Hyperprogressive disease in early‐phase immunotherapy trials: Clinical predictors and association with immune‐related toxicities

Abstract

BackgroundA subset of patients treated with immune checkpoint inhibitors experience an accelerated tumor growth rate (TGR) in comparison with pretreatment kinetics; this is known as hyperprogression. This study assessed the relation between hyperprogressive disease (HPD) and treatment‐related toxicity and clinical factors.MethodsThis study reviewed patients with solid tumors who were enrolled in early‐phase immunotherapy trials at Princess Margaret Cancer Centre between August 2012 and September 2016 and had computed tomography scans in the pre‐immunotherapy (reference) and on‐immunotherapy (experimental) periods. HPD was defined as progression according to Response Evaluation Criteria in Solid Tumors 1.1 at the first on‐treatment scan and a ≥2‐fold increase in TGR between the reference and experimental periods. Treatment‐related toxicities requiring systemic therapy, drug delays, or discontinuation were considered clinically significant adverse events (CSAEs).ResultsOf 352 patients, 182 were eligible for analysis. The median age was 60 years, and 54% were male. The Eastern Cooperative Oncology Group performance status was 0 (32%) or 1 (68%). The Royal Marsden Hospital (RMH) prognostic score was 0/1 in 59%. Single‐agent immunotherapy was given to 80% of the patients. Most patients (89%) received anti‐programmed death (ligand) 1 antibodies alone or in combination with other therapies. HPD occurred in 12 of 182 patients (7%). A higher proportion of females was seen among HPD patients (P = .01), but no association with age, performance status, tumor type, RMH prognostic score, combination immunotherapy, or CSAEs was found. The 1‐year overall survival rate was 28% for HPD patients and 53% for non‐HPD patients (hazard ratio, 1.7; 95% confidence interval, 0.9‐3.3; P = .11).ConclusionsHPD was observed in 7% of patients with solid tumors treated with immunotherapy. HPD was not associated with CSAEs, age, tumor type, or the type of immunotherapy but was more common in females.

Hyperprogression and Immune Checkpoint Inhibitors: Hype or Progress?

“…The phenomenon of enhanced progression after checkpoint blockade has been described with different checkpoint blockade agents and in numerous tumor types including, but not limited to, non‐small cell lung, head and neck, breast, gastric, and genitourinary cancers . The fact that various histologies that can be afflicted by HPD suggests that there could be common, histology‐agnostic biologic or molecular mechanism(s).…”

“…Another key question in HPD is whether there are clinical or molecular features that are associated with an increased risk of accelerated growth after checkpoint blockade. Predictors of HPD have included age ≥ 65 years, female gender, regional recurrence of disease, having more than two sites of metastases, low baseline highly differentiated CD4+ T cells or effector memory CD8+ T cells, high severely exhausted T cells or proliferating T regulatory cells, clustered CD163 + PD‐L1 + CD33 + macrophages with epithelioid morphology, and genomic markers (mainly MDM2 / MDM4 alterations and EGFR alterations; Table ) . There are inconsistencies between studies in that some have not shown age or sex to be predictors.…”

“…In summary, despite the numerous research teams that have documented HPD , the existence of this phenomenon remains a matter of dispute. Indeed, an analysis of the OAK trial , which was a randomized study of checkpoint blockade versus chemotherapy in lung cancer, did not show a difference in the number of “fast progressors” between the arms.…”

Role of medical imaging for immune checkpoint blockade therapy: From response assessment to prognosis prediction

“…Hyperprogressive disease refers to a remarkably accelerated tumor growth rate (TGR) that leads to poor prognosis in patients under ICB therapy particularly anti‐PD‐1/PD‐L1 agents . Currently, no consensus has been reached on the definition of HPD .…”

“…For instance, Champiat et al first reported HPD as a RECIST 1.1 progression before ICB therapy and a twofold or greater increase in TGR during immunotherapy, whereas Ferrar et al defined HPD as a disease progression at the first evaluation with at least an increase of 50% ΔTGR (the variation of TGR before and on treatment) (Figure ) . The incidence of HPD was reported to range from 7% to 29% across different types of carcinoma . However, the discordance in the definition of HPD across published literatures challenges the direct comparison of data.…”