ABSTRACT
BACKGROUND & AIMS: Our retrospective study has suggested encouraging outcomes of lenvatinib combined with PD-1 inhibitor and transarterial chemoembolization (TACE) on advanced hepatocellular carcinoma (HCC). This phase II trial was conducted to prospectively investigate the efficacy and safety of lenvatinib, sintilimab (a PD-1 inhibitor) plus TACE (Len-Sin-TACE) in patients with advanced stage HCC. METHODS: This was a single-arm phase II trial. Patients with BCLC stage C HCC were recruited. They received lenvatinib (bodyweight ≥60 kg, 12 mg; bodyweight <60 kg, 8 mg) orally once daily, sintilimab (200 mg) intravenously once every 3 weeks, and on demand TACE. The primary endpoint was progression-free survival (PFS) per mRECIST. RESULTS: Thirty patients were enrolled. The primary endpoint was met with a median PFS of 8.0 (95% confidence interval [CI]: 6.1-9.8) months per mRECIST, which was the same as that per RECIST 1.1. The objective response rate was 60.0% per mRECIST and 30.0% per RECIST 1.1. The disease control rate was 86.7% per mRECIST/RECIST 1.1. The median duration of response was 7.4 (95% CI: 6.6-8.2) months per mRECIST (n = 18) and 4.3 (95% CI: 4.0-4.6) months per RECIST 1.1 (n = 9). The median overall survival was 18.4 (95% CI: 14.5-22.3) months. Treatment-related adverse events (TRAEs) occurred in 28 patients (93.3%) and grade 3 TRAEs were observed in 12 patients (40.0%). There were no grade 4/5 TRAEs. CONCLUSIONS: Len-Sin-TACE showed promising antitumour activities with a manageable safety profile in patients with advanced stage HCC. The preliminary results need to be further evaluated with phase III randomized trials.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Phenylurea Compounds , Quinolines , Humans , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Carcinoma, Hepatocellular/therapy , Immune Checkpoint Inhibitors , Liver Neoplasms/therapy , Phenylurea Compounds/adverse effects , Phenylurea Compounds/therapeutic use , Quinolines/adverse effects , Quinolines/therapeutic use , Retrospective StudiesABSTRACT
PURPOSE: To investigate the efficacy and safety of tyrosine-kinase inhibitor (TKI) combined with iodine-125 seed brachytherapy (TKI-I) versus TKI alone for patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). METHODS: Data of patients with TACE-refractory HCC who received TKI (sorafenib or lenvatinib) or TKI-I from September 2018 to December 2020 were retrospectively analyzed. A propensity score matching (PSM) was performed to diminish potential bias. The primary endpoints were overall survival (OS) and time to progression (TTP). Tumor responses and treatment-related adverse events (TRAEs) were also compared between the two groups. RESULTS: A total of 132 patients were included in this study. Under PSM, 48 paired patients were selected for comparison. The median OS was 23.2 (95% CI 20.9-25.1) months in the TKI-I group versus 13.9 (95% CI 11.1-16.7) months in the TKI group (P < 0.001). The median TTP was 12.8 (95% CI 10.1-15.5) months in the TKI-I group versus 5.8 (95% CI 5.0-6.6) months in the TKI group (P < 0.001). Patients in the TKI-I group had higher objective response rate (68.8% vs. 33.3%, P = 0.001) and disease control rate (89.6% vs. 66.7%, P = 0.007) than those in the TKI group. The incidence and severity of TRAEs in the TKI-I group were comparable to those in the TKI group (any grade, 89.7% vs. 92.2%, P = 0.620; ≥grade 3, 33.8% vs. 32.8%, P = 0.902). CONCLUSIONS: TKI-I was safe and significantly improved survival over TKI alone in HCC patients with TACE refractoriness.
Subject(s)
Brachytherapy , Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Retrospective Studies , Tyrosine , /therapeutic useABSTRACT
Background: The application of chimeric antigen receptor (CAR) NK cells in solid tumors is hindered by lack of tumor-specific targets and inefficient CAR NK cell efficacy. It has been reported that mesothelin (MSLN) may be an ideal immunotherapy target for gastric cancer. However, the feasibility of using anti-MSLN CAR NK cells to treat gastric cancer remains to be studied. Methods: MSLN expression in primary human gastric cancer, normal tissues and cell lines were detected. MSLN and CD19 targeted CAR NK-92 (MSLN- and CD19-CAR NK) cells were constructed, purified and verified. N87, MKN-28, AGS and Huh-7 cells expressing the GFP and luciferase genes were transduced. Cell- and patient-derived xenograft (PDX) were established via NSG mice. The ability of MSLN-CAR NK cells to kill MSLN-positive gastric cancer cells were evaluated in vitro and in vivo. Results: MSLN-CAR NK cells can specifically kill MSLN-positive gastric cancer cells (N87, MKN-28 and AGS), rather than MSLN negative cell (Huh-7), in vitro. Moreover, compared with parental NK-92 cells and CD19-CAR NK cells, stronger cytokine secretions were secreted in MSLN-CAR NK cells cocultured with N87, MKN-28 and AGS. Furthermore, MSLN-CAR NK cells can effectively eliminate gastric cancer cells in both subcutaneous and intraperitoneal tumor models. They could also significantly prolong the survival of intraperitoneally tumor-bearing mice. More importantly, the potent antitumor effect and considerable NK cell infiltration were observed in the patient-derived xenograft treated with MSLN-CAR NK cells, which further warranted the therapeutic effects of MSLN-CAR NK cells to treat gastric cancer. Conclusion: These results demonstrate that MSLN-CAR NK cells possess strong antitumor activity and represent a promising therapeutic approach to gastric cancer.
