized monoclonal antibody against the programmed death-1 (PD-1) receptor.

Methods: We enrolled patients with locally advanced and/or metastatic anaplastic thyroid carcinoma in a phase II cohort of the study. Patients received 400 mg spartalizumab intravenously, once every 4 weeks. The overall response rate was determined according to RECIST v1.1.

Results: Forty-two patients were enrolled. Adverse events were consistent with those previously observed with PD-1 blockade. Most common treatment-related adverse events were diarrhea (12%), pruritus (12%), fatigue (7%), and pyrexia (7%). The overall response rate was 19%, including three patients with a complete response and five with a partial response. Most patients had baseline tumor biopsies positive for PD-L1 expression (n = 28/40 evaluable), and response rates were higher in PD-L1-positive (8/28; 29%) versus PD-L1-negative (0/12; 0%) patients. The highest rate of response was observed in the subset of patients with PD-L1 ≥ 50% (6/17; 35%). Responses were seen in both BRAF-nonmutant and BRAF-mutant patients and were durable, with a 1-year survival of 52.1% in the PD-L1-positive population.

Conclusion: To our knowledge, this is the first clinical trial to show responsiveness of anaplastic thyroid carcinoma to PD-1 blockade.

Trial registration: ClinicalTrials.gov NCT02404441.

FIG 1.

Duration of exposure to spartalizumab and percentage change from baseline in sum of diameters of target lesions, by programmed death-ligand 1 (PD-L1) expression at baseline. (A) Duration of exposure to spartalizumab. Mutant denotes BRAF mutation. (B) Best percentage change from baseline in sum of diameters of target lesions. Thirty-one patients were evaluable for best percentage change; 11 patients were not evaluable because of discontinuation or death before first postbaseline assessment (n = 8) or missing postbaseline assessment (n = 3). Best overall response by RECIST v1.1 is indicated. Where available, BRAF mutation status is indicated. Patient number refers to number in Data Supplement. CR, complete response; DCR, disease control rate [CR + PR + SD]; irRC, immune-related response criteria; NGS, next-generation sequencing; ORR, overall response rate [CR + PR]; PCR, polymerase chain reaction; PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown.

FIG 2.

Overall survival by PD-L1 expression at baseline. NE, not estimable; PD-L1, programmed death-ligand 1.

FIG 3.

Interferon γ (IFNγ) signature, by best percentage change from baseline in sum of diameters of target lesions. Best overall response by RECIST v1.1 is indicated. Data were available for 18 patients. Spearman coefficient, −0.67; 95% CI, −0.9 to −0.3. CR, complete response; PD, progressive disease; PD-L1, programmed death-ligand 1; PR, partial response; SD, stable disease.