Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial.

Journal Article (Journal Article;Multicenter Study)

PURPOSE: Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS). PATIENTS AND METHODS: Patients with AST received SBRT (30-50 Gy in 3-5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. 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: Sixty-eight 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 multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 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.

Full Text

Duke Authors

Cited Authors

  • Luke, JJ; Onderdonk, BE; Bhave, SR; Karrison, T; Lemons, JM; Chang, P; Zha, Y; Carll, T; Krausz, T; Huang, L; Martinez, C; Janisch, LA; Hseu, RD; Moroney, JW; Patel, JD; Khodarev, NN; Salama, JK; Ott, PA; Fleming, GF; Gajewski, TF; Weichselbaum, RR; Pitroda, SP; Chmura, SJ

Published Date

  • December 15, 2020

Published In

Volume / Issue

  • 26 / 24

Start / End Page

  • 6437 - 6444

PubMed ID

  • 33028595

Pubmed Central ID

  • PMC8561652

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-20-1790


  • eng

Conference Location

  • United States