Presenter(s)
C. X. Wang1, M. E. Daly2, E. M. Maverakis3, A. Merleev3, A. Marusina3, Y. H. Sun1, L. Vik1, J. Hunt1, S. K. J. Kim1, N. Seto4, N. Mahaffey5, E. Moore4, T. Li6, D. Gandara6, P. Lara6, J. Riess6, S. Chen7, K. Kelly8, and A. M. Monjazeb1; 1University of California Davis, Department of Radiation Oncology, Sacramento, CA, 2Department of Radiation Oncology, University of California - Irvine, Orange, CA, 3University of California Davis, School of Medicine, Department of Dermatology, Sacramento, CA, 4University of California Davis, Department of Radiology, Sacramento, CA, 5Office of Clinical Research, University of California Davis Comprehensive Cancer Center, Sacramento, CA, 6University of California Davis, Division of Hematology/Oncology, Department of Internal Medicine, Sacramento, CA, 7University of California Davis, Division of Biostatistics, Department of Public Health Sciences, Sacramento, CA, 8Scientific Affairs, International Association for the Study of Lung Cancer, Sacramento, CA
Purpose/Objective(s):
There has been long-standing interest in combining stereotactic body radiotherapy (SBRT) with immune checkpoint inhibitors (ICI). The optimal sequence of SBRT and ICI remains unclear. We aimed to evaluate the safety, efficacy, and immunologic impact of different sequences of Atezolizumab (ATZ), a PD-L1–targeting monoclonal antibody, with SBRT. Three study arms evaluated different treatment schedules: 1) concurrent – SBRT starting with cycle 1 of ATZ; 2) induction - SBRT starting with cycle 3 of ATZ; and 3) sequential – SBRT prior to cycle 1 of ATZ.Materials/Methods:
This single-institution phase I trial enrolled ICI naive patients with metastatic solid tumors with an ICI indication and =2 measurable lesions, including one amenable to SBRT (NCT02400814).The accrual target was 15 patients per arm. Patients received ATZ (1200 mg IV every 3 weeks) and SBRT (50 Gy in 5 fractions). The primary objective was to determine study arms worthy of further investigation based on a 30% objective response rate (ORR) using a Simon two-stage design. Secondary endpoints included safety and toxicity, radiographic response rate by immune related response criteria (irRC), and progression-free survival (PFS) by both irRC and RECIST 1.1. Correlative studies included bulk RNA sequencing of peripheral blood mononuclear cells (PBMCs) and spatial transcriptomics of paired pre- and post-treatment tumor biopsies.Results:
Twenty-eight patients were enrolled; 15 patients in the concurrent therapy arm and 13 patients in the induction therapy arm. The trial was closed early due to the changing landscape of first line ICI therapy and before accrual to arm 3. Cancer histology included NSCLC (64%), urothelial (7%), renal cell (21.0%), and HNSCC (7%). Treatment was well tolerated, with no grade 4–5 toxicities. Lymphopenia was the most common grade 3 adverse event (5/25). Twenty-five patients were evaluable for response. The ORR was 10/25 (40%) with 2 complete and 8 partial responses. Another 7 patients had stable disease as best response yielding a disease control rate of 68%. While both arms met the specified efficacy endpoint there were more responders and less progressive disease (PD) with induction compared to concurrent delivery [6/10 (60%) vs. 4/15 (27%) responders; and 2/10 (20%) vs. 6/15 (40%) PD] . Median OS was 23.1 months, and median PFS was 6.7 months, with a trend toward improved median PFS in the induction cohort (6.9 vs. 3.1 months, p=0.06) . Transcriptomic analyses demonstrated therapy-induced immune activation and DNA damage responses. Induction sequencing was associated with systemic and intratumoral immune activation signatures whereas concurrent therapy showed predominantly DNA damage–dominant signatures.Conclusion:
ATZ combined with SBRT is safe and demonstrates encouraging clinical activity in metastatic solid tumors. Induction sequencing resulted in high response rates and robust immune activation systemically and in the tumor microenvironment.