Hyperprogressive disease in patients with unresectable hepatocellular carcinoma receiving atezolizumab plus bevacizumab therapy

Abstract

Background: Atezolizumab plus bevacizumab was approved for hepatocellular carcinoma (HCC) patients in 2020, but treatment outcomes of atezolizumab plus bevacizumab in real-world settings remain unclear. Hyperprogressive disease (HPD), an acceleration of tumor growth occurring in some types of malignancies treated with immune checkpoint inhibitors, was assessed in HCC patients receiving atezolizumab plus bevacizumab.Methods: Tumor growth kinetics (TGK) and tumor growth rate (TGR) were calculated at pre-and post-treatment in 88 Japanese patients with HCC receiving atezolizumab plus bevacizumab. Hyperprogressive disease was defined as progressive disease (PD) with ≥ two-fold increase in TGK and TGR. The association of baseline characteristics with HPD was analyzed. Results:The best objective responses were partial response, stable disease, and PD in 12 (13.6%), 51 (58.0%), and 25 (28.4%) patients, respectively. The median progression-free survival was 5.0 months. Eleven (12.5%) and 9 (10.2%) patients had a TGK ratio and a TGR ratio of ≥2, respectively. Hyperprogressive disease was observed in nine patients (10.2%) and they showed significantly shorter overall survival than patients without HPD (median, 4.3 months vs. not reached; p < 0.001).Patients with HPD had larger and more intrahepatic tumors, higher levels of αfetoprotein and lactate dehydrogenase, and higher neutrophil-to-lymphocyte ratio (NLR) at baseline than patients without HPD. NLR of ≥3 at baseline was identified as the only independent factor associated with HPD in multivariate analysis.Conclusions: Hyperprogressive disease was observed in 10.2% of HCC patients receiving atezolizumab plus bevacizumab, and an elevated NLR at baseline had an increased risk of HPD.

Pretreatment Positron Emission Tomography with ¹⁸F-Fluorodeoxyglucose May Be a Useful New Predictor of Early Progressive Disease following Atezolizumab plus Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma

“…This difference may have been due to the small number of cases in the current study. In addition, it should be noted that previously reported NLR cut-off values for predicting patient outcomes differ between studies [15, 43-45], and NLRs change due to various patient conditions (e.g., infections and certain medications, particularly steroid-based immunosuppressive regimens). Therefore, more robust NLR cut-off values are desirable for use in daily clinical practice.…”

“…As in the previous reports [41,42], readministration of lenvatinib after diagnosed disease progression during immunotherapies has the potential of disease control effect in some patients. Recently, other researchers reported the utility of NLRs for predicting patient outcomes following Atezo/Bev treatment of HCC [15,[43][44][45]. Furthermore, Maesaka et al [15] reported an NLR cut-off value of ≥3 as a useful predictor for HPD.…”

“…Recently, other researchers reported the utility of NLRs for predicting patient outcomes following Atezo/Bev treatment of HCC [15,[43][44][45]. Furthermore, Maesaka et al [15] reported an NLR cut-off value of ≥3 as a useful predictor for HPD. However, in the present cohort, no significant differences in NLR were observed between the e-PD and non-e-PD populations (median NLR, 3.29 vs. 2.91, p = 0.624).…”

“…In HCC, HPD has been observed in patients treated with nivolumab or pembrolizumab, both of which failed to meet phase 3 trial primary endpoints [13, 14]. Recently, in patients with HCC receiving Atezo/Bev, a higher neutrophil-to-lymphocyte ratio (NLR) at baseline has been reported to increase the risk of HPD [15]. However, the characteristics and predictors of HPD in patients with HCC treated with Atezo/Bev remain unclear.…”

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.…”