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Cancer Treatment Reviews Apr 2024Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have gained therapeutical significance in cancer therapy over the last years. Due to the high... (Review)
Review
Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have gained therapeutical significance in cancer therapy over the last years. Due to the high efficacy of each substance group, additive or complementary effects are considered, and combinations are the subject of multiple prospective trials in different tumor entities. The majority of available data results from clinical phase I and II trials. Although regarded as well-tolerated therapies ICI-TKI combinations have higher toxicities compared to monotherapies of one of the substance classes and some combinations were shown to be excessively toxic leading to discontinuation of trials. So far, ICI-TKI combinations with nivolumab + cabozantinib, pembrolizumab + axitinib, avelumab + axitinib, pembrolizumab + lenvatinib have been approved in advanced renal cell (RCC), with pembrolizumab + lenvatinib in endometrial carcinoma and with camrelizumab + rivoceranib in hepatocellular carcinoma (HCC). Several ICI-TKI combinations are currently investigated in phase I to III trials in various other cancer entities. Further, the optimal sequence of ICI-TKI combinations is an important subject of investigation, as cross-resistances between the substance classes were observed. This review reports on clinical trials with ICI-TKI combinations in different cancer entities, their efficacy and toxicity.
Topics: Humans; Carcinoma, Hepatocellular; Tyrosine Kinase Inhibitors; Axitinib; Prospective Studies; Liver Neoplasms; Carcinoma, Renal Cell; Kidney Neoplasms; Phenylurea Compounds; Quinolines
PubMed: 38521009
DOI: 10.1016/j.ctrv.2024.102718 -
International Immunopharmacology Apr 2024In the realm of metastatic renal cell carcinoma (mRCC), the introduction of immune checkpoint inhibitors (ICIs) has revolutionized treatment paradigms. Despite their... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In the realm of metastatic renal cell carcinoma (mRCC), the introduction of immune checkpoint inhibitors (ICIs) has revolutionized treatment paradigms. Despite their effectiveness, the comprehensive safety profile of these therapies remains inadequately explored. This network meta-analysis aims to comparing the safety profiles of ICI-based treatments in mRCC, offering vital insights that could lead to the optimization of treatment strategies and improvement of patient care.
METHODS
We conducted a comprehensive search of PubMed, Cochrane Library, Embase, Web of Science, ClinicalTrials.gov, Google Schola, OpenGrey and Scopus through November 1, 2023. The risk of bias assessment was performed using the Risk of Bias version 2 tool.
RESULTS
Seven randomized controlled trials (RCTs) with a total of 5976 patients were included for data analysis. The risk of bias results showed that all RCTs were considered "some concerns". The probability of hypothyroidism (surface under the cumulative ranking curve (SUCRA) = 0.981), hyperthyroidism (SUCRA = 0.983) and dermatologic immune-related adverse events (irAEs) (SUCRA = 0.955) in the Nivolumab + Cabozantinib ranked the first. The Avelumab + Axitinib had the highest incidence of adrenal insufficiency (AI) (SUCRA = 0.976), hepatitis (SUCRA = 0.937) and colitis (SUCRA = 0.864). The Nivolumab + Ipilimumab exhibited the highest incidence of pneumonitis (SUCRA = 0.755). Pembrolizumab + Lenvatinib had the highest incidence of nephritic irAEs (SUCRA = 0.788). The ICI-based group showed a higher incidence of hypothyroidism, hyperthyroidism, dermatologic irAEs, hepatitis and nephritic irAEs than sunitinib. However, the confidence in the evidence regarding the impact of ICI-based treatments on AI, pneumonia, and colitis remains limited.
CONCLUSION
The analysis focused on the probability of irAEs occurrence in each system when mRCC patients were treated with different ICI-based therapies, potentially offering significant value for guiding clinical prevention, early diagnosis, and management of irAEs. The limitations of the study included the potential heterogeneity and low certainty of part of the evidence.
Topics: Humans; Carcinoma, Renal Cell; Immune Checkpoint Inhibitors; Nivolumab; Network Meta-Analysis; Kidney Neoplasms; Hepatitis; Colitis; Hyperthyroidism; Hypothyroidism; Randomized Controlled Trials as Topic
PubMed: 38518592
DOI: 10.1016/j.intimp.2024.111884 -
International Journal of Pharmaceutics Apr 2024Tyrosine kinase inhibitors (TKIs) can inhibit edema and neovascularization, such as in age-related macular degeneration and diabetic retinopathy. However, their topical... (Review)
Review
Tyrosine kinase inhibitors (TKIs) can inhibit edema and neovascularization, such as in age-related macular degeneration and diabetic retinopathy. However, their topical administration in ophthalmology is limited by their toxicity and poor aqueous solubility. There are multiple types of TKIs, and each TKI has an affinity to more than one type of receptor. Studies have shown that ocular toxicity can be addressed by selecting TKIs that have a high affinity for specific vascular endothelial growth factor receptors (VEGFRs) but a low affinity for epidermal growth factor receptors (EGFRs). Drugs permeate from the aqueous tear fluid into the eye via passive diffusion. Thus, a sustained high concentration of the dissolved drug in the aqueous tear fluid is essential for a successful delivery to posterior tissues such as the retina. Unfortunately, the aqueous solubility of the TKIs that have the most favorable VEGFR/EGFR affinity ratio, that is, axitinib and cabozantinib, is well below 1 µg/mL, making their topical delivery very challenging. This is a review of the drug-like properties of TKIs that are currently being evaluated or have been evaluated as ophthalmic drugs. These properties include their solubilization, cyclodextrin complexation, and ability to permeate from the aqueous tear fluid to the posterior eye segment.
Topics: Pharmaceutical Preparations; Tyrosine Kinase Inhibitors; Ophthalmology; Vascular Endothelial Growth Factor A; Administration, Topical; Protein Kinase Inhibitors
PubMed: 38508428
DOI: 10.1016/j.ijpharm.2024.124018 -
Expert Review of Pharmacoeconomics &... Jun 2024The current analysis aimed to evaluate the economic benefit of toripalimab plus axitinib for previously untreated RCC patients from the Chinese healthcare system... (Comparative Study)
Comparative Study
OBJECTIVE
The current analysis aimed to evaluate the economic benefit of toripalimab plus axitinib for previously untreated RCC patients from the Chinese healthcare system perspective.
METHODS
The partitioned survival model was developed to simulate 3-week patients' transition in 20-year time horizon to evaluate the cost-effectiveness of toripalimab plus axitinib compared with sunitinib for advanced RCC. Survival data were gathered from the RENOTORCH trial, and cost and utility inputs were obtained from the database and published literature. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were the model outputs. Subgroup analyses and sensitivity analyses were conducted to increase the comprehensiveness and estimate the robustness of the model results.
RESULTS
In the base-case analysis, compared with sunitinib, toripalimab plus axitinib could bring additional 1.19 LYs and 0.65 QALYs, with the marginal cost of $41,499.23, resulting in the ICER of $64,337.49/QALY, which is higher than the WTP threshold. And ICERs were always beyond the WTP threshold of all subgroups. Sensitivity analyses demonstrated the model results were robust.
CONCLUSIONS
Toripalimab plus axitinib was unlikely to be the cost-effective first-line therapy for patients with previously untreated advanced RCC compared with sunitinib from the Chinese healthcare system perspective.
Topics: Humans; Axitinib; Carcinoma, Renal Cell; Cost-Benefit Analysis; Quality-Adjusted Life Years; Kidney Neoplasms; China; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal, Humanized; Models, Economic; Sunitinib; Cost-Effectiveness Analysis
PubMed: 38506058
DOI: 10.1080/14737167.2024.2333334 -
Translational Andrology and Urology Feb 2024
PubMed: 38481862
DOI: 10.21037/tau-23-588 -
Journal of Bone and Mineral Research :... Apr 2024Sphingosine-1-phosphate (S1P) plays multiple roles in bone metabolism and regeneration. Here, we have identified a novel S1P-regulated osteoanabolic mechanism...
Sphingosine-1-phosphate (S1P) plays multiple roles in bone metabolism and regeneration. Here, we have identified a novel S1P-regulated osteoanabolic mechanism functionally connecting osteoblasts (OBs) to the highly specialized bone vasculature. We demonstrate that S1P/S1PR3 signaling in OBs stimulates vascular endothelial growth factor a (VEGFa) expression and secretion to promote bone growth in an autocrine and boost osteogenic H-type differentiation of bone marrow endothelial cells in a paracrine manner. VEGFa-neutralizing antibodies and VEGF receptor inhibition by axitinib abrogated OB growth in vitro and bone formation in male C57BL/6J in vivo following S1P stimulation and S1P lyase inhibition, respectively. Pharmacological S1PR3 inhibition and genetic S1PR3 deficiency suppressed VEGFa production, OB growth in vitro, and inhibited H-type angiogenesis and bone growth in male mice in vivo. Together with previous work on the osteoanabolic functions of S1PR2 and S1PR3, our data suggest that S1P-dependent bone regeneration employs several nonredundant positive feedback loops between OBs and the bone vasculature. The identification of this yet unappreciated aspect of osteoanabolic S1P signaling may have implications for regular bone homeostasis as well as diseases where the bone microvasculature is affected such as age-related osteopenia and posttraumatic bone regeneration.
Topics: Male; Mice; Animals; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors; Vascular Endothelial Growth Factor A; Osteogenesis; Endothelial Cells; Mice, Inbred C57BL; Osteoblasts; Lysophospholipids; Sphingosine
PubMed: 38477738
DOI: 10.1093/jbmr/zjae006 -
International Journal of Biological... Apr 2024Vascular endothelial growth factor B (VEGFB) has been well demonstrated to play a crucial role in regulating vascular function by binding to the VEGF receptors (VEGFRs)....
Vascular endothelial growth factor B (VEGFB) has been well demonstrated to play a crucial role in regulating vascular function by binding to the VEGF receptors (VEGFRs). However, the specific role of VEGFB and VEGFRs in pubertal mammary gland development remains unclear. In this study, we observed that blocking the VEGF receptors with Axitinib suppressed the pubertal mammary gland development. Meanwhile, the proliferation of mammary epithelial cells (HC11) was repressed by blocking the VEGF receptors with Axitinib. Additionally, knockdown of VEGFR1 rather than VEGFR2 and NRP1 elicited the inhibition of HC11 proliferation, suggesting the essential role of VEGFR1 during this process. Furthermore, Axitinib or VEGFR1 knockdown led to the inhibition of the PI3K/Akt pathway. However, the inhibition of HC11 proliferation induced by Axitinib and or VEGFR1 knockdown was eliminated by the Akt activator SC79, indicating the involvement of the PI3K/Akt pathway. Finally, the knockdown of VEGFB and VEGFR1 suppressed the pubertal development of mice mammary gland with the inhibition of the PI3K/Akt pathway. In summary, the results showed that knockdown of the VEGFB/VEGFR1 signaling suppresses pubertal mammary gland development of mice via the inhibition of the PI3K/Akt pathway, which provides a new target for the regulation of pubertal mammary gland development.
Topics: Animals; Mice; Proto-Oncogene Proteins c-akt; Vascular Endothelial Growth Factor B; Phosphatidylinositol 3-Kinases; Axitinib; Receptors, Vascular Endothelial Growth Factor; Cell Proliferation
PubMed: 38471613
DOI: 10.1016/j.ijbiomac.2024.130782 -
Scientific Reports Mar 2024To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs)... (Observational Study)
Observational Study
To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs) related to various MKIs treated for renal cell carcinoma. We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS) in an observational and retrospective manner. Selecting electrolyte disorders' adverse events to multikinase inhibitors (axitinib, cabozantinib, lenvatinib, pazopanib, sunitinib, and sorafenib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of electrolyte disorders induced by MKIs (which were treated for renal cell carcinoma) between January 2004 and December 2022. As of December 2022, 2772 MKIs (which were treated for renal cell carcinoma) ICSRs were related to electrolyte disorders AEs. In general, there were more AEs cases in males, except lenvatinib and 71.8% of the cases were submitted from North America. ICSRs in this study, the age group most frequently affected by electrolyte disorders AEs was individuals aged 45-64 years for axitinib, cabozantinib, pazopanib, and sunitinib, whereas electrolyte disorders AEs were more common in older patients (65-74 years) for sorafenib and lenvatinib. For all EDs documented in ICSRs (excluding missing data), the most common adverse outcome was hospitalization(1429/2674, 53.4%), and the most serious outcome was death/life-threat(281/2674, 10.5%). The prevalence of mortality was highest for sunitinib-related EDs (145/616, 23.5%), excluding missing data (n = 68), followed by cabozantinib-related EDs (20/237, 8.4%), excluding missing data (n = 1). The distribution of time-to-onset of Each drug-related ICSRs was not all the same, and the difference was statistically significant (P = 0.001). With the criteria of ROR, the six MKIs were all significantly associated with electrolyte disorders AEs, the strongest association was the association between cabozantinib and hypermagnesaemia. MKIs have been reported to have significant electrolyte disorders AEs. Patients and physicians need to recognize and monitor these potentially fatal adverse events.
Topics: Aged; Humans; Male; Anilides; Axitinib; Bayes Theorem; Carcinoma, Renal Cell; Electrolytes; Indazoles; Kidney Neoplasms; Pharmacovigilance; Phenylurea Compounds; Pyridines; Pyrimidines; Quinolines; Retrospective Studies; Sorafenib; Sulfonamides; Sunitinib; United States; United States Food and Drug Administration; Female; Middle Aged
PubMed: 38454105
DOI: 10.1038/s41598-024-56335-4 -
IJU Case Reports Mar 2024Patients with translocation renal cell carcinoma (tRCC) have a poor prognosis without standardized treatment.
INTRODUCTION
Patients with translocation renal cell carcinoma (tRCC) have a poor prognosis without standardized treatment.
CASE PRESENTATION
The first case was of a 72-year-old woman who underwent robot-assisted partial nephrectomy for a left renal tumor and was pathologically diagnosed with tRCC. Recurrence was observed in the left retroperitoneal soft tissue. After treatment with avelumab-axitinib, continued progression-free survival was confirmed at the 90-week follow-up. The second case was of a 41-year-old woman referred to our hospital and presented with translocation renal cell carcinoma metastasis to a para-aortic lymph node. After treatment with avelumab-axitinib, continued progression-free survival was confirmed at the 43-week follow-up.
CONCLUSION
The outcomes of these cases indicate that avelumab-axitinib therapy has a long-term antitumor effect in some patients with tRCC.
PubMed: 38440705
DOI: 10.1002/iju5.12685 -
IJU Case Reports Mar 2024Combination therapies of immune checkpoint and tyrosine kinase inhibitors for end-stage kidney disease and patients on hemodialysis need careful consideration as few...
INTRODUCTION
Combination therapies of immune checkpoint and tyrosine kinase inhibitors for end-stage kidney disease and patients on hemodialysis need careful consideration as few case reports provide suitable management decisions.
CASE PRESENTATION
A 70-year-old man who had undergone hemodialysis for 6 years due to nephrosclerosis. Avelumab plus axitinib combination therapy was performed for repeated lung metastasis, and a complete response was achieved without major side effects.
CONCLUSION
A complete response was achieved after Ave plus Axi combination therapy for clear cell renal cell carcinoma in a patient undergoing dialysis. This suggests that Ave plus Axi combination therapy may be safe and effective for dialysis patients.
PubMed: 38440696
DOI: 10.1002/iju5.12689