Long-term follow-up for the CLEAR trial confirms the deep and durable tumor-response benefit of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma (aRCC). The results ...support the use of this combination as a standard-of-care first-line treatment for aRCC.
In the phase 3 CLEAR trial, lenvatinib plus pembrolizumab (L + P) showed superior efficacy versus sunitinib in treatment-naïve patients with advanced renal cell carcinoma (aRCC). The combination treatment was associated with a robust objective response rate of 71%. Here we report tumor responses for patients in the L + P arm in CLEAR, with median follow-up of ∼4 yr at the final prespecified overall survival (OS) analysis. Tumor responses were assessed by independent review using Response Evaluation Criteria in Solid Tumors v1.1. Patients with a complete response (CR; n = 65), partial response (PR) with maximum tumor shrinkage ≥75% (near-CR; n = 59), or PR with maximum tumor shrinkage <75% (other PR; n = 129), were characterized in terms of their baseline characteristics. The median duration of response was 43.7 mo (95% confidence interval CI 39.2–not estimable) for the CR group, 30.5 mo (95% CI 22.4–not estimable) for the near-CR group, and 17.2 mo (95% CI 12.5–21.4) for the other PR group. The 36-mo OS rates were consistently high in the CR (97%), near-CR (86%), and other PR (62%) groups. Robust objective response rates were observed across International Metastatic RCC Database Consortium favorable-risk (69%, 95% CI 60–78%), intermediate-risk (73%, 95% CI 67–79%), and poor-risk (70%, 95% CI 54–85%) subgroups. The robust response to L + P supports this combination as a standard-of-care first-line treatment for patients with aRCC.
The CLEAR trial enrolled patients with advanced kidney cancer who had not previously received any treatment for their cancer. Here we report results for tumor shrinkage observed in the group that received lenvatinib plus pembrolizumab combination treatment during the trial. Shrinkage of target tumors with this combination was long-lasting and was observed in patients irrespective of their disease severity.
This trial is registered on ClinicalTrials.gov as NCT02811861.
We herein report two patients with hepatocellular carcinoma (HCC) who exhibited intraabdominal bleeding caused by tumor rupture soon after lenvatinib initiation. A hypervascular nodule was present in ...the lateral segment manifesting extrahepatic protrusion in an 81-year-old-man and in the caudate lobe, which was completely occupied by the tumor, in an 83-year-old-man. Both patients were given lenvatinib, and epigastralgia occurred suddenly three and five days later. Computed tomography revealed high-attenuation areas suggesting bleeding around the left and caudate lobes. Considering the strong antiangiogenic effects by lenvatinib, transcatheter arterial embolization should be performed before lenvatinib initiation in patients with subcapsular HCC.
Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective ...observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age >65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74–39.00, p < 0.01, history of diabetes mellitus (OR 7.79, 95% CI 1.31–46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22–13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0–2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.
The recent randomized controlled phase III CLEAR trial results are the last to complement immune checkpoint inhibitor (ICI)-based doublet combination therapies for treatment-naïve metastatic ...clear-cell renal cell carcinoma. The CLEAR trial demonstrated an improved progression-free survival (PFS), overall survival (OS), and an objective response rate (ORR) benefit for the combination of lenvatinib plus pembrolizumab over sunitinib. The CheckMate-9ER trial update demonstrated an ongoing PFS, OS, and quality-of-life benefit for cabozantinib plus nivolumab over sunitinib as did the update of Keynote-426 for axitinib plus pembrolizumab in the intention-to-treat population, with a PFS benefit seen across all International Metastatic Database Consortium (IMDC) subgroups. In the IMDC intermediate- and poor-risk groups, the CheckMate-214 trial of ipilimumab plus nivolumab confirmed the OS benefit with a PFS plateauing after 30 months. The RCC Guidelines Panel recommends three tyrosine kinase inhibitors + ICI combinations of axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab across all IMDC risk groups in advanced first-line RCC, and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate- and poor-risk groups.
New data from combination trials with immune checkpoint inhibitors for advanced kidney cancer confirm a survival benefit for lenvatinib plus pembrolizumab, cabozantinib plus nivolumab (with improved quality-of-life), axitinib plus pembrolizumab, and ipilimumab plus nivolumab. These combination therapies are recommended as first-line treatment for advanced kidney cancer.
Longer follow-up data and new trial data from phase III randomised controlled trials investigating immune checkpoint blockade (programmed death-receptor PD-1 or its ligand PD-L1) in advanced clear-cell renal cell carcinoma (RCC) in combination with tyrosine kinase inhibitors or dual immunotherapy have recently been released. The RCC Guidelines Panel recommends the combinations of axitinib plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab across all International Metastatic Database Consortium (IMDC) risk groups in advanced first-line RCC and dual immunotherapy of ipilimumab and nivolumab in IMDC intermediate- and poor-risk groups.
Lenvatinib is a multi-targeted tyrosine kinase inhibitor available for the treatment of unresectable hepatocellular carcinoma (HCC). We herein report an 84-year-old-man with interstitial pneumonia ...caused by lenvatinib. Four months after the start of lenvatinib administration for HCC, chest computed tomography revealed bilateral ground-glass opacity. However, he continued to take lenvatinib for four more months until he complained of dyspnea on exertion. This is a case of lenvatinib-induced interstitial pneumonia that progressed relatively slowly with a long asymptomatic period despite the appearance of pneumonia on image findings.
•TKIs for advanced HCC are associated with a range of adverse events.•Adverse events may lead to TKI treatment discontinuation.•Concomitant medications and comorbidities may influence adverse ...events.•Prevention and management of adverse events can help to maintain full dose treatment.•The literature contains approaches for adverse event management.
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Sorafenib, regorafenib, lenvatinib and cabozantinib are tyrosine kinase inhibitors (TKIs) that target, in part, vascular endothelial growth factor receptors, and are approved in various regions of the world for the treatment of advanced HCC. All these agents are associated with a range of adverse events (AEs) that can have a substantial impact on patients’ health-related quality of life. Fatigue, diarrhoea, hand–foot skin reaction, nausea, vomiting, decreased appetite, hypertension and weight loss are among the most common AEs experienced with these four TKIs. In this review, we discuss strategies for the management of these AEs in patients with advanced HCC, with the aim of maximizing treatment benefits and minimizing the need for TKI treatment discontinuation. We also consider potential TKI–drug interactions and discuss the use of TKIs in patients with liver dysfunction or who have experienced tumour recurrence after liver transplantation. Use of appropriate AE management strategies and avoidance of contraindicated drugs should help patients with advanced HCC to achieve optimal outcomes with TKIs.
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•We review the molecular mechanism of resistance to lenvatinib in hepatocellular carcinoma cells.•We summarize the use of combination therapy to overcome lenvatinib resistance.•We ...discuss future directions for overcoming resistance to lenvatinib in hepatocellular carcinoma.
Lenvatinib is a multikinase inhibitor that suppresses vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor α (PDGFRα), as well as the proto-oncogenes RET and KIT. Lenvatinib has been approved by the US Food and Drug Administration (FDA) for the first-line treatment of hepatocellular carcinoma (HCC) due to its superior efficacy when compared to sorafenib. Unfortunately, the development of drug resistance to lenvatinib is becoming increasingly common. Thus, there is an urgent need to identify the factors that lead to drug resistance and ways to mitigate it. We summarize the molecular mechanisms that lead to lenvatinib resistance (LR) in HCC, which involve programmed cell death (PCD), translocation processes, and changes in the tumor microenvironment (TME), and provide strategies to reverse resistance.
Sorafenib is the first-line drug used for patients with advanced hepatocellular carcinoma (HCC). However, acquired sorafenib resistance in cancer patients limits its efficacy. Here, we performed the ...first genome-wide CRISPR/Cas9-based screening on sorafenib-treated HCC cells to identify essential genes for non-mutational mechanisms related to acquired sorafenib resistance and/or sensitivity in HCC cells. KEAP1 was identified as the top candidate gene by Model-based Analysis of Genome-wide CRISPR/Cas9 Knockout (MAGeCK). KEAP1 disrupted HCC cells were less sensitive than wild-type cells in short- and long-term sorafenib treatments. Compared to wild-type cells, KEAP1-disrupted cells showed lower basal and sorafenib-induced reactive oxygen species (ROS) levels and were more resistant to oxidative stress-induced cell death. The absence of KEAP1 led to increased activity of Nrf2, a key transcription factor controlling antioxidant responses, as further evidenced by increased expression of Nrf2-controlled genes including NQO1, GPX2 and TXNRD1, which were positively associated with chemoresistance. In addition, KEAP1 disruption counteracted the reduction of cell viability and the elevation of ROS caused by lenvatinib, a drug that recently showed clinical efficacy as a first-line treatment for unresectable HCC. Finally, Keap1 disruption also increased the resistance of cells to regorafenib, a recently approved drug to treat HCC as a second line therapy. Taken together, our data indicate that deregulation of the KEAP1/Nrf2 pathway following KEAP1 inactivation contributes to sorafenib, lenvatinib, and regorafenib resistance in human HCC cells through up-regulation of Nrf2 downstream genes and decreased ROS levels.
Lenvatinib is emerging as the first-line therapeutic option for advanced hepatocellular carcinoma (HCC), but drug resistance remains a major hurdle for its long-term therapy efficiency in clinic. ...N6-methyladenosine (m6A) is the most abundant mRNA modification. Here, we aimed to investigate the modulatory effects and underlying mechanisms of m6A in lenvatinib resistance in HCC. Our data revealed that m6A mRNA modification was significantly upregulated in the HCC lenvatinib resistance (HCC-LR) cells compared to parental cells. Methyltransferase-like 3 (METTL3) was the most significantly upregulated protein among the m6A regulators. Either genetic or pharmacological inhibition of m6A methylation through METTL3 deactivation in primary resistant cell line MHCC97H and acquired resistant Huh7-LR cells decreased cell proliferation and increased cell apoptosis upon lenvatinib treatment in vitro and in vivo. In addition, the specific METTL3 inhibitor STM2457 improved tumor response to lenvatinib in multiple mouse HCC models, including subcutaneous, orthotopic and hydrodynamic models. The MeRIP-seq results showed that epidermal growth factor receptor (EGFR) was a downstream target of METTL3. EGFR overexpression abrogated the METTL3 knocked down-induced cell growth arrest upon lenvatinib treatment in HCC-LR cells. Thus, we concluded that targeting METTL3 using specific inhibitor STM2457 improved the sensitivity to lenvatinib in vitro and in vivo, indicating that METTL3 may be a potential therapeutic target to overcome lenvatinib resistance in HCC.
•METTL3 is correlated with clinical outcomes of lenvatinib therapy in HCC.•METTL3-m6A axis promotes the translation level of EGFR.•STM2457 exerts a synergistic effect with lenvatinib in HCC.•METTL3 may serve as a biomarker and therapeutic target on the treatment of lenvatinib.
There have been few reports on use of molecular-targeted drugs as preoperative therapy for giant hepatocellular carcinoma that is difficult to resect. We report a case in which preoperative ...administration of lenvatinib in a patient with giant hepatocellular carcinoma resulted in tumor shrinkage and spared the remnant liver volume. The patient was a 78-year-old man with a 19-cm hepatocellular carcinoma protruding from segment (S) 5 and S6 of the liver, and intrahepatic metastasis in S8. The tumor was close to the posterior segmental branch of the portal vein. Extended posterior segmentectomy plus S8 partial resection (31.9% of the whole liver) was assumed to be required for curative resection. Since the ICG retention rate was 28.3% and there was a risk of early postoperative recurrence, we re-evaluated the patient after administration of lenvatinib. After six weeks of this treatment, the main tumor had shrunk in size and intrahepatic metastasis had disappeared. As a result, inferior segmental resection (10.7% of the whole liver) with a sufficient liver volume could be performed. This case suggests that lenvatinib may be a potential preoperative treatment option for giant hepatocellular carcinoma.
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