A Pilot Study of Radiation Therapy in Combination With Pembrolizumab in Patients With Metastatic Renal Cell Cancer Jianqing Lin, MD, Andrew J. Song, MD, Jean Hoffman-Censits, MD, Benjamin E. Leiby, PhD, Madalina Tuluc, MD, Colette Shaw, MD, Larry Harshyne, PhD, RhondaKean, Voichita Bar-Ad, MD, Robert B. Den, MD, Mark D. Hurwitz, MD, Jennifer Louie, Sherin Philipose, Sandeep P. Deshmukh, MD, Jennifer M. Johnson, MD, PhD, Adam P. Dicker, MD, PhD, Douglas C. Hooper, PhD, William K. Kelly, DO, and Bo Lu, MD, PhD Objectives: There is no study published regarding the benefit of radi- ation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immu- nomodulatory activity of RT alone or in combination with pem- brolizumab in solid tumors. Materials and Methods: mRCC patients were treated with a combi- nation of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Results: Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥ 3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to non- responders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92). Conclusion: Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single- agent nivolumab. Key Words: radiation therapy, pembrolizumab, metastatic renal cell cancer, combination therapy (Am J Clin Oncol 2019;00:000–000) I mmunotherapy has been an important option for the treatment of metastatic renal cell cancer (mRCC), but was not widely adopted until the discovery of immune checkpoint inhibitors (ICIs). Nivolumab gained regulatory approval for mRCC patients who progressed on prior tyrosine kinase inhibitors (TKIs) with a response rate of 25%. 1 Therefore, novel agents and treatment modality are highly needed to improve outcomes beyond single-agent ICI. Immunotherapy combined with radiation therapy (RT) is a relatively new treatment modality that has emerged for various diseases, and sequential therapy is now considered the standard of care for locally advanced non–small cell lung cancer. 2 Preclinical data showed that RT-induced upregulation of programmed death-ligand 1 (PD-L1) expression in tumor and infiltrating immune cells and that the combination with ICI synergistically promoted antitumor immunity. 3 A recent phase I study with 24 patients, of which 2 patients were renal cell cancer (RCC) patients, utilized upfront hypofractionated radiotherapy followed by pembrolizumab. This trial showed a well-tolerated safety profile with no grade ≥ 3 treatment- related adverse events (AEs). One RCC patient achieved a complete response (CR) on imaging and the other had stable disease (SD) for 7 months. 4 Our primary hypothesis was that radiation-induced tumor immunity may be augmented with ICI to break immune tolerance. Combining RT with immunotherapy may yield potentially syner- gistic systemic/abscopal antitumor effects and achieve better and sustained disease control. We also hypothesized that different RT doses and schedules, and sequencing of RT before and after ICI may generate different immune-modulatory effects and eventually differ- ent patient outcomes. Therefore, we designed an exploratory study to investigate the immunomodulatory activity of RT in combination with pembrolizumab in solid tumors including mRCC. 5 We previously reported immune biomarkers of treatment failure for 1 mRCC patient in this study. 6 Here we report a pilot study of RT in combination with pembrolizumab in mRCC patients progressing on TKI. In addition to PD-L1 expression and tumor-infiltrating lymphocytes (TIL) in tumor tissue, 3 as the host immune function may have been altered with TKI exposure, we explored the baseline and the kinetics of T-cell subsets (also T-helper cell subsets Th1 and Th2) during the From the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA. Supported through a grant by Merck & Co as an investigator-initiated trial (MISP#51690). Merck & Co served as the study sponsor and provided the study drug. Present address: Jianqing Lin: Department of Medicine, Division of Hematology/ Oncology, GW Cancer Center, George Washington University School of Medicine and Health Science, Washington, DC 20052. Present address: Jean Hoffman-Censits: Department of Medical Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231. J.L. and A.J.S. contributed equally and are cofirst authors. The authors declare no conflicts of interest. Reprints: Jianqing Lin, MD, 2150 Pennsylvania Avenue, NW, Washington, DC 20037. E-mail: jilin@mfa.gwu.edu. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0277-3732/19/000-000 DOI: 10.1097/COC.0000000000000636 ORIGINAL ARTICLE American Journal of Clinical Oncology  Volume 00, Number 00, ’’ 2019 www.amjclinicaloncology.com | 1 Copyright r 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.