Stereotactic Body Radiation Therapy Plus Anti-PD1/IL8 Therapy for Advanced Solid Tumors

Abstract

<h3>Purpose/Objective(s)</h3> Anti-PD-(L)1 immunotherapy improves outcomes for patients across various cancers; however, many patients do not benefit. Previous studies combining multi-site stereotactic body radiation therapy (SBRT) with anti-PD1 have demonstrated feasibility and showed increased interferon signaling after SBRT. Elevated levels of serum IL8 (sIL8) associate with lack of response to anti-PD1 and we have observed that elevated IL8 is strongly associated with lack of response to immunotherapy and SBRT combinations. BMS-986253 is a fully human neutralizing antibody that binds to sIL8. The present study aims to evaluate safety and preliminary efficacy of combining BMS-986253 with nivolumab and SBRT in patients with advanced solid tumors, chiefly melanoma (MEL) and renal cell carcinoma (RCC). <h3>Materials/Methods</h3> This is a phase 1 open label single arm study which will include safety and efficacy cohorts. Patients will receive SBRT to 1-4 metastatic sites in 3 or 5 fractions with a total dose of 30-50 Gy depending on anatomic subsite and dose/fractionation. SBRT treatment planning parameters and organ at risk constraints are based on NRG BR-001 study results. SBRT will be followed by nivolumab (480mg q4 weeks) and IV BMS-986253 (2400mg q2 weeks) within seven days of completing SBRT. In the initial safety portion of the clinical trial, we will include 30 patients with advanced/metastatic solid tumors. The primary endpoint of dose limiting toxicity will be assessed by continual Bayesian monitoring. The toxicities will be attributed to combination of SBRT/immunotherapy as opposed to individual components. After completion of the safety phase, an efficacy phase will be launched. To detect a lower bound of 20% for response rate with a one-sided confidence interval, 20 patients are required. Translational correlatives include paired biopsies pre/post SBRT to interrogate gene expression changes using scRNAseq and bulk RNAseq, TCRseq, PBMC profiling for IL8 gene expression, serum IL8 levels before/during/after combination treatment, and T cell radiomics analyses of irradiated metastases to correlate with clinical outcomes. <h3>Results</h3> The phase I trial is active and recruiting patients. <h3>Conclusion</h3> Blocking IL8 in conjunction with anti-PD1 therapy and SBRT is a rational, biomarker-driven approach that may overcome resistance and broaden immunotherapy benefit in patients for whom anti-PD1 therapy is inadequate. This trial is registered at ClinicalTrials.gov, NCT04572451.