Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?

Abstract

Immunotherapy (IO) has altered the therapeutic landscape for multiple cancers. There are emerging data from retrospective studies on a subset of patients who do not benefit from IO, instead experiencing rapid progression with dramatic acceleration of disease trajectory, termed 'hyperprogressive disease' (HPD). The incidence of HPD ranges from 4% to 29% from the studies reported. Biological basis and mechanisms of HPD are currently being elucidated, with one theory involving the Fc region of antibodies. Another group has shown EGFR and MDM2/MDM4 amplifications in patients with HPD. This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease. Thus, prospective studies are urgently needed to confirm the underlying biology, predict patients who are susceptible to HPD, and determine the modality of therapy post progression.

Keywords: cancer clinical trials; hyperprogressive disease; immune checkpoint inhibitors; immunotherapy.

Figure 1.. Potential Outcomes of Immunotherapy.

(A) Gray shading indicates stable disease, where changes in tumor are either minimal or nonexistent; green shading indicates a durable response where the tumor shrinks and is sustained over time; blue shading indicates pseudoprogression, where initial enlargement of the tumor is seen on imaging with subsequent shrinkage on subsequent scans. (B) Orange shading indicates a nondurable response, where initially shrinkage in the tumor is seen, regarded as a response; however, after time, the tumor begins to progress; yellow shading indicates progressive disease where the tumor enlarges on subsequent scans; and red shading shows hyperprogressive disease, where tumor growth becomes expansive on imaging.

Figure 2.. Case Study of a Patient’s Scans Exhibiting Hyperprogression.

A case study of a female in her 60s with renal cell carcinoma. The tumor showed significant progression with nivolumab. (A) A baseline scan before treatment with nivolumab demonstrated an infiltrative retroperitoneal mass involving her right kidney and renal vessels. (B) A restaging scan done 6 weeks after nivolumab therapy demonstrated an increase in the retroperitoneal mass and new hepatic metastases. (C) A follow-up scan done 10 weeks after initiation of nivolumab demonstrated an extensive increase in size of the retroperitoneal mass and a significant increase in size and number of new hepatic metastases, confirming disease progression. Abbreviation: PD-1, programmed cell death 1.

Figure 3.. Hyperprogressive Disease (HPD) and Immunotherapy: Quite the Debate.

Evidence supporting HPD from immunotherapy includes nine published studies showing HPD, multiple various groups across the world reporting this phenomenon with differing criteria, lab-based evidence to support the role of Fc antibodies, senescent T cells, as well as genomic data showing MDM2 and EGFR mutations from two independent groups. Limitations to the evidence for HPD include a lack of a common biomarker in all studies, all studies being retrospective, the possibility of the natural history of aggressive disease subtypes, a lack of defined biological mechanism, and multiple definitions used to define HPD. Abbreviation: PD-(L)1, programmed cell death (ligand) 1.