Lenvatinib combined with nivolumab in advanced hepatocellular carcinoma-real-world experience

Abstract

Lenvatinib, a multi-tyrosine kinase inhibitor that inhibits vascular endothelial growth factor and fibroblast growth factor receptors pathway, activated the immune response in tumor microenvironment. However, the combination of lenvatinib and anti-PD-1 has been reported in early phase studies. Hence, this study aims to explore the efficacy and toxicity of lenvatinib combined with nivolumab in the real-world setting. Advanced HCC patients who underwent lenvatinib combined with nivolumab (L + N group) treatment at Taipei Veterans General Hospital (Taipei, Taiwan) were reviewed between January 2016 and December 2020. Treatment response and outcomes were collected and analyzed. A control group with lenvatinib (L group) was also included for comparison. Forty patients were included in L + N group and 47 in L group. The L + N group demonstrated a higher objective response rate than L group (45.0% vs. 23.4%, p = 0.03). The L + N group also achieved longer PFS (7.5 vs. 4.8 months, p = 0.05) and OS (22.9 vs. 10.3 months, p = 0.01) than L group. Patients with HBV infection and REFLECT criteria fit demonstrated a trend of better prognosis. The PFS for those with PR, SD and PD groups were 11.2, 6.4, and 2.2 months and OS were non-reached, 14.6 and 4.7 months, respectively. Portal vein thrombosis (HR 4.3, 95% C.I. 1.5–12.8) and AFP > 400 ng/mL (HR 3.3, 95% C.I. 1.1–9.3) were poor prognostic factors and nivolumab used remained a protective factor (HR 0.2, 95% C.I. 0.1–0.7). Dermatitis (35.0%), pruritis (27.5%), and hypothyroidism (27.5%) were the common toxicities. Few patients developed grade 3/4 toxicities, including dermatitis (15%), gastrointestinal bleeding (7.5%), hypertension (5.0%), pneumonitis (2.5%) and stomatitis (2.5%). This is the first real-world data reporting the promising efficacy and tolerable toxicities of lenvatinib combined with nivolumab in advanced HCC. Further randomized trials are prompted.

The action and resistance mechanisms of Lenvatinib in liver cancer

“…This synergistic effect results in normalizing vascularization, which may have impacts on reducing the cancer's resistance to Lenvatinib 67 . In a phase II study of Lenvatinib plus Nivolumab, results were promising, with the Lenvatinib plus Nivolumab group achieving a higher ORR at 45%, longer PFS at 7.5 months, and longer OS at 22.9 months compared to the Lenvatinib group alone 68 . Lenvatinib scored 23.4%, 4.8 months, and 10.3 months for ORR, PFS, and OS, respectively 68 .…”

“…In a phase II study of Lenvatinib plus Nivolumab, results were promising, with the Lenvatinib plus Nivolumab group achieving a higher ORR at 45%, longer PFS at 7.5 months, and longer OS at 22.9 months compared to the Lenvatinib group alone 68 . Lenvatinib scored 23.4%, 4.8 months, and 10.3 months for ORR, PFS, and OS, respectively 68 . Importantly, Lenvatinib plus Nivolumab demonstrates comparable effects in comparison to Atezolizumab and Bevacizumab, which is considered a new first‐line therapy with greater efficacy than Sorafenib and Lenvatinib, which gives patients another option in treating their cancer 68 …”

Adjuvant therapy following curative treatments for hepatocellular carcinoma: current dilemmas and prospects

“…TKIs can not only improve antitumor immune responses by modulating macrophages and myeloid-derived suppressor cells to enhance effector T cell responses, but also help to increase the expression of PD-1 on T cells, thus promoting the action of PD-1 inhibitors (93,94). Atezolizumab plus bevacizumab (95), Lenvatinib plus Pembrolizumab (81), and Lenvatinib plus Nivolumab (96) 97), the 1-year DFS rate of the enrolled patients was 53.85%. In addition, a small RCT including 32 patients conducted buy Zhao et al (98) published preliminary results in 2021, which confirmed the superiority of camrelizumab plus apatinib compared with HAIC as adjuvant therapy in patients with high-risk recurrence factors following LR (the median DFS was not reached vs. 10.5 months).…”

“…TKIs can not only improve antitumor immune responses by modulating macrophages and myeloid-derived suppressor cells to enhance effector T cell responses, but also help to increase the expression of PD-1 on T cells, thus promoting the action of PD-1 inhibitors ( 93 , 94 ). Atezolizumab plus bevacizumab ( 95 ), Lenvatinib plus Pembrolizumab ( 81 ), and Lenvatinib plus Nivolumab ( 96 ) et al. have demonstrated stronger anti-tumor effects than single agents in advanced HCC.…”

Challenges in translating clinical guidelines into real-life practice for management of hepatocellular carcinoma in Taiwan

“…[4] In addition, we published another study showing that the combination of lenvatinib and nivolumab had better efficacy than lenvatinib alone. [5] Furthermore, Wu et al reported that the combination of lenvatinib and pembrolizumab had a high disease control rate and did not affect the ALBI score. [6] Unfortunately, the combination of lenvatinib and pembrolizumab was found to have limited benefits due to the failure of the Leap-002 trial.…”