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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-γ-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 dose-limiting 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.

Author information

Luke JJ1, Lemons JM1, Karrison TG1, Pitroda SP1, Melotek JM1, Zha Y1, Al-Hallaq HA1, Arina A1, Khodarev NN1, Janisch L1, Chang P1, Patel JD1, Fleming GF1, Moroney J1, Sharma MR1, White JR1, Ratain MJ1, Gajewski TF1, Weichselbaum RR1, Chmura SJ1.
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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, Mark J. Ratain, Thomas F. Gajewski, Ralph R. Weichselbaum, and Steven J. Chmura, The University of Chicago, Chicago, IL; Julia R. White, The Ohio State University, Columbus, OH.