Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors

Jason J. Luke, Jeffrey M. Lemons, Theodore G. Karrison, Sean P. Pitroda, James M. Melotek, Yuanyuan Zha, Hania A. Al-Hallaq, Ainhoa Arina, Nikolai N. Khodarev, Linda Janisch, Paul Chang, Jyoti D. Patel, Gini F. Fleming, John Moroney, Manish R. Sharma, Julia R. White, Mark J. Ratain, Thomas F. Gajewski, Ralph R. Weichselbaum, Steven J. Chmura*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

240 Scopus citations

Abstract

Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1-treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre-and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-g-induced gene expression. Results A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT. Patients included in the analysis were treated with SBRT and at least one cycle of pembrolizumab. Most (94.5%) of patients received SBRT to two metastases. Median follow-up for toxicity was 5.5 months (interquartile range, 3.3 to 8.1 months). Six patients experienced doselimiting toxicities with no radiation dose reductions. In the 68 patients with imaging follow-up, the overall objective response rate was 13.2%. Median overall survival was 9.6 months (95% CI, 6.5 months to undetermined) and median progression-free survival was 3.1 months (95% CI, 2.9 to 3.4 months). Expression of interferon-γ -associated genes from post-SBRT tumor biopsy specimens significantly correlated with nonirradiated tumor response. Conclusion Multisite SBRT followed by pembrolizumab was well tolerated with acceptable toxicity. Additional studies exploring the clinical benefit and predictive biomarkers of combined multisite SBRT and PD-1-directed immunotherapy are warranted.

Original languageEnglish (US)
Pages (from-to)1611-1618
Number of pages8
JournalJournal of Clinical Oncology
Volume36
Issue number16
DOIs
StatePublished - Jun 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors'. Together they form a unique fingerprint.

Cite this