Abstract LB_C12: Alisertib and pembrolizumab in Rb-deficient head and neck squamous cell carcinomas (HNSCC)

Abstract

Preclinical studies demonstrate that cancers with retinoblastoma (Rb) loss are dependent upon Aurora kinases for survival. Additionally, our lab demonstrated that human papilloma virus (HPV)+ cancer cells, in which the viral E7 leads to Rb degradation, undergo apoptosis and immunogenic cell death when treated with the Aurora kinase A inhibitor alisertib (Ali) supporting the clinical combination of pembrolizumab (P) and Ali. All patients received 200mg P every 21d in combination with Ali. Ten advanced solid tumor patients were treated in the phase I portion with the recommended phase II Ali dose of 40mg PO BID for 7d every 21d. There were no objective responses, but one phase I patient previously treated with P remains on therapy with stable disease (SD) for >2 years. The phase II study enrolled 14 patients with immunotherapy- and platinum- resistant HPV+ HNSCC. There were no objective responses, but 7 patients had SD: 3 of them for >10 months. PDL1 expression did not correlate with progression free survival (PFS, p=0.59). The median OS has not been reached. The median PFS was 1.4 months. Toxicities were as expected. Ali caused cytopenias that lead to dose reductions in 2 patients on the phase II trial at cycles 13 and 16. P had to be discontinued in one patient due to elevated liver function tests. Pharmacokinetic (PK) analysis for Ali was performed on cycle 1, d1 and d7 in 12 phase II patients. On d7, PK parameters increased with an accumulation index of 1.54. With limited sampling over the dosing interval, the mean values were: Cmax of 688 and 1300 ng/mL; ahalf-life 4.6 and 7.7 hours; estimated trough concentration at end of dosing period C12 of 278 and 512 ng/mL; and area under the concentration-time curve (AUC0-12) of 3754 and 9738 ng*h/mL on d1 and d7 respectively. These values were similar to prior findings with Ali indicating no drug interactions with P. Cell-free plasma was collected at baseline and every 2 cycles then subjected to a multiplex assay using antibody-coated beads and a fluorescent detection system for simultaneous quantification of 20 immune markers. Higher levels of IL-17 and pronounced increases in the levels of TH2 cytokines IL-10 and IL-4 along with the pro-inflammatory cytokine IL-1β in the in the pretreatment plasma correlated with poor outcome. Levels of cytokines representative of TH1 responses (e.g., IL-12, IFNγ) were not different between those 3 patients with prolonged SD vs. others. Analysis of the HPV ctDNA, ELISpot, and multi-color flow cytometry for phenotypic and functional characterization of lymphocyte/myeloid cells are underway and will be presented. Although there were no objective responses, the combination of Ali and P was well tolerated and led to prolonged SD in patients who had previously progressed on immunotherapy supporting our hypothesis that Aurora A inhibition can reverse immunotherapy resistance in Rb-deficient HNSCC. Additionally, an imbalance of cytokine response favoring TH2 and TH17 over TH1 immunity predicts poor outcome in HPV+ HNSCC patients treated with Ali and P.

Citation Format: Faye M Johnson, Madison P O'Hara, J Jack Lee, Yun Qing, Hai Tran, Soma Ghosh, Lacin Yapindi, Peixin Jiang, Alexandre Reuben, George Blumenschein, Jagannadha Sastry. Alisertib and pembrolizumab in Rb-deficient head and neck squamous cell carcinomas (HNSCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C12.