Outcome and Immune Correlates of a Phase II Trial of High-Dose Interleukin-2 and Stereotactic Ablative Radiotherapy for Metastatic Renal Cell Carcinoma.

Purpose This phase II clinical trial evaluated whether the addition of stereotactic radiotherapy (SAbR), which may promote tumor antigen presentation, improves the overall response rate (ORR) to high-dose IL-2 (HD-IL-2), in metastatic renal cell carcinoma (mRCC). Experimental design Patients with pathologic evidence of clear cell RCC and radiographic evidence of metastasis were enrolled in this single arm trial and were treated with SAbR, followed by HD-IL-2. ORR was assessed based on non-irradiated metastases. Secondary endpoints included overall survival (OS), progression-free survival (PFS), toxicity, and treatment-related tumor-specific immune response. Correlative studies involved whole exome and transcriptome sequencing, T-cell receptor sequencing, cytokine analysis, and mass cytometry on patient samples. Results Thirty ethnically-diverse mRCC patients were enrolled. A median of 2 metastases were treated with SAbR. Among 25 patients evaluable by RECIST-v1.1, ORR was 16% with 8% complete responses. Median OS was 16 months. Treatment-related adverse events (AEs) included 22 grade {greater than or equal to}3 events that were not dissimilar from HD-IL-2 alone. There were no grade 5 AEs. A correlation was observed between SAbR to lung metastases and improved PFS (p=0.0165). Clinical benefit correlated with frameshift mutational load, mast cell tumor infiltration, decreased circulating tumor-associated T-cell clones and T-cell clonal expansion. Higher regulatory/CD8+ T-cell ratios at baseline in the tumor and periphery correlated with no clinical benefit. Conclusions Adding SAbR did not improve the response rate to HD-IL-2 in patients with mRCC in this study. Tissue analyses suggest a possible correlation between frameshift mutation load as well as tumor immune infiltrates and clinical outcomes.