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Phase I/II Study of the Aurora Kinase A Inhibitor Alisertib and Pembrolizumab in Refractory, Rb-Deficient Head and
Faye M Johnson1,2, Madison P O'Hara1,2, Lacin Yapindi1
1Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Purpose:
Effective therapy for recurrent head and neck squamous cell carcinoma (HNSCC) that is refractory to chemotherapy and immunotherapy is a considerable need. Aurora kinase A inhibition leads to apoptosis and immunogenic cell death in preclinical models of human papilloma virus (HPV)-driven cancers.
Patients And Methods:
Alisertib was administered orally twice daily on days 1-7 and pembrolizumab on day 1 of a 21-day cycle to adults with advanced solid tumors (phase I) or with immunotherapy- and platinum-resistant, HPV-positive HNSCC (phase II).
Results:
The recommended phase II alisertib dose was 40 mg, which had only the expected toxicity including cytopenia that led to dose reductions in two phase II patients at cycles 13 and 16. We saw no objective responses, but the combination led to prolonged stable disease (SD) in several patients, including two of 10 phase I patients (8 and 27 months). Eight of the 15 HPV-positive patients had SD, of which four (heavily pretreated) had ≥6 months, with median overall and progression-free survival durations of 16.8 and 1.4 months, respectively. In circulating immune cells and plasma, patients with SD had markedly higher levels of HLA de novo resistance-expressing NK cells than did progressive disease patients who demonstrated a more immunosuppressive and inflammatory profile. Pharmacokinetics did not indicate any significant drug-drug interactions between pembrolizumab and alisertib.
Conclusions:
The combination of alisertib and pembrolizumab was well tolerated and led to prolonged SD in some immunotherapy-resistant patients, supporting our hypothesis that Aurora kinase A inhibition can reverse immunotherapy resistance of retinoblastoma protein-deficient HNSCC.
Insights
This study investigated alisertib and pembrolizumab for recurrent head and neck squamous cell carcinoma (HNSCC). The combination showed prolonged stable disease in some patients, suggesting Aurora kinase A inhibition can overcome immunotherapy resistance.
Area of Science:
- Oncology
- Immunotherapy
- Head and Neck Cancer Research
Background:
- Recurrent head and neck squamous cell carcinoma (HNSCC) refractory to chemotherapy and immunotherapy presents a significant therapeutic challenge.
- Aurora kinase A inhibition has shown potential in preclinical models for inducing apoptosis and immunogenic cell death in human papilloma virus (HPV)-driven cancers.
Purpose of the Study:
- To evaluate the safety and efficacy of combining alisertib (Aurora kinase A inhibitor) with pembrolizumab in patients with advanced solid tumors and immunotherapy-resistant, HPV-positive HNSCC.
- To test the hypothesis that Aurora kinase A inhibition can reverse immunotherapy resistance in retinoblastoma protein-deficient HNSCC.
Main Methods:
- A phase I/II clinical trial was conducted, administering alisertib orally and pembrolizumab intravenously in 21-day cycles.
- Patients included those with advanced solid tumors (Phase I) and those with immunotherapy- and platinum-resistant, HPV-positive HNSCC (Phase II).
- Recommended Phase II dose of alisertib was determined, and toxicity, pharmacokinetic interactions, and clinical responses were assessed.
Main Results:
- The combination was well-tolerated, with expected toxicities such as cytopenia requiring dose reductions in some patients.
- No objective responses were observed, but prolonged stable disease (SD) was achieved in several patients, including those with HPV-positive HNSCC (8 of 15 patients).
- Patients with SD exhibited higher levels of HLA de novo resistance-expressing NK cells compared to those with progressive disease, who showed a more immunosuppressive profile. No significant drug-drug interactions were detected.
Conclusions:
- The combination of alisertib and pembrolizumab demonstrated tolerability and induced prolonged stable disease in a subset of immunotherapy-resistant HNSCC patients.
- These findings support the hypothesis that Aurora kinase A inhibition can overcome immunotherapy resistance in retinoblastoma protein-deficient HNSCC.
- The observed immune profiles in patients with stable disease warrant further investigation into mechanisms of resistance and response.
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