Radiotherapy and pembrolizumab: Improved survival associated with local tumor response following multi-site

Improved survival associated with local tumor response following multi-site radiotherapy and pembrolizumab: secondary analysis of a phase I trial:

Purpose: Multi-site stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (AST). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS). Experimental Design: Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to 2-4 metastases followed by pembrolizumab (200mg IV every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65cc. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial-coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11-matched) prior to pembrolizumab and were analyzed via RNA microarray. Results: 68 patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On MVA, TMC was independently associated with a reduced risk for death (hazard ratio, 0.36; 95% CI, 0.17-0.75; P=0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T cell genes and irradiated tumor response. Conclusions: In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.