Improved survival associated with local tumor response following multisite radiotherapy and pembrolizumab: Secondary analysis of a phase i trial

Jason J. Luke, Benjamin E. Onderdonk, Sandeep R. Bhave, Theodore Karrison, Jeffrey M. Lemons, Paul Chang, Yuanyuan Zha, Tim Carll, Thomas Krausz, Lei Huang, Carlos Martinez, Linda A. Janisch, Robyn D. Hseu, John W. Moroney, Jyoti D. Patel, Nikolai N. Khodarev, Joseph K. Salama, Patrick A. Ott, Gini F. Fleming, Thomas F. GajewskiRalph R. Weichselbaum, Sean P. Pitroda, Steven J. Chmura*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Purpose: Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRTþP) 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 ¼ 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 SBRTþP, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.

Original languageEnglish (US)
Pages (from-to)6437-6444
Number of pages8
JournalClinical Cancer Research
Volume26
Issue number24
DOIs
StatePublished - Dec 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Improved survival associated with local tumor response following multisite radiotherapy and pembrolizumab: Secondary analysis of a phase i trial'. Together they form a unique fingerprint.

Cite this