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European Urology Apr 2024
Re: Marc-Oliver Grimm, Mototsuga Oya, Toni K. Choueiri, et al. Impact of Prior Cytoreductive Nephrectomy on Efficacy in Patients with Synchronous Metastatic Renal Cell Carcinoma Treated with Avelumab plus Axitinib or Sunitinib: Post Hoc Analysis from the JAVELIN Renal 101 Phase 3 Trial. Eur Urol...
PubMed: 38570248
DOI: 10.1016/j.eururo.2024.02.027 -
Clinical Genitourinary Cancer Jun 2024Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell... (Review)
Review
Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC). TKIs meet traditional criteria for using therapeutic drug monitoring (TDM), but research is still limited. Understanding the role of TDM in individualizing treatment strategies could help optimize treatment. Here we review the state of knowledge of TDM for TKIs in mRCC treatment. A comprehensive literature review of original research studies focusing on TDM of TKIs in mRCC treatment, clinical in vivo studies reporting on pharmacokinetics-pharmacodynamics, therapeutic ranges, drug concentrations, dose adjustments, clinical outcomes, or other relevant aspects related to TDM. We reviewed studies involving human subjects published in peer-reviewed journals. A narrative synthesis approach was employed to summarize the findings. Key themes and trends related to TDM of TKIs in mRCC treatment were identified and synthesized to provide a comprehensive overview of the current state of knowledge. Our search yielded 25 articles. Most were observational. The most consistently reported association between plasma concentration and effect was pazopanib Ctrough >20 µg/mL, but this concentration was not significant across all studies. We found inconsistent evidence for sunitinib and cabozantinib. For axitinib, we found a clear exposure-response relationship, but research was too diverse to conclude on a therapeutic window to use for TDM. We found much heterogeneity between recommended time of measurement (minimum plasma concentration [C], maximal plasma concentration [C], area under the curve [AUC]) and large variation in plasma concentration associated with clinical outcomes, which makes it difficult to recommend specific concentration intervals based on 1 or more of these measurements. Results were more consistent with TKIs continuously administered. Further research is needed to elucidate the long-term impact of TDM to possibly establish standardized therapeutic intervals. Prospective studies are suggested. The application of TDM in TKI-combination therapy is warranted in future research.
Topics: Humans; Carcinoma, Renal Cell; Drug Monitoring; Protein Kinase Inhibitors; Kidney Neoplasms; Indazoles; Sulfonamides; Pyrimidines; Antineoplastic Agents; Axitinib; Sunitinib; Treatment Outcome; Tyrosine Kinase Inhibitors
PubMed: 38555681
DOI: 10.1016/j.clgc.2024.102064 -
Medicine Mar 2024Treatment with a combination of immune checkpoint inhibitors (ICIs) (pembrolizumab or nivolumab) and oral Tyrosine Kinase Inhibitors (TKI) targeting angiogenesis... (Review)
Review
RATIONALE
Treatment with a combination of immune checkpoint inhibitors (ICIs) (pembrolizumab or nivolumab) and oral Tyrosine Kinase Inhibitors (TKI) targeting angiogenesis (axitinib, cabozantinib or lenvatinib) has shown benefits in terms of efficacy and survival in metastatic renal cell carcinoma (mRCC), with a favorable toxicity profile. However, some rare and serious treatment-related adverse events can be difficult to manage.
PATIENT CONCERNS
Here we report the first case of an mRCC patient who, after only 2 administrations of pembrolizumab-axitinib, experienced severe multiorgan failure (MOF) with heart failure, oliguria and acute hepatitis requiring aggressive supportive treatment in intensive care unit.
DIAGNOSES
A diagnosis of severe MOF induced by pembrolizumab plus axitinib was considered.
INTERVENTIONS
The patient was treated with dobutamine, levosimendan along with high-dose steroids under continuous cardiologic monitoring.
OUTCOMES
After treatment, the patient had a full recovery and was discharged from the hospital.
LESSONS
We reviewed all the other cases of MOF reported during treatment with combined ICI-TKI in cancer patients in order to summarize incidence, clinical manifestations and management with a specific focus on the need for prompt recognition and aggressive management under multidisciplinary care.
Topics: Female; Humans; Carcinoma, Renal Cell; Axitinib; Kidney Neoplasms; Antibodies, Monoclonal, Humanized
PubMed: 38552059
DOI: 10.1097/MD.0000000000037606 -
Blood Advances May 2024The human kinome, which comprises >500 kinases, plays a critical role in regulating numerous essential cellular functions. Although the dysregulation of kinases has been...
The human kinome, which comprises >500 kinases, plays a critical role in regulating numerous essential cellular functions. Although the dysregulation of kinases has been observed in various human cancers, the characterization and clinical implications of kinase expressions in myelodysplastic syndromes (MDS) have not been systematically investigated. In this study, we evaluated the kinome expression profiles of 341 adult patients with primary MDS and identified 7 kinases (PTK7, KIT, MAST4, NTRK1, PAK6, CAMK1D, and PRKCZ) whose expression levels were highly predictive of compromised patient survival. We then constructed the kinase stratification score (KISS) by combining the weighted expressions of the 7 kinases and validated its prognostic significance in 2 external MDS cohorts. A higher KISS was associated with older age, higher peripheral blood and marrow blast percentages, higher Revised International Prognostic Scoring System (IPSS-R) risks, complex karyotype, and mutations in several adverse-risk genes in MDS, such as ASXL1, EZH2, NPM1, RUNX1, STAG2, and TP53. Multivariate analysis confirmed that a higher KISS was an independent unfavorable risk factor in MDS. Mechanistically, the KISS-high patients were enriched for gene sets associated with hematopoietic and leukemic stem cell signatures. By investigating the Genomics of Drug Sensitivity in Cancer database, we identified axitinib and taselisib as candidate compounds that could potentially target the KISS-high myeloblasts. Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS and inform novel therapeutic opportunities.
Topics: Humans; Myelodysplastic Syndromes; Nucleophosmin; Male; Female; Prognosis; Gene Expression Profiling; Aged; Middle Aged; Adult; Risk Assessment; Molecular Targeted Therapy; Aged, 80 and over
PubMed: 38527292
DOI: 10.1182/bloodadvances.2023011512 -
European Urology Mar 2024Combinations of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitor (ICI) against PD1/PD-L1 are the...
BACKGROUND
Combinations of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitor (ICI) against PD1/PD-L1 are the standard first-line therapy for patients with metastatic renal cell carcinoma (mRCC), irrespective of the prognostic class.
OBJECTIVE
To investigate the feasibility and safety of withdrawing VEGFR-TKI but continuing anti-PD1/PD-L1 in patients who achieve a response to their combination.
DESIGN, SETTING, AND PARTICIPANTS
This was a single-arm phase 2 trial in patients with treatment-naïve mRCC with prior nephrectomy, without symptomatic/bulky disease and no liver metastases.
INTERVENTION
Enrolled patients received axitinib + avelumab; after 36 wk of therapy those who achieved a tumour response interrupted axitinib and continued avelumab maintenance until disease progression.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary endpoint was the rate of patients without progression 8 wk after the axitinib interruption. The secondary endpoints were the median value for progression-free (mPFS) and overall (mOS) survival and the safety in the overall population.
RESULTS AND LIMITATIONS
Seventy-nine patients were enrolled and 75 were evaluated for efficacy. A total of 29 (38%) patients had axitinib withdrawn, as per the study design, with 72% of them having no progression after 8 wk and thus achieving the primary endpoint. The mPFS of the overall population was 24 mo, while the mOS was not reached. The objective response rate was 76% (12% complete response and 64% partial response), with 19% of patients having stable disease. In the patients who discontinued axitinib, the incidence of adverse events of any grade was 59% for grade 3 and 3% for grade 4. This study was limited by the lack of a comparative arm.
CONCLUSIONS
The TIDE-A study demonstrates that the withdrawal of VEGFR-TKI with ICI maintenance is feasible for selected mRCC patients with evidence of a response to the VEGFR-TKI + ICI combination employed in first-line therapy. Axitinib interruption with avelumab maintenance leads to decreased side effects and should be investigated further as a new strategy to delay tumour progression.
PATIENT SUMMARY
We evaluated whether certain patients with advanced kidney cancer treated with the fist-line combination of axitinib plus avelumab can interrupt the axitinib in case of a tumour response after 36 wk of therapy. We found that axitinib interruption improved the safety of the combination, while the maintenance with avelumab might delay tumour progression.
PubMed: 38521617
DOI: 10.1016/j.eururo.2024.02.014 -
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