title: Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate.
abstract: Purpose:Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be "hyperprogressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with "hyperprogression" after immunotherapy.Experimental Design:Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N= 155). We defined hyperprogression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace.Results:Amongst 155 patients, TTF <2 months was seen in all six individuals withMDM2/MDM4amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared with the 2 months before immunotherapy). In multivariate analysis,MDM2/MDM4andEGFRalterations correlated with TTF <2 months. Two of 10 patients withEGFRalterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase).Conclusions:Some patients withMDM2family amplification orEGFRaberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed.Clin Cancer Res; 23(15); 4242-50. ©2017 AACR.
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California. smkato@ucsd.edu.
authors.forename: Shumei
authors.initials: S
authors.lastname: Kato
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California.
authors.forename: Aaron
authors.initials: A
authors.lastname: Goodman
authors.affiliation: Department of Pathology, University of California San Diego Moores Cancer Center, La Jolla, California.
authors.forename: Vighnesh
authors.initials: V
authors.lastname: Walavalkar
authors.affiliation: Biostatistics Division, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Barkauskas
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California.|Department of Radiation Medicine and Applied Sciences, University of California San Diego Moores Cancer Center, La Jolla, California.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sharabi
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California, San Diego Moores Cancer Center, La Jolla, California.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D014408:Biomarkers, Tumor / Q000235:genetics*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D018797:Cell Cycle Proteins; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D017211:Treatment Failure
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011518:Proto-Oncogene Proteins; C000594389:atezolizumab; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C512478:EGFR protein, human; D066246:ErbB Receptors