Genomics of Immunotherapy-Associated Hyperprogressors—Response

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 starting immunotherapy. We believe that having images at all three time points is essential to establishing hyperprogression (as opposed to standard resistance). Although the explosive tumor growth described in the Forschner correspondence is suspicious for hyperprogression, without the imaging approximately 2 months pretreatment, it is not possible to distinguish accelerated from natural progression.

In our previous report (1), 4 patients with MDM2 amplification had true hyperprogression that met the aforementioned definition. Two patients with EGFR alterations also met these criteria. Multivariate analysis demonstrated that both MDM2 family and EGFR alterations were independently associated with TTF <2 months.

One of the major roles of MDM2 is to suppress the function of p53, which leads to tumorigenesis (3). Interestingly, in our previous report (1), MDM2/4 amplification was significantly associated with TTF <2 months (OR = 10.8, P = 0.02) while TP53 alterations were not predictive of TTF (OR = 1.52, P = 0.29). Although the exact mechanism relating MDM2 amplification and hyperprogression is unclear, the data suggest there may be a p53-independent (noncanonical) role for MDM2. Alternatively, a yet unidentified gene coamplified with MDM2 could also be operative. We agree with Forschner and colleagues that close observation is required in patients with MDM2 family gene amplification in the context of immunotherapy. Further investigation is urgently needed.

See the original Letter to the Editor, p. 6374