Risk Stratification Based on Whole Body Tumor Burden can be Key for Refining the Role of Combining Radiation Therapy and Immune Checkpoint Inhibitors in Metastatic Disease

Abstract

<h3>Purpose/Objective(s)</h3> Two recent trials showed conflicting findings of adding RT to immune checkpoint inhibitors (ICI) in unselected patients with metastatic disease. Although the current definition of oligometastatic disease is based on the number of metastases and involved organs, little is known about which quantitative methods (lesion number and sum of 2D or 3D measurements) are suitable for better risk stratification in RT and ICI combination trials. Here, we investigated the clinical utility of different quantitative characteristics of metastatic disease in advanced melanoma patients who received pembrolizumab. <h3>Materials/Methods</h3> 86 patients with metastatic or unresectable malignant melanoma were treated with pembrolizumab between 2015 and 2020. We 3-dimensionally contoured all metastases on available imaging at the time of pembrolizumab initiation. Then, total number of metastases, sum of 10 target lesions per RECIST criteria, 3D volume of total gross tumors and involved organs (liver, lung, brain, and bone) were collected for analysis. The study endpoints included overall survival (OS), progression-free survival (PFS) and PFS-2 (progression after the next line of therapy). <h3>Results</h3> In total, 1049 metastases were contoured and the average number, 2D-tumor size, and 3D-tumor volume of total metastases before treatment initiation were 12±14/patient, 12.8±20.19 cm/patient, and 94±183 cc/patient, respectively. High correlation between the number of metastatic lesions and baseline 2D-tumor size was observed (ρ = 0.90), but moderate correlation was seen between the number of metastatic lesions and 3D-tumor volume (ρ = 0.59). At a median follow-up of 15.9 (range, 1.2-57.0) months, the number of metastatic lesions, 2D-tumor size, and 3D-tumor volume showed significant correlation with OS, PFS and PFS-2 in a continuous manner (e.g., 1-5, 6-10, 11-20 and >20; ≤ 10 cm, 10-20 cm, 20-40 cm and >40 cm; and ≤ 10 cc, 10-30 cc, 30-130 cc and > 130cc, respectively). In multivariate analysis, tumor involvement in liver (hazard ratio [HR] 1.79) and brain (HR 5.52) were independently associated with poor OS along with quantitative characteristics. <h3>Conclusion</h3> Through this hypothesis-generating study, we demonstrated the prognostic value of baseline tumor burden and metastasis locations in metastatic melanoma patients receiving pembrolizumab. Our results are helpful for better risk stratifying and designing clinical study which refines the role of RT in combination with immunotherapy.