Anti-PD-1 antibodies plus lenvatinib in patients with unresectable hepatocellular carcinoma who progressed on lenvatinib: a retrospective cohort study of real-world patients

Abstract

Background: Lenvatinib, a multi-targeted tyrosine kinase inhibitor (TKI), has proven efficacy as the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, there is no standard effective second-line treatment option following progression on lenvatinib therapy. Because of the comprehensive coverage of therapeutic targets of lenvatinib, the remission rate of other TKI treatments in HCC patients resistant to lenvatinib is quite low.Methods: In this study, the effectiveness and safety of anti-programmed cell death protein-1 (PD-1) antibodies plus lenvatinib were assessed in 46 patients between April 2018 and April 2020 at the Zhongshan Hospital, Fudan University, by retrospectively reviewing their clinical data. Patients with unresectable HCC who progressed on lenvatinib were given standard doses of lenvatinib and anti-PD-1 antibodies. They were followed-up every 6-8 weeks with medical imaging and laboratory tests and treatment-related adverse reactions were investigated. Results:The objective response and the disease control rates were 23.9% (11/46) and 71.7% (33/46), respectively by Response Evaluation Criteria in Solid Tumours 1.1 (RECIST). After a median follow-up period of 15.6 [interquartile range (IQR), 11.2-22.0] months, the median progression-free survival (PFS) and overall survival (OS) were 6.9 months [95% confidence interval (CI): 2.1-11.8] and 14.5 months (95% CI: 6.8-22.3), respectively. The most common treatment-related adverse events were anorexia (43.5%), hypothyroidism (43.5%), hypertension (36.9%), fatigue (34.8%), and diarrhea (26.1%). Grade 3/4 events occurred in 16 patients (34.8%). Emotional functioning and overall quality of life were improved significantly following the initiation of anti-PD-1 antibodies plus lenvatinib therapy (fatigue, 4.9±7.5 vs. 11.1±12.7,

Comparison of Immunotherapy in different time in combination with Lenvatinib for the treatment of unresectable hepatocellular carcinoma: a real-world study

“…Preclinical studies have suggested that Lenvatinib can increase the in ltration of CD8 + T cells in the tumor microenvironment by blocking VEGF to temporarily normalizing the tumor vessels, thereby amplifying the value ICIs and increasing tumor sensitivity to this combination therapy [14][15][16][17][18]. Numerous cohort studies have reported the superiority of the combinations of Lenvatinib plus ICIs compared with Lenvatinib monotherapy [19][20][21][22][23][24], which is consistent with these ndings from this study.…”

Efficacy and safety of transarterial chemoembolization combined with first-line tyrosine kinase inhibitors and programmed death-1 inhibitors for progressed hepatocellular carcinoma

“…However, TACE has the potential to enhance clinical effectiveness by increasing the release of antigens [37]; further, rst-line TKI like sorafenib or lenvatinib can increase PD-L1 expression in tumors and promote immune cell in ltration into the tumor [40]. Combining rst-line TKI plus PD-1 inhibitors can result in unique immunomodulatory effects, which can overcome the challenges of a low response rate and TKI resistance [41][42][43]. Thereby, it was expected that combining TACE with rst-line TKI plus PD-1 inhibitor therapy could increase the tumor response rate and would be effective in improving the prognosis of our study patients.…”

ACTB may serve as a predictive marker for the efficacy of lenvatinib in patients with HBV-related early-stage hepatocellular carcinoma following partial hepatectomy: a retrospective cohort study

“…Lenvatinib has been recently discovered to reduce tumor PD-L1 levels and inhibit Treg differentiation, thereby enhancing the efficacy of anti-PD-1 through FGFR4 inhibition ( 12 , 39 ). A stabilized inverse probability of treatment weighting (SIPTW)-weighted multivariate Cox regression analysis showed that continuous use of lenvatinib can prolong the OS and PFS in patients with unresectable HCC (u-HCC).…”

“…Lenvatinib is an orally administered multikinase inhibitor that selectively targets PDGF receptor α, fibroblast growth factor (FGF) receptors 1–4 (FGFR1–4), vascular endothelial growth factor (VEGF) receptors 1–3, KIT and RET. It has been authorized as a first-line systemic treatment for advanced HCC patients ( 10 - 12 ). This was the result of a randomized phase-III clinical trial in patients with advanced HCC, which demonstrated that lenvatinib had comparable OS to sorafenib while exhibiting superior progression-free survival (PFS) ( 13 ).…”