Hyperprogressive Disease Caused by PD-1 Inhibitors for the Treatment of Pan-Cancer

Abstract

Background. Nowadays, PD-1/PD-L1 inhibitors are widely used to treat various malignant tumors. However, during the immunotherapy in a few patients, a flare-up of tumor growth occurred. This new pattern of progression is called hyperprogressive disease (HPD). Patients and Methods. The retrospective study included 377 patients with various malignant tumors treated with PD-1 inhibitors (nivolumab or pembrolizumab) in the Chinese PLA General Hospital from January 2015 to January 2019. Clinicopathologic variables, tumor growth rate (TGR), and treatment outcomes were analyzed in patients with pan-cancer treated with PD-1 inhibitors. HPD was defined as the difference of TGR before and during immunotherapy exceeding 50%. Results. In 38 of 377 patients (10.08%), HPD occurred after treatment with PD-1 inhibitors. Patients with HPD had lower overall survival (OS) than those without HPD (median OS, 3.6months (95% CI, 3.0–4.2) vs. 7.3 months (95% CI, 5.9–8.7); P < 0.01 ). Factors related to HPD include more than 2 metastatic sites, ECOG performance status ≥ 2 , hepatic metastases, and lactate dehydrogenase level greater than normal upper limit. KRAS status was significantly associated with HPD in patients with colorectal cancer. In the exploratory predictors’ analysis, the rapid increase of characteristic tumor markers (such as CEA in colorectal cancer, CA199 in pancreatic cancer and cholangiocarcinoma) within one month was found to be associated with the occurrence of HPD. Conclusions. HPD was developed with different rates in a variety of malignant tumor patients treated with PD-1 inhibitors and related to some clinicopathological features and poor prognosis. Tumor markers, especially CA199, might be served as early predictors of HPD.

A Composite Biomarker of Derived Neutrophil–Lymphocyte Ratio and Platelet–Lymphocyte Ratio Correlates With Outcomes in Advanced Gastric Cancer Patients Treated With Anti-PD-1 Antibodies

“…Based on the current clinical trial results, the positive effect of immune checkpoint inhibitors is very apparent (22). Comparatively, immunotherapy drugs are expensive and prone to drug resistance and even superprogress (23,24). Therefore, finding an effective predictive marker is an urgent matter to be solved.…”

Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer

“…The importance of pre-baseline CT scanning in diagnosing HPD was thus highlighted, but only 71 eligible patients were enrolled in this study. Later, Abbar et al [19] expanded the study to 169 advanced NSCLC patients treated with ICI; the incidence of HPD (11.3%, 5.7%, 17.0%, 9.6% and 31.7%) was calculated based on five indicators. In addition to the discovery of large heterogeneity, the definition of HPD based on TTF standard was correlated with OS, while the other diagnostic criteria were not correlated with OS.…”

“…Chen et al . [ 20 ] reviewed the medical records of 377 patients with multiple malignancies and reported the incidence of HPD (10.08%). Factors associated with HPD include the presence of more than two metastatic sites, Eastern Cooperative Oncology Group score ≥ 2, liver metastasis, and lactic dehydrogenase level higher than the normal upper limit.…”

“…The clinical prognostic markers used in these analyses were similar to those reported by Chen et al . [ 20 ] . Ferrara et al .…”

Immune Cells in Hyperprogressive Disease under Immune Checkpoint-Based Immunotherapy

“…As shown in Table 1 , the correlations between HPD and ICIs have been shown across multiple types of tumor. A number of studies have proved the influence of HPD on OS, progression-free survival (PFS), and the rate of tumor progression [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. As ICIs become more prevalent, improved knowledge of HPD is urgently needed to precisely determine which patients should receive immunotherapy.…”