Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial

Abstract

<b><i>Introduction:</i></b> Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for the treatment of advanced/metastatic hepatocellular carcinoma (aHCC). Avelumab is a human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3. We report the final analysis from VEGF Liver 100 (NCT03289533), a phase 1b study evaluating safety and efficacy of avelumab plus axitinib in treatment-naive patients with aHCC. <b><i>Methods:</i></b> Eligible patients had confirmed aHCC, no prior systemic therapy, ≥1 measurable lesion, Eastern Cooperative Oncology Group performance status ≤1, and Child-Pugh class A disease. Patients received avelumab 10 mg/kg intravenously every 2 weeks plus axitinib 5 mg orally twice daily until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and investigator-assessed objective response per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) for HCC. <b><i>Results:</i></b> Twenty-two Japanese patients were enrolled and treated with avelumab plus axitinib. The minimum follow-up was 18 months as of October 25, 2019 (data cutoff). Grade 3 treatment-related adverse events (TRAEs) occurred in 16 patients (72.7%); the most common (≥3 patients) were hypertension (<i>n</i> = 11 [50.0%]), palmar-plantar erythrodysesthesia syndrome (<i>n</i> = 5 [22.7%]), and decreased appetite (<i>n</i> = 3 [13.6%]). No grade 4 TRAEs or treatment-related deaths occurred. Ten patients (45.5%) had an immune-related AE (irAE) of any grade; 3 patients (13.6%) had an infusion-related reaction (IRR) of any grade, and no grade ≥3 irAE and IRR were observed. The objective response rate was 13.6% (95% CI: 2.9–34.9%) per RECIST 1.1 and 31.8% (95% CI: 13.9–54.9%) per mRECIST for HCC. <b><i>Conclusion:</i></b> Treatment with avelumab plus axitinib was associated with a manageable toxicity profile and showed antitumor activity in patients with aHCC.

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial

“…4 Several immune checkpoint inhibitor combi nation strategies have been studied for their potential to augment an antitumour immune response. [5][6][7][8][9][10] Hepatocellular carcinoma is associated with immune tolerance, which is potentially related to overexpression of cytokine pathways in the tumour microenvironment, resulting in the recruitment of immunosuppressive cells and the inhibition of cells associated with immune response. VEGF overexpression can inhibit T-cell function, increase myeloid-derived suppressor cells and…”

Durvalumab plus tremelimumab in unresectable hepatocellular carcinoma

“…This result may be attributed to the difference in regimen, in which only one initial priming with anti-CTLA-4 was performed in the HIMALAYA Study. In addition, the hypertension, proteinuria, hand-foot skin reaction, and bleeding events, which are frequently observed in patients treated with anti-PD-1/PD-L1 antibody + anti-VEGF/TKI combination immunotherapy ( 4 - 6 ), were rarely observed.…”

Efficacy and safety of immune checkpoint inhibitors-combined antiangiogenic drugs in the treatment of hepatocellular carcinoma: A systematic review and meta analysis

“…The meta-analysis showed that the combined ORR ( 22 , 25 – 27 ) and DOR ( 25 , 27 ) of PD-1 combined with antiangiogenic inhibitors in hepatocellular carcinoma was HR=19.11, 95% CI=15.99, 22.22, I 2 = 92.7%, p=0.000 and HR=12.26, 95% CI=10.32, 14.21, I 2 = 95.7%, p=0.000. Clinical trials of F. Hoffmann-La Roche Ltd ( 22 ) showed that the ORR of PD-1 combined with antiangiogenic drugs and without PD-1 were HR=27.30, 95% CI=22.54, 32.48 and HR=11.90, 95% CI=7.35, 18.03.…”