Hyper-progressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate

By S. Kato, A. Goodman, V. Walavalkar, D. Barkauskas, A. Sharabi, Razelle Kurzrock. Clinical Cancer Research, 2017

762 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/38b90f33ee5c0e8d4edeb20914fd5bdc8632d0cd

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Citations in the corpus

Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. (2018, result): “treated with ICI and was associated with MDM2/MDM4 amplifications.(28) In the current series, MDM2/MDM4 amplifications were identified in eight patients, and PFS was not substantially different in this group compared with the overall patient cohort (HR, 1.”
Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations (2018, background): “In a separate study, tumors from 155 patients with advanced cancers treated with PD-1/PD-L1 inhibitors were evaluated by next-generation sequencing to evaluate potential genomic markers associated with hyperprogressive disease defined as time-to-treatment failure (TTF < 2 months, > 50% increase in t”
PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer (2019, neutral): “S1 and Tables S2 and S4, one HPD patient possessed MDM2 gene amplification as reported in other types of cancer (case 3 in SI Appendix, Table S2) (7), while no patients without HPD had the MDM2 gene family alteration (SI Appendix, Fig.”
The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC) (2019, background): “aging, and >two-fold increase in progression pace” [91], “a tumor growth kinetics ratio equal to or greater than two” [79].”