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MO_34_2802 - Interim Safety and Toxicity Analysis of a Prospective Phase II Randomized Trial of Checkpoint Blockade Immunotherapy Combined With Stereotactic Body Radiation Therapy in Advanced Metastatic Disease

Monday, October 22
10:45 AM - 12:15 PM
Location: Innovation Hub, Exhibit Hall 3

Interim Safety and Toxicity Analysis of a Prospective Phase II Randomized Trial of Checkpoint Blockade Immunotherapy Combined With Stereotactic Body Radiation Therapy in Advanced Metastatic Disease
A. Sharabi1, S. Kim2, J. Proudfoot3, S. Kato4, H. Patel5, M. Nunez2, P. D. Sanders2, K. Guram2, S. Miyauchi2, D. R. Simpson4, E. Cohen2, S. Patel6, E. Weihe4, L. K. Mell4, A. J. Mundt Jr7, and R. Kurzrock4; 1UC San Diego, Moores Cancer Center, Dept of Radiation Oncology, La Jolla, CA, 2University of California, San Diego Moores Cancer Center, La Jolla, CA, 3UCSD, La Jolla, CA, 4University of California, San Diego, La Jolla, CA, 5University of California - San Diego Moores Cancer Center, San Diego, CA, 6UC San Diego, Moores Cancer Center, Dept of Hematology/Oncology, La Jolla, CA, 7Department of Radiation Medicine, University of California, San Diego, La Jolla, CA

Purpose/Objective(s): Checkpoint blockade immunotherapy (CBI) targeting the PD-1 and CTLA-4 pathways is revolutionizing oncology. However, objective response rates for single agent CBI in solid malignancies remain low and combinatorial strategies are required to improve outcomes. Our group has pioneered the use of radiation (RT) and stereotactic body radiation therapy (SBRT) in combination with anti-PD-1 CBI. We previously demonstrated in tumor models that RT+ CBI can enhance antigen specific immune responses and improve local and systemic tumor control. Nevertheless, the clinical benefit of SBRT+CBI remains unclear. Our primary objective was to conduct a clinical trial to test the hypothesis that SBRT + CBI increases objective response rates (ORR) compared to CBI alone. Here we present an interim analysis.

Materials/Methods: We designed and opened an investigator initiated Phase II study (ClinicalTrials.gov NCT02843165) which randomizes patients (1:1) with advanced metastatic disease to receive investigators choice of anti-PD-1/PD-L1 CBI versus anti-PD-1/PD-L1 CBI combined with concurrent SBRT. SBRT was started 1-21 days after C1D1 of CBI and was prescribed at 9.5Gy x 3 fractions delivered to 1-3 non-CNS tumor foci consecutively or every other day. The study is powered to detect a 33% relative improvement in ORR with a total anticipated enrollment of 146. Safety and Toxicity was analyzed prospectively for all patients using CTCAE 4.0. ORR are measured from unirradiated tumors using RECIST 1.1 criteria. Three research blood draws are obtained to analyze immune correlates. We performed an interim analysis of safety and toxicity among all patients and between treatment groups.

Results: We have enrolled a total of 35 patients at this time. There were a total of 126 CTCAE toxicity events observed with 67 (53.2%) Low grade (CTCAE 1-2), and 59 (46.8%) High grade (CTCAE 3-5) events with a mean followup of 5.1 months. The most common toxicities were fatigue, nausea, pain, and rash. The most common SBRT treatment sites were lung, liver, adrenal gland, and soft tissue. Experimental treatment attributions are as follows: 18 events (14.3%) Unrelated, 44 events (34.9%) Unlikely, 48 events (38.1%) Possible, and 13 events (10.3%) Probable or Definite. There were 7 (5.5%) high grade events attributed as probably or definitely related to study: one grade 4 fatigue, one grade 3 weight loss, one grade 3 rash, and two grade 3 electrolyte abnormalities, and two grade 3 acute kidney injury. When comparing between CBI and CBI+SBRT treatment groups there was no significant difference in any grade of toxicity at this time.

Conclusion: Our interim analysis suggests that SBRT to lung, liver, adrenal and soft tissues prescribed at 9.5Gy x 3 fractions combined with concurrent anti-PD-1/PD-L1 CBI appears to be safe and well tolerated in patients with advanced metastatic disease. Continued analysis of safety and toxicity, ORR, and immune correlates between randomized treatment groups is ongoing.

Author Disclosure: A. Sharabi: Employee; University of California San Diego. Research Grant; Varian Medical Systems. Advisory Board; AstraZeneca. Scientific Advisory Committee Member; San Diego Center for Precision Immunotherapy. S. Kim: Stock; Sellas Life Sciences. J. Proudfoot: None. S. Kato: None. H. Patel: None. S. Miyauchi: None. E. Cohen: Consultant; Eisai; Merck; Bristol-Merys Squibb; AstraZeneca. Stock Options; Human Longevity, Inc. L.K. Mell: None. A.J. Mundt: Honoraria; Up to Date, US Oncology, Varian Medical Systems. R. Kurzrock: Research Grant; Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health. Consultant; Sequenom, LOXO, Actuate Therapeutics. Stock; CureMatch.

Andrew Sharabi, MD, PhD

University of California, San Diego

Disclosure:
Employment
University of California San Diego: Assistant Professor: Employee

Compensation
AstraZeneca: Advisory Board; Varian Medical Systems: Research Grants

Leadership
San Diego Center for Precision Immunotherapy: Advisory Board

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