Genomics of Immunotherapy-Associated Hyperprogressors—Response

Abstract

Forschner and colleagues reported a patient with melanoma who experienced rapid increase in tumor burden while being treated with ipilimumab and nivolumab (246% and 377% increase compared with baseline after 1 and 3 months, respectively). The patient's tumor continued to spread quickly after switching to pembrolizumab. Molecular profiling revealed MDM2 amplification. Forschner and colleagues note that MDM2 requires further exploration as a marker for immunotherapy resistance. However, they note, it is unclear whether their patient experienced hyperprogression postimmunotherapy or progression that reflected the natural disease course. Hyperprogression after anti-PD-1/PD-L1 therapies is a relatively new outcome pattern (1). A publication from Institut Gustave Roussy (Villejuif, France) found hyperprogression in 9% of immunotherapy-treated patients; our article noted that MDM2 amplification and EGFR alterations correlated with hyperprogression in a subset of patients treated with anti-PD1/PD-L1 compounds (1, 2). We defined hyperprogression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and, importantly, >2-fold increase in progression pace (1). Progression pace was calculated on the basis of baseline imaging (2 months prior to immunotherapy initiation), imaging right before immunotherapy, and follow-up imaging after

Integrated analysis of the immunological and genetic status in and across cancer types: impact of mutational signatures beyond tumor mutational burden

“…12 To overcome these limitations, several novel and complementary biomarkers are currently under investigation. Additional to negative predictors of response, [13][14][15][16] which might play an increasingly important role in the near future, tumor mutational burden (TMB) approximating neo-antigenicity 17,18 was observed to predict response to various checkpoint agents in different cancer types. 11,19,20 The potential of TMB as biomarker for immune therapy response independent from PD-L1 was demonstrated in phase III non-small cell lung carcinoma (NSCLC) trials including a retrospective analysis of the Checkmate 026 trial and more recent corroborative data obtained from the Checkmate 227 trial.…”

Hyperprogressive Disease in Anorectal Melanoma Treated by PD-1 Inhibitors

“…For example, a recent study of 155 patients treated with anti-PD-1/anti-PD-L1 therapy reported that all six individuals with MDM2/MDM4 amplification experienced time-to-treatment failure (TTF) of less than 2 months, and four of the six patients exhibited an HPD response ( 17 ). This study further showed that eight of 10 patients with EGFR mutations experienced TTF of less than 2 months, and 2 of 10 demonstrated HPD.…”

Assessment of hyperprogression versus the natural course of disease development with nivolumab with or without ipilimumab versus placebo in phase III, randomized, controlled trials

“…1 4 6 9 10 13 16 Various studies have also identified potential associations between HPD and a range of genomic (eg, MDM2 and EGFR mutations) and immune-cell (eg, PD-1-positive regulatory T cells) biomarkers, but there is no clear consensus as to their predictive values. [17][18][19][20][21][22][23][24] The main limitation of previous studies of HPD is that they are based on retrospective analyses of small, nonrandomized, single-arm clinical trials and observational studies. 1 6 9 10 13 16 The data from such studies do not allow an assessment of whether the HPD phenomenon is caused by ICI treatment, or whether it reflects variability in disease progression, which can be masked with alternative treatments such as cytotoxic chemotherapy.…”