@article{74445b999f224df78916cb2e00ba1cdb,
title = "Phase I Study of Stereotactic Body Radiotherapy plus Nivolumab and Urelumab or Cabiralizumab in Advanced Solid Tumors",
abstract = "Background: CD137 agonism and CSF-1R blockade augment stereotactic body radiotherapy (SBRT) and anti-PD1 in pre-clinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF-1R inhibitor). Patients and methods: This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies. SBRT was delivered to 1-4 metastases with nivolumab+urelumab or nivolumab+cabiralizumab given concurrently and following SBRT. Dose limiting toxicity (DLT) was the primary endpoint with anatomic location-specific SBRT doses deemed safe if =33% DLT frequency was observed. Secondary endpoints included RECISTv1.1 response, progression-free survival (PFS), overall survival (OS), and molecular correlative studies. Results: Sixty patients were enrolled, and median follow-up for living patients is 13.8 months. Of these, 23 (38%) received SBRT+nivolumab+urelumab and 37 (62%) received SBRT+nivolumab+cabiralizumab. Seven patients (12%) experienced a DLT (n=3 grade 3, n=4 grade 4) in the following anatomic cohorts: abdominal/pelvic (3/17, 18%), liver (1/13, 8%), central lung (2/14, 14%), and peripheral lung (1/12, 8%). Of 41 patients radiographically evaluable for best overall response including 55 radiated and 23 unirradiated RECIST target lesions, 2 had complete responses (5%), 7 had partial responses (17%), 12 had stable disease (29%), and 20 had progression (49%). Median estimated PFS and OS are 3.0 months (95% CI 2.9-4.8) and 17.0 months (95% CI 6.8-undetermined), respectively. No patients with elevated pre-SBRT serum interleukin-8 experienced a response. Conclusions: SBRT to =4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest anti-tumor activity.",
keywords = "Immunotherapy, Neoplasm metastasis, Radiotherapy, Receptors, Interleukin-8, Tumor Microenvironment",
author = "Foster, {Corey C.} and Fleming, {Gini F.} and Karrison, {Theodore G.} and Liao, {Chih Yi} and Desai, {Ami V.} and Moroney, {John W.} and Ratain, {Mark J.} and Rita Nanda and Polite, {Blase N.} and Hahn, {Olwen M.} and O{\textquoteright}Donnell, {Peter H.} and Vokes, {Everett E.} and Kindler, {Hedy L.} and Robyn Hseu and Janisch, {Linda A.} and Julia Dai and Hoffman, {Mark D.} and Weichselbaum, {Ralph R.} and Pitroda, {Sean P.} and Chmura, {Steven J.} and Luke, {Jason J.}",
note = "Funding Information: CCF: No relationship to disclose. GFF: Personal fees from Up To Date, Vaniam Group, GSK, and ASCO as well as non-financial support from Corcept. She serves as the principal investigator of industry trials supported by Merck, Syndax, 47 Inc, Sanofi, Astex, EMD Sereno, Roche/Genentech, Syros, Tesaro, Iovance, Sermonix, Incyte, Compugen, and Eisai. She is an unpaid member on a clinical trial steering committee and institutional PI of an industry trial for Abbvie. These conflicts are outside the submitted work. TGK: No relationship to disclose. CYL: Research support from Bristol-Myers Squibb (institutional). AVD: Stock or other ownership interests with Pfizer. Consulting or advisory role with Merck. Research funding (all to institution for industry-sponsored clinical trials) from Merck, Roche, Jubilant DraxImage, YmAbs Therapeutics, and Actuate. Travel, accommodations, and expenses from GlaxoSmithKline. JWM: No relationship to disclose. MJR: Personal fees from multiple generic companies, Ayala, Arvinas, Cyclacel, Aptevo, Shionogi, other from Dicerna, personal fees and other from Genentech, other from BeiGene, other from AbbVie, other from Corvus, other from Bristol-Myers Squibb, other from Xencor, outside the submitted work. In addition, MJR has a patent US6395481B1 with royalties paid to Mayo Medical, a patent EP1629111B1 with royalties paid to Mayo Medical, a patent US8877723B2 issued, a patent US9617583B2 issued, and a provisional patent pending and Director and Treasurer, Value in Cancer Care Consortium. RN: Advisory board for Aduro, Clovis, Daiichi Sankyo Inc., Genentech, Immunomedics, MacroGenics, Merck, Pfizer, and Seattle Genetics. DSMB for G1 therapeutics. Research funding from AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics, Merck, OBI Pharm, Inc., Odonate Therapeutics, Pfizer, and Seattle Genetics. BNP: Research funding from Merck and consultant role with Signatera outside the submitted work. OMH: No relationship to disclose. PHO: Stock and other ownership interests with Allergan. Honoraria from Genentech/Roche, Merck, Astellas Pharma, Seattle Genetics, Atheneum Partners, Health Advances, Janssen, Dedham Group, Schlesinger Associates, FirstWord Publication, Pfizer, and CLD. Consulting or advisory role with Merck. Institutional research funding from Boehringer Ingelheim, Merck, Genentech/Roche, AstraZeneca/MedImmune, Acerta Pharma, Janssen, Seattle Genetics, Bristol Myers Squibb, and Astellas Pharma. Travel, accommodations, and expenses from Merck, Seattle Genetics/Astellas, Genentech/Roche, and Janssen. Other relationships with Janssen, Nektar, NIH, and Dragonfly Therapeutics. EEV: Consulting or advisory role with AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Merck, Novartis, and Regeneron. HLK: Personal fees from Aldeyra Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Kyowa, Merck, Paredox Therapeutics, Deciphera, Inhibrx, and Inventiva all outside the submitted work. Non-financial support from AstraZeneca, Boehringer-Ingelheim, Merck, Paredox Therapeutics, and Inventiva all outside the submitted work. RH: No relationship to disclose. LJ: No relationship to disclose. JD: No relationship to disclose. MDH: No relationship to disclose. RRW: Stock and other ownership interests with Boost Therapeutics, Immvira LLC, Reflexion Pharmaceuticals, Coordination Pharmaceuticals Inc., Magi Therapeutics, and Oncosenescence. Consulting or advisory role for Aettis Inc., AstraZeneca, Coordination Pharmaceuticals, Genus, Merck Serono S.A., Nano Proteagen, NKMax America Inc., Shuttle Pharmaceuticals, Highlight Therapeutics, S.L. Patent pending entitled, “Methods and Kits for Diagnosis and Triage of Patients with Colorectal Liver Metastases.” Research grants with Varian and Regeneron. Compensation including travel, accommodations, or expense reimbursement from AstraZeneca, Boehringer Ingelheim LTD, and Merck Serono S.A. SPP: No relationship to disclose. JJL: Scientific Advisory Board: (no stock) 7 Hills, Spring bank (stock) Actym, Alphamab Oncology, Arch Oncology, Kanaph, Mavu, Onc.AI, Pyxis, Tempest. Consultancy with compensation: Abbvie, Aligos, Array, Bayer, Bristol-Myers Squibb, Checkmate, Cstone, Eisai, EMD Serono, KSQ, Janssen, Merck, Mersana, Novartis, Partner, Pfizer, RefleXion, Regeneron, Ribon, Rubius, Silicon, Tesaro, Werewolf, Xilio, Xencor. Research Support: (all to institution for clinical trials unless noted) AbbVie, Agios (IIT), Array (IIT), Astellas, Bristol-Myers Squibb (IIT & industry), Corvus, EMD Serono, Immatics, Incyte, Kadmon, Macrogenics, Merck, Spring bank, Tizona, Xencor. Travel: Bristol-Myers Squibb, Janssen, Mersana, Pyxis. Patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research Inc.. All rights reserved.",
year = "2021",
month = oct,
day = "15",
doi = "10.1158/1078-0432.CCR-21-0810",
language = "English (US)",
volume = "27",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "20",
}