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A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer

Authors: Monjazeb, Arta M.; Giobbie-Hurder, Anita; Lako, Ana; Thrash, Emily M.; Brennick, Ryan C.; Kao, Katrina Z.; Manuszak, Claire; Gentzler, Ryan D.; Tesfaye, Anteneh; Jabbour, Salma K.; Alese, Olatunji B.; Rahma, Osama E.; Cleary, James M.; Sharon, Elad; Mamon, Harvey J.; Cho, May; Streicher, Howard; Chen, Helen X.; Ahmed, Mansoor M.; Mariño-Enríquez, Adrian; Kim-Schulze, Seunghee; Gnjatic, Sacha; Maverakis, Emanual; Marusina, Alina I.; Merleev, Alexander A.; Severgnini, Mariano; Pfaff, Kathleen L.; Lindsay, James; Weirather, Jason L.; Ranasinghe, Srinika; Spektor, Alexander; Rodig, Scott J.; Hodi, F. Stephen; Schoenfeld, Jonathan D.

Online: https://clincancerres.aacrjournals.org/content/27/9/2470

Issue: Clin Cancer Res. 2021 May 1;27(9):2470-2480.


Purpose: Prospective human data are lacking regarding safety, efficacy, and immunologic impacts of different radiation doses administered with combined PD-L1/CTLA-4 blockade. Patients and Methods: We performed a multicenter phase II study randomly assigning patients with metastatic microsatellite stable colorectal cancer to repeated low-dose fractionated radiation (LDFRT) or hypofractionated radiation (HFRT) with PD-L1/CTLA-4 inhibition. The primary endpoint was response outside the radiation field. Correlative samples were analyzed using multiplex immunofluorescence (IF), IHC, RNA/T-cell receptor (TCR) sequencing, cytometry by time-of-flight (CyTOF), and Olink. Results: Eighteen patients were evaluable for response. Median lines of prior therapy were four (range, 1–7). Sixteen patients demonstrated toxicity potentially related to treatment (84%), and 8 patients had grade 3–4 toxicity (42%). Best response was stable disease in 1 patient with out-of-field tumor shrinkage. Median overall survival was 3.8 months (90% confidence interval, 2.3–5.7 months). Correlative IF and RNA sequencing (RNA-seq) revealed increased infiltration of CD8+ and CD8+/PD-1+/Ki-67+ T cells in the radiation field after HFRT. LDFRT increased foci of micronuclei/primary nuclear rupture in two subjects. CyTOF and RNA-seq demonstrated significant declines in multiple circulating immune populations, particularly in patients receiving HFRT. TCR sequencing revealed treatment-associated changes in T-cell repertoire in the tumor and peripheral blood. Conclusions: We demonstrate the feasibility and safety of adding LDFRT and HFRT to PD-L1/CTLA-4 blockade. Although the best response of stable disease does not support the use of concurrent PD-L1/CTLA-4 inhibition with HFRT or LDFRT in this population, biomarkers provide support that both LDFRT and HFRT impact the local immune microenvironment and systemic immunogenicity that can help guide future studies.