Faculty Collaboration Database

Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Res 2017 Aug 01;23(15):4242-4250

Date

03/30/2017

Pubmed ID

28351930

Pubmed Central ID

PMC5647162

DOI

10.1158/1078-0432.CCR-16-3133

Scopus ID

2-s2.0-85026810566 (requires institutional sign-in at Scopus site)   671 Citations

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 with MDM2/MDM4 amplification. 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/MDM4 and EGFR alterations correlated with TTF <2 months. Two of 10 patients with EGFR alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase).Conclusions: Some patients with MDM2 family amplification or EGFR aberrations 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.

Author List

Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
B7-H1 Antigen
Biomarkers, Tumor
CTLA-4 Antigen
Cell Cycle Proteins
ErbB Receptors
Female
Gene Expression Regulation, Neoplastic
Genomics
Humans
Immunotherapy
Male
Middle Aged
Neoplasms
Nuclear Proteins
Programmed Cell Death 1 Receptor
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-mdm2
Treatment Failure