Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate

Abstract

Purpose Checkpoint inhibitors demonstrate salutary anti-cancer 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 “hyper-progressors,” with a greatly accelerated rate of tumor growth and clinical deterioration compared to pre-therapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with “hyper-progression” after immunotherapy. Method 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 hyper-progression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared to pre-immunotherapy 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 to the two 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 hyper-progressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase). Conclusion 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 progression on immunotherapy. Further investigation is urgently needed.

Prevalence ofPDL1Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors

“…The case was presented at the molecular tumor board, and treatment with checkpoint inhibition was debated because of the presence of MDM2 amplification, which has been associated with hyperprogression. 33 However, because of the grave prognosis of glioblastoma, the patient was prescribed combination therapy with nivolumab and the MET inhibitor cabozantinib (after signing consent for an institutional review board-approved protocol [Study of Molecular Profile-Related Evidence to Determine Individualized Therapy for Advanced or Poor Prognosis Cancers (I-PREDICT) 23 ]). Brain magnetic resonance imaging (eFigure 2 in Supplement 1) performed 4 weeks after therapy initiation demonstrated a partial response with decreased enhancement within the primary mass and decreased mass effect.…”

Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

“…22 This phenomenon is called hyperprogression and affects approximately 9% of patients who receive PD-1/PD-L1 inhibitors. 23 Hyperprogression has been defined as a time to treatment failure < 2 months from checkpoint inhibitor initiation, a > 50% increase in tumor burden compared with pre-immunotherapy imaging, and a more than two-fold increase in progression pace.…”

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

“…We note in passing the recent reports of hyperprogression [65] . Tumor size has been observed to dramatically increase with anti-PD-1/PD-L1 treatment, although whether this is more than a statistical fluctuation has been questioned [66] .…”