Effect Of Lenvatinib Research Articles

Atezolizumab/bevacizumab and lenvatinib for hepatocellular carcinoma: A comparative analysis in a European real-world cohort.

Immunotherapy-based combinations are currently the standard of care in the systemic treatment of patients with HCC. Recent studies have reported unexpectedly long survival with lenvatinib (LEN), supporting its use in first-line treatment for HCC. This study aims to compare the real-world effectiveness of LEN to atezolizumab/bevacizumab (AZ/BV). A retrospective analysis was conducted to evaluate the effectiveness and safety of frontline AZ/BV or LEN therapy in patients with advanced HCC across 18 university hospitals in Europe. The study included 412 patients (AZ/BV: n=207; LEN: n=205). Baseline characteristics were comparable between the 2 treatment groups. However, patients treated with AZ/BV had a significantly longer median progression-free survival compared to those receiving LEN. The risk of hepatic decompensation was significantly higher in patients with impaired baseline liver function (albumin-bilirubin [ALBI] grade 2) treated with AZ/BV compared to those with preserved liver function. Patients with alcohol-associated liver disease had poorer baseline liver function compared to other etiologies and exhibited a worse outcome under AZ/BV. In this real-world cohort, survival rates were similar between patients treated with LEN and those treated with AZ/BV, confirming that both are viable first-line options for HCC. The increased risk of hepatic decompensation in patients treated with AZ/BV who have impaired baseline liver function underscores the need for careful monitoring. Future trials should aim to distinguish more clearly between metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease.

Real-world safety and effectiveness of lenvatinib in unresectable hepatocellular carcinoma in Korea: post-marketing study.

Aim: This post-marketing surveillance study evaluated the safety and effectiveness of lenvatinib as first-line treatment for unresectable hepatocellular carcinoma in Korea.Materials & methods: Adverse drug reactions (ADRs) and other safety and effectiveness end points were assessed in patients who initiated lenvatinib according to the approved label in republic of Korea.Results: Among 658 lenvatinib-treated patients, ADRs were reported in 57.8%; ADRs grade ≥3 in 13.5%. The most common grade ≥3 ADRs were asthenia (1.2%) and hepatic encephalopathy (1.2%). Physician-reported tumor responses (n=511) were complete (1.0%) or partial (12.9%) response and stable (45.2%) or progressive disease (40.9%); objective response rates were higher with longer lenvatinib treatment duration (p<0.001).Conclusion: Lenvatinib was generally well tolerated and effective in real-world clinical practice in Korea.Clinical trial registration: ClinicalTrials.gov NCT05225207.

Effects of lenvatinib on glucose, cholesterol, triglycerides and estimated cardiovascular risk in patients with advanced thyroid cancer.

Multitarget kinase inhibitors (MKIs) are effective options in the treatment of cancer, significantly increasing the progression-free survival (PFS) of many tumors. Data about severity and prevalence of metabolic adverse events is scarce and may be significant in patients with a better survival. The aim of this study was to investigate glucose and lipids values of patients treated with lenvatinib. Secondary aims included evaluating changes in the estimated risk of cardiovascular disease and the relationship between metabolic alterations and tumor response to therapy. A retrospective pilot study on 29 patients with advanced differentiated thyroid cancer was conducted. Clinical and biochemical characteristics were collected at the day of therapy initiation and follow up. The 10-year risk of cardiovascular disease was estimated with the SCORE2 and SCORE2-OP algorithms. Tumor burden change was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). No differences in glucose values were observed. A significant increase in total cholesterol (208 ± 41 versus 245 ± 67 mg/dl), triglycerides (112 [interquartile range, 58-326] versus 157 [78-296] mg/dl), calculated LDL cholesterol (128 [66-204] versus 140 [81-308] mg/dl) and cardiovascular risk was observed from baseline to follow up. Furthermore, these parameters increase progressively with increasing tumor response to therapy. Despite limitations, this study shows an association between the use of lenvatinib and the development of lipid alterations in patients with advanced thyroid cancer. However, further investigation is necessary for a more comprehensive understanding of the adverse metabolic profile of MKIs.

Dual effects of targeting neuropilin-1 in lenvatinib-resistant hepatocellular carcinoma: inhibition of tumor growth and angiogenesis.

In the era of immunotherapy, lenvatinib (LEN) still holds an important position in the sequential treatment of advanced hepatocellular carcinoma (HCC). However, the sustained therapeutic effect of LEN is not sufficient, and there is a need to address the development of resistance. Neuropilin-1 (NRP1) is known to act as a coreceptor for epidermal growth factor receptor (EGFR), Met, and vascular endothelial growth factor receptor 2 (VEGFR2), which have been reported to be involved in LEN resistance. In this study, we used cell culture and in vivo xenograft models to evaluate the contribution of NRP1 in the acquisition of LEN resistance in HCC as well as the potential of NRP1 as a therapeutic target. LEN resistance increased EGF/EGFR and hepatocyte growth factor (HGF)/Met signaling in liver cancer cells and VEGFA/VEGFR2 and HGF/Met signaling in vascular endothelial cells, thereby promoting cell proliferation, cell migration, and angiogenesis. We found that activation of NRP1 is essential for the enhancement of these signaling. In addition, NRP1 inhibition combined with LEN therapy synergistically improved the antitumor effects against LEN-resistant HCC, indicating that NRP1 is an attractive therapeutic target.NEW & NOTEWORTHY We demonstrated that neuropilin-1 (NRP1) was an essential coreceptor mediating the activation of multiple signaling pathways in the acquisition of resistance to lenvatinib (LEN) in HCC. The addition of NRP1 inhibition to LEN had a synergistic antitumor effect on LEN-resistant HCC in culture and in vivo xenograft models.

Analysis of the Safety and Effectiveness of Lenvatinib + TACE-HAIC + PD-1 Inhibitor for Intermediate and Advanced Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the fourth leading cause of cancer death in the world. Aims: This study aimed to investigate the efficacy and safety of Lenvatinib + PD-1 inhibitor + TACEHAIC (LePTaHAIC) versus Sorafenib + TACE (SorTACE) for patients with intermediate and advanced HCC. Methods: In this retrospective study, patients diagnosed with BCLC stage B/C HCC were included. All patients were treated with LePTaHAIC (LePTaHAIC group) or SorTACE (SorTACE group) between September 2019 and September 2020. Outcomes, including progression-free survival (PFS), conversion surgical resection rate, objective remission rate (ORR), overall survival (OS), and treatment-related adverse events (AEs) were analyzed and compared between the two treatment modalities. Results: In total, 65 eligible patients were recruited, with 35 assigned to receive LePTaHAIC and 30 assigned to undergo SorTACE. Median PFS (11.4 vs. 5.13 months) and OS (26 vs. 10.08 months) in the LePTaHAIC group were significantly higher compared to the SorTACE group (both P &lt; 0.0001). The ORR (mRECIST standard) of the LePTaHAIC group was markedly higher compared to the SorTACE group (71.4% vs. 40%, P = 0.01). In the LePTaHAIC group, 11 patients underwent surgical resection (BCLC stage B: n = 4, BCLC stage C: n = 7) and 3 patients achieved complete pathological remission (pCR), while one patient in the SorTACE group underwent surgical resection. The conversion surgical resection rate of the LePTaHAIC group was significantly higher compared to the SorTACE group [31.4% (11/35) vs. 3.3% (1/30), P = 0.004]. Patients with LePTaHAIC had more frequent grade 3-4 treatmentrelated AEs, especially thrombocytopenia, compared to the SorTACE group (22.9% vs. 3.3%, P = 0.02). Conclusion: LePTaHAIC exhibited acceptable toxic effects and improved survival compared to SorTACE in intermediate and advanced HCC.

Abstract P24: Elucidating the Mechanism of Action of Lenvatinib in Estrogen Receptor-Positive (ER+) Breast Cancer

Abstract Background: ER+ breast cancer is the most common subtype of breast cancer. Although most patients respond initially to endocrine therapy (ET), endocrine resistance inevitably develops, leading to disease progression. Lenvatinib, a multi-kinase inhibitor, demonstrated clinical benefit in the treatment of patients with advanced ER+ breast cancer who have progressed on ET in a phase Ib/II clinical trial from our group. Our study aims to elucidate the molecular mechanism of action of lenvatinib in ER+ breast cancer. Methods: A cell viability assay was performed to assess the sensitivity of four ER+ cell lines to lenvatinib. Western blot was used to elucidate its effect on downstream pathway signalling, and cell cycle arrest investigated through flow cytometry. A series of functional assays, including BrdU, colony formation and wound-healing assays assessed proliferative, clonogenic and migratory activity respectively. The effect of lenvatinib on epithelial-mesenchymal transition (EMT) was analysed using RT-qPCR, and compared with siRNA knockdown (KD) of Fgfr1 and Fgfr2. Results: ER+ cell lines demonstrated sensitivity to lenvatinib in the micromolar range. Western blot showed downregulation of FGFR1, FGFR2, pERK and pAKT expression post-treatment. Lenvatinib was found to induce a G1 phase arrest, suppressed cell proliferation in a dose-dependent manner, and diminished both the clonogenic ability and migratory activity of ER+ cells. Lenvatinib treatment reduced expression of Fgfr1, Fgfr2 and the mesenchymal markers N-cad and Fibronectin, while increasing the expression of the epithelial markers E-cad and Claudin-1, indicating potential inhibition of EMT. A similar change in EMT marker expression was observed in Fgfr1 KD but not Fgfr2 KD cells. Conclusion: Lenvatinib demonstrated potent anti-cancer activity and induction of G1 phase arrest, leading to decreased cell proliferation, reduction of clonogenic ability and cell migration. EMT inhibition was also observed, possibly through the FGFR1 signalling pathway. Citation Format: Natasha Gandasasmita, Gauri Vaidya, Arpita Datta, Charlie Marvalim, Joline Si Jing Lim, Soo Chin Lee. Elucidating the Mechanism of Action of Lenvatinib in Estrogen Receptor-Positive (ER+) Breast Cancer [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P24.

Lenvatinib plus Pembrolizumab Combination Therapy for Advanced or Recurrent Endometrial Cancer: A Single-Center, Retrospective Analysis.

A multi-kinase inhibitor, lenvatinib, plus an immune checkpoint inhibitor, pembrolizumab, became a viable therapeutic option for advanced or recurrent endometrial cancer in Japan by the end of 2021. The Japanese population has a relatively unique genetic background. Hence, the safety profile and effectiveness of lenvatinib plus pembrolizumab may differ between the Japanese and other populations. This single-center, retrospective study aimed to evaluate the treatment efficacy of lenvatinib plus pembrolizumab and the safety profile of the associated adverse events. The clinical records of 15 patients, who received lenvatinib plus pembrolizumab for advanced or recurrent endometrial cancer at the Tohoku University Hospital, were reviewed. Best overall response and disease control rates were 40.0% and 73.3%, respectively. Treatment was discontinued owing to disease progression and adverse events in six patients, respectively. As of the end of July 2023, treatment was ongoing in the remaining three patients. The median treatment and progression-free survival durations were 118 and 258 days, respectively. Relative dose intensity of lenvatinib was not positively associated with progression-free survival, neither during the first 4 weeks after treatment initiation nor during the entire treatment period. All patients experienced one or more adverse events, the most common of which were hypothyroidism (90%) and hypertension (83.3%). Among the 15 patients, 13 required lenvatinib dose reduction owing to adverse events. One patient developed grade 4 interstitial pneumonia requiring intensive care. Our results validate the short-term efficacy of lenvatinib plus pembrolizumab, and indicate that dose optimization of lenvatinib could be individualized without impairing efficacy.

AZGP1 activation by lenvatinib suppresses intrahepatic cholangiocarcinoma epithelial-mesenchymal transition through the TGF-β1/Smad3 pathway

Intrahepatic cholangiocarcinoma (ICC) is a primary liver malignancy and is characterized by highly aggressive and malignant biological behavior. Currently, effective treatment strategies are limited. The effect of lenvatinib on ICC is unknown. In this study, we found that AZGP1 was the key target of lenvatinib in ICC, and its low expression in ICC cancer tissues was associated with a poor prognosis in patients. Lenvatinib is a novel AZGP1 agonist candidate for ICC that inhibits ICC-EMT by regulating the TGF-β1/Smad3 signaling pathway in an AZGP1-dependent manner. Furthermore, we found that lenvatinib could increase AZGP1 expression by increasing the acetylation level of H3K27Ac in the promoter region of the AZGP1 gene, thereby inhibiting EMT in ICC cells. In conclusion, lenvatinib activates AZGP1 by increasing the acetylation level of H3K27Ac on the AZGP1 promoter region and regulates the TGF-β1/Smad3 signaling pathway in an AZGP1-dependent manner to inhibit ICC-EMT. This study offers new insight into the mechanism of lenvatinib in the treatment of ICC and provides a theoretical basis for new treatment methods.

Effectiveness of lenvatinib in progressive metastatic radioiodine refractory well differentiated and poorly differentiated thyroid carcinoma

Effectiveness of lenvatinib in progressive metastatic radioiodine refractory well differentiated and poorly differentiated thyroid carcinoma

Abstract 5124: The effect of lenvatinib in combination with chemotherapy plus immune checkpoint inhibitors on tumor microenvironments in the mouse syngeneic tumor model

Abstract Introduction: Lenvatinib (LEN) is an oral, multiple-receptor, tyrosine kinase inhibitor that mainly targets vascular endothelial growth factor and fibroblast growth factor receptors. Combination therapy with LEN and everolimus is approved for people with advanced renal cell carcinoma (RCC). Combination therapy with LEN and pembrolizumab, an anti human-programmed-cell-death-1 (PD-1) antibody, is also approved for the treatment of people with advanced endometrial cancer and advanced RCC. In this study, we investigated the antitumor activity of LEN in combination with chemotherapy and immune checkpoint inhibitors (ICIs), and explored the mechanism of action underlying these effects, in the mouse lung cancer syngeneic model. Methods: In the LL/2 mouse Lewis lung carcinoma model, LEN was dosed at either 3 or 10 mg/kg (orally; once daily for 2 weeks) with or without cisplatin 4 mg/kg (intravenously; 3 or 4 times, twice weekly) and with or without anti-PD-1 200 ug/head + anti cytotoxic T-lymphocyte antigen 4 (CTLA4) antibodies 10mg/kg (intraperitoneally; twice weekly). Functional blood vessels were evaluated in tumor microenvironments by injections of Hoechst 33342 (Hoechst) into the tail veins of mice. The Hoechst-stained area and expressions of angiogenesis/immune-cell-related molecules were analyzed by immunohistochemistry (IHC) analysis. Results: In this model, the combination treatment of LEN 3 mg/kg + cisplatin showed significant tumor growth inhibitory activity compared with each single agent without any marked body-weight loss. LEN 10 mg/kg + cisplatin did not show enhanced antitumor activity vs LEN 10 mg/kg as a single agent. IHC analysis using anti-CD31 antibody showed that LEN 3 mg/kg daily decreased microvessel density in tumors after 4 days. In addition, LEN 3 mg/kg daily for 4 days showed a trend toward an increase of the number of functional blood vessels stained with Hoechst in the tumor microenvironment compared with untreated controls. The combination of LEN 3 mg/kg + cisplatin + ICIs (anti-PD-1+anti-CTLA4) significantly inhibited tumor growth compared with combinations of cisplatin + ICIs. Conclusion: Our findings show that LEN 3 mg/kg enhances the antitumor activity of cisplatin in the LL/2 mouse Lewis lung carcinoma tumor model; and LEN 3 mg/kg + cisplatin + ICIs shows greater antitumor activity compared with cisplatin + ICIs. The results of the IHC analysis suggest that LEN 3 mg/kg inhibits angiogenesis. Conversely, LEN 3 mg/kg increases functional vessels in tumor microenvironments. This situation could enhance combination antitumor activity of chemotherapy, and also chemotherapy + ICIs combination treatment. Further analysis of the mechanism of action of LEN 3 mg/kg in combination with chemotherapy + ICIs is warranted. Citation Format: Yu Kato, Yoichi Ozawa, Keito Adachi, Masahiko Kume, Yusuke Adachi, Yudai Narita, Megumi Kuronishi, Junji Matsui, Akira Yokoi, Yasuhiro Funahashi. The effect of lenvatinib in combination with chemotherapy plus immune checkpoint inhibitors on tumor microenvironments in the mouse syngeneic tumor model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5124.

Effectiveness of lenvatinib plus immune checkpoint inhibitors in primary advanced hepatocellular carcinoma beyond oligometastasis.

Targeted therapy combined with immune checkpoint inhibitors is considered a promising treatment for primary advanced hepatocellular carcinoma (HCC). Nevertheless, the difference between synchronous and asynchronous treatment of lenvatinib with programmed death receptor-1 (PD-1) inhibitor in advanced HCC is still unclear. The aim of this investigation is to evaluate the effectiveness of synchronous and asynchronous of lenvatinib and PD-1 inhibitor on the advanced HCC beyond oligometastasis. In this study, 213 patients from four institutions in China were involved. Patients were split into two collections: (1) lenvatinib plus PD-1 inhibitor were used synchronously (synchronous treatment group); (2) patients in asynchronous treatment group received PD-1 inhibitor after 3 months of lenvatinib treatment prior to tumour progression. To analyse progression-free survival (PFS), overall survival (OS), efficacy and safety of patients in both groups, we employed propensity score matching (PSM). The 6-, 12- and 24-month OS rates were 100%, 93.4% and 58.1% in the synchronous treatment group and 100%, 71.5% and 25.3% in the asynchronous treatment group, respectively. In contrast to the asynchronous treatment group, the group treated synchronously exhibited a substantially enhanced OS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.30-0.66; p < .001). The 6-, 12- and 18-month PFS rates were 82.6%, 42.6% and 10.8% in the synchronous treatment group and 63.3%, 14.2% and 0% in the asynchronous treatment group, respectively. A significant difference was observed in the PFS rate (HR, 0.46; 95% CI, 0.33-0.63; p < .001) between the two collections. Patients with advanced HCC beyond oligometastasis, simultaneous administration of lenvatinib and PD-1 inhibitor led to significant improvements in survival.

Safety and Effectiveness of Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma in Real-World Clinical Practice: An Observational Post-Marketing Study in Japan.

Lenvatinib was approved for use in unresectable hepatocellular carcinoma (uHCC) in Japan in 2018. Patients with diverse clinical characteristics receive lenvatinib treatment in clinical practice. Thus, it is crucial to evaluate the safety and effectiveness of lenvatinib in real-world clinical settings. This study aimed to evaluate the real-world safety and effectiveness of lenvatinib for uHCC in clinical practice in Japan. Between July 2018 and January 2019, patients with uHCC who were administered lenvatinib for the first time were enrolled in this prospective, multicenter, observational post-marketing study (NCT03663114). Patients were orally administered lenvatinib and followed up for 12 months. For safety, adverse drug reactions (ADRs) were evaluated. For effectiveness, the objective response rate (ORR) was calculated to evaluate tumor response. Overall survival (OS) was estimated using the Kaplan-Meier method. Data of 703 patients (median age, 73 years; 80.2% males) were analyzed. The median (range) treatment duration was 25.3 (0.3-68.9) weeks. The mean ± standard deviation initial dose was 7.37 ± 1.65 mg in patients with body weight <60 kg and 10.43 ± 2.49 mg in those with body weight ≥60 kg. ADRs (any grade) were reported in 84.9% of the patients, with Grade ≥3 ADRs reported in 42.5% of the patients. The most common ADRs (>10%) were decreased appetite, fatigue, hypertension, proteinuria, palmar-plantar erythrodysesthesia, hypothyroidism, and diarrhea. The median OS of the 703 patients was 498.0 days. In 494 patients assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), the ORR was 39.5% (95% confidence interval: 35.1-43.9%). Patients with better liver or renal function at baseline achieved significantly higher ORR than those with worse liver or renal function. In patients with uHCC in real-world clinical practice in Japan, treatment with lenvatinib was generally well tolerated, and no new safety concerns were identified. The ORR and median OS were similar to or better than the results of the Japanese subset of the global Phase III REFLECT trial. Our results demonstrated that clinically meaningful treatment responses were achieved with lenvatinib in real-world clinical practice.

Abstract 6190: Anti-tumor effects of lenvatinib plus anti-PD-1 in syngeneic murine cervical cancer models

Abstract Immune checkpoint inhibitors (ICIs) have been applied in patients with various solid tumors since they were approved by U.S. FDA in 2011. However, only less than 20% of patients benefit from ICIs including anti-programmed cell death protein 1 (aPD-1). Recently, many studies to improve the response of ICIs are in progress, and especially, vascular endothelial growth factor receptors (VEGFR) pathway was emerged as major target. VEGFR inhibitors regulate the differentiation of tumor-associated macrophage, antigen presenting dendritic cell, and T cell infiltration, so they make a synergic antitumor effect with ICIs. In this study, we investigated the effect of lenvatinib combined with anti-mouse PD-1 in syngeneic murine cervical cancer models to show whether VEGFRi enhance the antitumor effect of ICIs. We established syngeneic mouse models of cervical cancer to confirm synergic effect by lenvatinib combined with aPD-1. 1x107 cells of U14 cells were injected subcutaneously into the flanks of BALB/c wild- type (immunocompetent) mice and BALB/c nude (immunocompromised) mice. They were treated with lenvatinib when the tumor volume reached at 200 mm3, subsequently, aPD-1 was administered in immunocompetent mice. We administrated lenvatinib (10 mg/kg, orally, daily) and aPD-1(200 µg per mouse, intraperitoneally (I.P), twice a week) for 3 weeks. Tumor volume was measured twice a week. After the end of the experiment, we harvested tumors and spleens, and performed histological analysis. All experiments were approved by the Institutional Animal Use and Care Committee (IACUC) in Asan Institute for Life Science.Although the tumor was increased despite lenvatinib treatment in immunocompromised model with BALB/c nude mice, on the 17th day after injection, the tumor growth was inhibited in lenvatinib group compared with vehicle group (2914 mm3 vs. 3663 mm3, respectively) (P=0.0014). On the other hand, the tumor volume was significantly reduced by lenvatinib in the immunocompetent model (278 mm3 in Len vs. 490 mm3 in Veh) (P=0.0347), particularly the tumor size was decreased since 2 weeks of injection. Subsequently, we investigated the synergistic effects of combination with lenvatinib and aPD-1 in immunocompetent model. Each single treatment group showed the reduction of tumor volume compared to vehicle group (278 mm3 in Len and 258 mm3 in aPD-1 vs. 490 mm3 in Veh). Furthermore, the lenvatinib plus aPD-1 combination group reduced tumor volume to 110mm3 on the 24th day after injection and it was significantly different compared to each single treatment group (P=0.13868 and P=0.27385, respectively).In this study, anti-tumor effect of aPD-1 was enhanced by the regulation of tumor microenvironment with lenvatinib in immunocompetent murine cervical cancer models. In conclusion, addition of lenvatinib is expected to increase the efficacy of ICIs in patients with cervical cancer who have the resistance or insensitivity to ICIs. Citation Format: Su-Bin Park, Ji-Sik Kang, Min-Je Kim, Shin-Wha Lee, Dong-Woo Kang, Yong-Man Kim. Anti-tumor effects of lenvatinib plus anti-PD-1 in syngeneic murine cervical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6190.

Abstract 5136: Development of a novel gene expression signature that correlates with intratumor microvessel density and antitumor activity of lenvatinib

Abstract Lenvatinib is a multiple receptor tyrosine kinase inhibitor and an angiogenesis inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. In our previous study, we reported that human xenograft tumors sensitive to lenvatinib showed higher microvessel density (“MVD (IHC)”) than relatively resistant tumors in immunohistochemistry (IHC). Although MVD (IHC) is a potential indicator to predict antitumor activity of lenvatinib, available IHC data are limited. Here, we investigated a novel gene expression signature (MVD gene score) calculated from RNA-sequencing (RNA-seq) data that reflects MVD (IHC) and antitumor effect of lenvatinib. Tumor tissues were collected from 12 mouse syngeneic tumor models followed by RNA-seq. We also stained CD31 in the same tumors and calculated MVD (IHC) score by dividing the number of CD31 positive blood vessels by tumor area. Genes that met the following criteria were selected for MVD gene score calculation: (1) genes that are specifically expressed on endothelial cell cluster in in-house single cell RNA-seq data using Hepa 1-6 mouse hepatocellular carcinoma tumor tissues; (2) well-known angiogenesis markers from literature or genes whose expression show significant correlation with MVD (IHC) in mouse syngeneic tumor models. MVD gene score was calculated as the average of logarithm transformed gene expression values. In order to examine applicability of MVD gene score, we compared MVD (IHC) and MVD gene score to lenvatinib antitumor activities on mouse syngeneic tumors. We measured MVD (IHC) and computed MVD gene score from RNA-seq data using matched tumor tissues of 12 mouse syngeneic models. MVD gene score was correlated with MVD (IHC). As reported, lenvatinib sensitive tumor models showed higher MVD (IHC) score. They also showed higher MVD gene score calculated from RNA-seq data. Our newly developed MVD gene score has a potential to predict the antitumor activity of angiogenic inhibitors such as lenvatinib using RNA-seq data in tumor samples. Further validation study is ongoing using various human tumor samples. Citation Format: Megumi Kuronishi, Yoichi Ozawa, Takayuki Kimura, Yu Kato. Development of a novel gene expression signature that correlates with intratumor microvessel density and antitumor activity of lenvatinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5136.

Network Pharmacology-Based Strategy to Investigate the Mechanisms of Lenvatinib in the Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a complex and refractory malignant tumor, ranking the third cause of cancer-related deaths worldwide. Lenvatinib is currently employed to treat advanced, unresectable HCC as a first-line drug. The purpose of this study was to explore the pharmacological mechanisms of lenvatinib acting on HCC through the analysis of differential expressed genes based on network pharmacology. The target genes of lenvatinib were collected from PubChem, SwissTargetPrediction, PharmMapper, and BATMAN-TCM online public databases. In addition, related gene targets for HCC were obtained using NCBI Gene Expression Omnibus (NCBI-GEO) database. Afterward, the protein-protein interaction (PPI) network was established to visualize and understand the interaction relationships of overlapping gene targets from both lenvatinib and HCC. Furthermore, according to the data obtained, Gene Ontology (GO) analysis indicated that these intersectant genes were mainly enriched in response to xenobiotic stimulus, gland development, ion channel complex, membrane raft, and steroid binding. Besides, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis suggested that the therapeutic effects of lenvatinib on HCC probably involved bile secretion, MAPK signaling pathway, cGMP-PKG signaling pathway, PI3K-Akt signaling pathway, and Ras signaling pathway. Moreover, a total of six key differential genes, namely, ALB, CCND1, ESR1, AR, CCNA2, and AURKA, were identified as most significant targets associated with lenvatinib treating HCC and further verified by molecular docking, which demonstrated that lenvatinib had a strong binding efficiency with these six key gene-encoded proteins. Taken together, this study systematically provided new insights for researchers to determine the intervention mechanisms of lenvatinib in HCC therapy.

Lenvatinib Plus Anti-PD-1 Combination Therapy for Advanced Cancers: Defining Mechanisms of Resistance in an Inducible Transgenic Model of Thyroid Cancer.

Background: Combination therapy with lenvatinib plus programmed death-1 (PD-1) immune checkpoint blockades (ICBs) is under investigation in many solid tumors, including thyroid cancer. Lenvatinib is known to reduce angiogenesis and may overturn the immunosuppressive effects of vascular endothelial growth factor in the tumor microenvironment. Previous studies investigating the effects of VEGF receptor inhibition on the immune response were performed in rapidly growing tumor models where immune equilibrium is not established before treatment. We hypothesize that physiologically relevant preclinical models are necessary to define mechanisms of resistance to immune-targeted combination therapies. Methods: We utilized the TPO-CreER/BrafV600E/wt/Trp53Δex2-10/Δex2-10 inducible transgenic model of advanced thyroid cancer to investigate lenvatinib treatment in the context of an anti-PD-1 ICB. Following tumor establishment, 3.5 months postinduction, mice were treated with high- (10 mg/kg) or low-dose (2 mg/kg) lenvatinib, anti-PD-1, or combination of lenvatinib with anti-PD-1. Tumor volume and lung metastases were assessed in each group. Immune infiltrate was characterized by flow cytometry and immunohistochemistry, and TCRß sequencing was performed to further investigate the T cell response. Results: Both low- and high-dose lenvatinib reduced tumor volume, while anti-PD-1 had no effect, alone or in combination. Although both low- and high-dose lenvatinib reduced vascular density, low-dose lenvatinib was superior in controlling tumor size. Lung metastases and survival were not improved with therapy despite the effects of lenvatinib on primary tumor size. Low-dose lenvatinib treatment led to a subtle reduction in the dominant Ly6G+CD11b+ myeloid cell population and was associated with increased CD4+ T cell infiltrate and enrichment in 4-1BB+ and granzyme B+ CD4+ T cells and FoxP3+ regulatory T cells. Polyclonal T cell expansion was evident in the majority of mice, suggesting that a tumor-specific T cell response was generated. Conclusions: The effects of lenvatinib on the immune response were most pronounced in mice treated with low-dose lenvatinib, suggesting that dose should be considered in clinical application. While the immune-modulating potential of lenvatinib is encouraging, alterations in the immune milieu and T cell activation status were insufficient to sustain durable tumor regression, even with added anti-PD-1. Additional studies are necessary to develop more effective combination approaches in low-mutation burden tumors, such as thyroid cancer.

The Effect of Lenvatinib in Patients with Thyroid Cancer with Pericardial Metastasis, Which Can Cause Cardiac Tamponade

The Effect of Lenvatinib in Patients with Thyroid Cancer with Pericardial Metastasis, Which Can Cause Cardiac Tamponade

Impact of lenvatinib on renal function: long-term analysis of differentiated thyroid cancer patients

BackgroundBecause lenvatinib is well known to induce proteinuria by blocking the vascular endothelial growth factor (VEGF) pathway, renal function is a concern with long-term administration of lenvatinib. The long-term effects of lenvatinib on renal function in patients with advanced differentiated thyroid carcinoma (DTC) were analyzed.MethodThis study involved 40 DTC patients who continued lenvatinib therapy for ≥6 months. Estimated glomerular filtration rate (eGFR) was calculated as an indicator of renal function. The temporal course of eGFR, effects of baseline eGFR on eGFR changes, and factors affecting renal impairment were investigated.ResultsThe overall cohort showed sustainable decreases in eGFR, with decreased values of 11.4, 18.3, and 21.0 mL/min/1.73 m2 at 24, 36, and 48 months after starting treatment, respectively. No differences in eGFR decrease every 6 months were seen for three groups classified by baseline eGFR ≥90 mL/min/1.73 m2 (n = 6), < 90 but ≥60 mL/min/1.73 m2 (n = 26), or < 60 but ≥45 mL/min/1.73 m2 (n = 8). Grade 3 proteinuria was associated with declines in eGFR (p = 0.0283). Long observation period was also associated with decreases in eGFR (p = 0.0115), indicating that eGFR may decrease in a time-dependent manner.ConclusionLenvatinib can induce declines in eGFR, particularly with treatment duration > 2 years, regardless of baseline eGFR. Proteinuria is a risk factor for declines in eGFR. Patients who start lenvatinib with better renal function show a renal reserve capacity, prolonging clinical outcomes. Decision-making protocols must balance the benefits of lenvatinib continuation with acceptable risks of harm.

Correction to: Safety and Effectiveness of Lenvatinib in 594 Patients with Unresectable Thyroid Cancer in an All-Case Post-Marketing Observational Study in Japan

Correction to: Safety and Effectiveness of Lenvatinib in 594 Patients with Unresectable Thyroid Cancer in an All-Case Post-Marketing Observational Study in Japan

Abstract 966: Lenvatinib induces apoptosis and inhibits metastasis through downregulate Wnt/GSK3β/NF-κB in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is a prevalent cancer type and also the leading cause of cancer death among Taiwanese. The current treatments for liver cancer include eradication, chemical, targeted and radiotherapy… etc. Unfortunately, radiation therapy is quite harmful to patients and results in hepatic injury. Other treatment methods can only prolong patient's life for few months, and has considerable side effects; therefore, it is extremely important to find other more effective drugs for HCC. HCC patients with higher expression level of ASPM (abnormal spindle-like microcephaly associated) have significantly lower survival rate than those of patients with lower expression level. ASPM is the co-activator of Wnt, which can activate the Wnt/β-catenin signaling pathway to increase the performance of GSK3β (Glycogen synthase kinase 3 beta) and regulate angiogenesis. In addition, studies have also found that GSK3β can also activate the transcription factor NF-κB, causing a large number of downstream proteins upregulation and thus triggered tumor growth and metastasis. Recent studies suggested that sorafenib has ability to inhibit the activation of transcription factor NF-κB and the expression of its downstream related proteins. Lenvatinib is also a multi-kinase inhibitor and had been approved by FDA for HCC treatment, which is more effective and with fewer skin side effects than sorafenib. However, whether the anti-tumor efficacy of lenvatinib in HCC was associated with the regulation of Wnt/GSK3β/NF-κB in HCC is remaining unclear. We aim to investigate whether the effect of lenvatinib in HCC, such as apoptosis induction and tumor metastasis inhibition, were associated with the inactivation of Wnt/GSK3B/NF-κB. Our studies demonstrated that lenvatinib can induce cytotoxicity of human HCC Hep3B and Huh7 cells. Lenvatinib may induce apoptosis effect via activated extrinsic- and intrinsic-apoptosis related molecules, including cleaved caspase-3, -8 and -9. Lenvatinib also significantly inhibited metastasis through the reduction of NF-κB-mediated metastasis associated proteins expression (MMP-2, MMP-9 and VEGF) and inhibition of invasion/migration ability in HCC cells. In addition, the inhibition of ASPM, Wnt and GSK3β were found after lenvatinib treatment in both in vitro and in vivo models. NF-κB activation was also effectively suppressed by lenvatinib in cells and animal model. Tumor growth inhibition was also found in lenvatinib treatment group. In conclusion, lenvatinib induces apoptosis and suppresses metastasis was associated with Wnt/GSK3β/NF-κB inactivation. Citation Format: Tsu-Lan Chao, Zhao-Lin Tan, I-Tsang Chiang, Yuan Chiang, Fei-Ting Hsu. Lenvatinib induces apoptosis and inhibits metastasis through downregulate Wnt/GSK3β/NF-κB in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 966.