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Objective: To develop a method for determining the concentration of axitinib in beagle dog plasma and utilize this method to investigate the pharmacokinetics of orally administered axitinib in beagle dogs. Methods: Plasma samples were processed using acetonitrile precipitation and analyzed by UPLC-MS/MS with sunitinib as an internal standard (IS). Chromatographic separation was achieved on a Waters Acquisition UPLC BEH C18 column (50 mm × 2.1 mm, 1.7 μm) with a gradient elution of acetonitrile and 0.1 % formic acid. Mass spectrometry uses an electrospray ion source for positive ion detection in a multiple reaction monitoring mode. The monitored ion transitions for axitinib and sunitinib were m/z 387 → 355.96 and m/z 399.3 → 282.96, respectively. Six beagle dogs were administered 0.33 mg/kg of axitinib orally, and venous blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h post-dose for pharmacokinetic analysis. Results: The assay demonstrated a linear range of 0.5–100 ng/mL (r2 = 0.9992), and the lower limit of quantification was up to 0.5 ng/mL. Precision, as assessed by relative standard deviation (RSD), was within 8.64 % for both intraday and interday variability. The relative error (RE) for precision from −2.77 %–1.20 %. The recovery rate of the analytes exceeded 85.28 % and the matrix effect was approximately 100 %. Plasma samples maintained stability under various conditions, including room temperature storage for 12 h, processed on an automatic sampler at 4 °C for 6 h, three freeze-thaw cycles, and long-term storage at −80 °C for 60 days. Pharmacokinetic parameters were determined using DAS 2.0 software, revealing a half-life (T1/2) of 6.05 h and an area under the curve (AUC (0 → ∞)) of 97.13 ng h/mL for axitinib. Conclusions: The UPLC-MS/MS method developed in this study offers high specificity, rapid analysis, high recovery, excellent linearity, and minimal plasma volume requirements, making it well-suited for pharmacokinetic and drug interaction studies in beagles dogs.

Purpose: To evaluate the safety and tolerability of a single dose of axitinib injectable suspension (CLS-AX), a pan-anti-VEGF tyrosine kinase inhibitor (TKI), administered via suprachoroidal injection in patients with neovascular age-related macular degeneration (nAMD). Design: Phase I/IIa, open-label, sequential dose escalation. Participants: Anti-VEGF treatment-experienced patients with active subfoveal choroidal neovascularization secondary to nAMD. Methods: The study included 4 cohorts (0.03, 0.10, 0.50, and 1.0 mg) of approximately 5 patients each enrolled in a dose-escalating fashion. Enrolled patients received intravitreal aflibercept (2 mg) followed by a single unilateral dose of CLS-AX 1 month later. All patients were followed monthly for 3 months with the option of an additional 3 months of extended follow-up for cohorts 2 to 4. End points included systemic and ocular safety and tolerability, visual acuity, retinal thickness, and need for aflibercept therapy. Main Outcome Measures: The number of patients reporting treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), changes in ophthalmic examinations, and the number of patients qualifying for additional therapy for nAMD based on protocol-defined criteria. Results: OASIS enrolled 27 patients with nAMD with mean age of 81 years, mean duration of nAMD diagnosis of 54 months, and between 5 and 90 prior anti-VEGF treatments. Twenty-six patients completed through 3 months, with 14 entering and completing the 3-month extension. No SAEs, drug-related TEAEs, or TEAEs leading to discontinuation were observed after CLS-AX administration; there were no adverse events related to ocular inflammation, vasculitis, intraocular pressure, or dispersion of drug into the vitreous or anterior chamber. Through 6 months, stable mean best-corrected visual acuity and stable mean central subfield thickness (CST) were observed, suggestive of TKI biologic effect. No aflibercept therapy was administered up to 3 months in 58% (15/26) of patients who completed 3 months of follow-up in OASIS. In the Extension, 57% (8/14) of patients went up to 6 months without receiving aflibercept therapy. Conclusions: Up to 1.0 mg CLS-AX, a highly potent TKI targeted to the suprachoroidal space (SCS) via the SCS Microinjector, was well tolerated, with stable mean visual acuity and mean CST. A majority of patients followed for 6 months did not require aflibercept therapy. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Vascular endothelial growth factor receptor inhibitors (VEGFRi), namely axitinib, are commonly used chemotherapeutic agents in patients with cancer; however, this medication has a significant cardiovascular side effect profile, such as high-grade hypertension. We performed this updated meta-analysis of RCTs to compile cardiovascular adverse events, such as all-grade and high-grade (>3) hypertension, the risk for thrombosis (DVT and PE), and peripheral edema. A systematic search was performed on PubMed, Cochrane, and Embase from inception until October 2023 for studies using axitinib to treat various cancers. Trials with patients randomly allocated for VEGFRi drug therapy with axitinib and reported all-grade hypertension as an outcome were included. Statistical analysis was performed using Cochrane Review Manager to calculate pooled proportions of odds ratios (OR) with a 95 % confidence interval (CI) using the random-effects model, Mantel−Haenszel method. A total of 8 RCTs and 2502 patients were included in the review. Compared with the placebo group, the VEGFRi (Axitinib) therapy group was associated with a higher risk of all-grade and high-grade hypertension, hand–foot syndrome, and fatigue. Furthermore, there was no increased risk of thromboembolism (DVT/PE) or hypothyroidism. However, a lower risk of peripheral edema was noted between the two groups. Screening for patients with preexisting hypertension, identifying risk factors for cardiovascular diseases before the initiation of VEGFRi therapy, and careful monitoring of high-risk patients during VEGFRi therapy, as well as prompt treatment with antihypertensive drugs, will help mitigate the adverse effects. Further evaluation using prospective designs is required to study the clinical significance and develop mitigation strategies.

Axitinib, marketed as Inlyta, finds various medical applications in the treatment of conditions such as breast cancer, myeloid leukemia, and juvenile myelomonocytic leukemia. Initially, the synthesis of this cytidine analog, and its deoxy derivative decitabine, was carried out in Czechoslovakia to explore their potential as chemotherapeutic agents for cancer treatment. Recent research has been focused on understanding the reactivity and chemical structure of Axitinib, which are believed to contribute to its anticancer properties. As part of this investigation, the adsorption process of Axitinib onto a fullerene (C60) adsorbent in the gas and water phases was examined using the DFT/B3LYP/6-311+G(d, p) method. This analysis involved the assessment of the adsorption energy and a chemical perspective on the interaction between Axitinib and the adsorbent molecule. Furthermore, various thermodynamic characteristics, including Gibbs free energy (-4004.73 kJ), Enthalpy (-4004.52 kJ), and Entropy (709.79 J/mol-kelvin), as well as thermodynamic capacity (349.69 J/mol-kelvin), were calculated. Additionally, key electronic parameters, such as σ(0.20), µ(-2.97), ω(0.88), χ(2.97), and η(5.01) (all in eV), were estimated to elucidate the compound's chemical properties. The calculation of the HOMO (-7.99 eV) and LUMO (2.04 eV) energy levels revealed six regions of chemical activity for Axitinib, confirming its thermodynamic stability and indicating the significance of this adsorption process in delivering Axitinib to biological mechanisms.

Background: Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib., Methods: We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia., Results: Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed., Conclusion: We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Pembrolizumab/Axitinib combination is approved as first-line therapy in mRCC. The aim of this study is to evaluate outcomes of PAXI combo in the real-world in Italy., Methods: This is a prospective study including patients diagnosed with mRCC who received combination as first-line therapy in recruiting Italian Centers. Data about patient characteristics, safety and outcome were collected., Results: 170 pts have been treated from December 2020 to September 2023. The majority had clear-cell histology (83%). Sarcomatoid feature was present in 33%of available cases. About one half of patients (55%) had synchronous metastasis. In 58% of cases nephrectomy was performed, of which 27% were cytoreductive and 4% were deferred nephrectomies. Lung metastases were identified in 106 patients (62%), bone and liver involvement in 66 and 29 patients (38.8% and 17.1%) respectively. Stratifying by IMDC criteria, 32 patients (18.8%) were at favorable-risk, 106 (62.4%) at intermediate-risk, and 32 (18.8%) at poor-risk. At time of analysis, treatment was ongoing in 49% of patients. Progression occurred in 45% of patients. Median PFS was 19.2 months (95% CI: 15-NR). With a median follow-up of 19.3 months (range 1.3-34.5), at 24-months and 36-months landmark analysis 62% (95% CI, 53-70) and 58% (95% CI, 47-69) of treated patients are still alive respectively. Disease control rate was achieved in 84.6% of patients: 4.3% reached a complete response, 52% had a partial response and 28.8% a stable disease. Primary progression was observed in 15.3% of patients. In the multivariate analysis, the prognostic significance of age ≥ 65 years, non-clear cell histology, IMDC score, and adverse events and gender interaction as predictors of worse OS were confirmed., Conclusion: This is the first available prospective study on first-line Pembrolizumab/Axitinib combination in real world scenario. Our findings support the effectiveness and safety of first-line this combination in mRCC and reveal that gender emerged as a prognostic factor in relation to the occurrence of adverse events., Competing Interests: Disclosure The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

von Hippel–Lindau (VHL) disease is an autosomal dominant hereditary disease with benign and malignant tumors occurring in various organs including the kidneys. In patients with renal cell carcinoma (RCC) lesions in both kidneys, it is difficult to determine the treatment strategy. We report a case of VHL disease with RCC treated via partial nephrectomy after 6 months of axitinib therapy. Then, the patient continued to receive low-dose axitinib therapy without any signs of tumor progression for 3 years after surgery. Axitinib combined with surgery might be a treatment option for patients with VHL disease harboring bilateral RCC.

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the abnormal accumulation of surfactant-derived substances in the lungs. To the best of our knowledge, the successful treatment of metastatic renal cell carcinoma in patients with PAP has not been reported. Here, we describe such treatment of a patient via avelumab plus axitinib therapy. After four courses of treatment, computed tomography showed size reduction of the pulmonary metastatic nodule and improvement of PAP. This study highlights that avelumab plus axitinib therapy is a safe and effective treatment option for metastatic renal cell carcinoma, even in patients with PAP.

Background: Cognitive decline leading to dementia, accompanied by the accumulation of amyloid-beta (Aβ) in neuritic plaques together with the appearance of neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein (tau), are previously noted hallmarks of Alzheimer's disease (AD). We previously discovered hypervascularity in brain specimens from AD patients and consistent with this observation, we demonstrated that overexpression of Aβ drives cerebrovascular neoangiogenesis leading to hypervascularity and coincident tight-junction disruption and blood-brain barrier (BBB) leakiness in animal models of AD. We subsequently demonstrated that amyloid plaque burden and cerebrovascular pathogenesis subside when pro-angiogenic Aβ levels are reduced. Based on these data, we propose a paradigm of AD etiology where, as a compensatory response to impaired cerebral blood flow (CBF), Aβ triggers pathogenic cerebrovascular neoangiogenesis that underlies the conventional hallmarks of AD. Consequently, here we present evidence that repurposing anti-cancer drugs to modulate cerebrovascular neoangiogenesis, rather than directly targeting the amyloid cascade, may provide an effective treatment for AD and related vascular diseases of the brain. Methods: We explored whether the anti-cancer drug, Axitinib, a small molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR) can inhibit aberrant cerebrovascular neoangiogenic changes, reduce Aβ deposits and reverse cognitive decline in an animal model of AD. One month post-treatment with Axitinib, we employed a battery of tests to assess cognition and memory in aged Tg2576 AD mice and used molecular analysis to demonstrate reduction of amyloid plaques, BBB leakage, hypervascularity and associated disease pathology. Findings: Targeting the pro-angiogenic pathway in AD using the cancer drug, Axitinib, dramatically reduced cerebrovascular neoangiogenesis, restored BBB integrity, resolved tight-junction pathogenesis, diminishes Aβ depositions in plaques and effectively restores memory and cognitive performance in a preclinical mouse model of AD. Interpretation: Modulation of neoangiogenesis, in an analogous approach to those used to treat aberrant vascularization in cancer and also in the wet form of age-related macular degeneration (AMD), provides an alternative therapeutic strategy for intervention in AD that warrants clinical investigation. Funding: None

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., Competing Interests: Declaration of competing interest AMS received travel and congress registration support from MSD, Lilly and PharmaMar and lecture honoraria from AstraZeneca. BK received honoraria for lectures or advisory board participation from AstraZeneca, Boehringer Ingelheim, BMS, Daiichi Sankyo, Eli Lilly, Ipsen, MSD, Novartis, Roche. AS received travel support from Lilly. JMR received travel support by Roche, Bristol-Meyers Squibb and lecture honoraria by Bristol-Meyers Squibb, Roche, Amgen and Novartis. MP has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC., Patients and Methods: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety., Results: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group., Conclusion: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975., (Copyright © 2023 X. Yan, M. Ye, Q. Zou, P. Chen, Z. He, B. Wu, D. He, C. He, X. Xue, Z. Ji, H. Chen, S. Zhang, Y. Liu, X. Zhang, C. Fu, D. Xu, M. Qiu, J. Lv, J. Huang, X. Ren, Y. Cheng, W. Qin, X. Zhang, F. Zhou, L. Ma, J. Guo, D. Ding, S. Wei, Y. He, H. Guo, B. Shi, L. Liu, F. Liu, Z. Hu, X. Jin, L. Yang, S. Zhu, J. Liu, Y. Huang, T. Xu, B. Liu, T. Sun, Z. Wang, H. Jiang, D. Yu, A. Zhou, J. Jiang, G. Luan, C. Jin, J. Xu, J. Hu, Y. H, Jun, W. Zhai, X. Sheng, Shanghai Junshi Biosciences Co. LTD, Shanghai Junshi Biosciences Co. LTD., a. Published by Elsevier Ltd.. All rights reserved.)

Background: The outcome of patients with resectable mucosal melanoma is poor. Toripalimab combined with axitinib has shown impressive results in metastatic mucosal melanoma with an objective response rate of 48.3% and a median progression-free survival of 7.5 months in a phase Ib trial. It was hypothesized that this combination administered in the neoadjuvant setting might induce a pathologic response in resectable mucosal melanoma, so we conducted this trial., Patients and Methods: This single-arm phase II trial enrolled patients with resectable mucosal melanoma. Patients received toripalimab 3 mg/kg once every 2 weeks (Q2W) plus axitinib 5 mg two times a day (b.i.d.) for 8 weeks as neoadjuvant therapy, then surgery and adjuvant toripalimab 3 mg/kg Q2W starting 2 ± 1weeks after surgery for 44 weeks. The primary endpoint was the pathologic response rate according to the International Neoadjuvant Melanoma Consortium recommendations., Results: Between August 2019 and October 2021, 29 patients were enrolled and received treatment, of whom 24 underwent resection. The median follow-up time was 34.2 months (95% confidence interval 20.4-48.0 months). The pathologic response rate was 33.3% (8/24; 4 pathological complete responses and 4 pathological partial responses). The median event-free survival for all patients was 11.1 months (95% confidence interval 5.3-16.9 months). The median overall survival was not reached. Neoadjuvant therapy was tolerable with 8 (27.5%) grade 3-4 treatment-related adverse events and no treatment-related deaths. Tissue samples of 17 patients at baseline and after surgery were collected (5 responders and 12 nonresponders). Multiplex immunohistochemistry demonstrated a significant increase in CD3+ (P = 0.0032) and CD3+CD8+ (P = 0.0038) tumor-infiltrating lymphocytes after neoadjuvant therapy, particularly in pathological responders., Conclusions: Neoadjuvant toripalimab combined with axitinib in resectable mucosal melanoma demonstrated a promising pathologic response rate with significantly increased infiltrating CD3+ and CD3+CD8+ T cells after therapy., Competing Interests: Disclosure JG serves consulting/advisory roles in Merck Sharp & Dohme, Roche, Bayer, Novartis, Simcere Pharmaceutical Group, Shanghai Junshi Biosciences, and Oriengene. GVL is a consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, QBiotics, and Regeneron. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In the phase III JAVELIN Renal 101 trial, first-line avelumab + axitinib improved progression-free survival (PFS) and objective response rate versus sunitinib in patients with advanced renal cell carcinoma across all International Metastatic RCC Database Consortium (IMDC) risk groups (favorable, intermediate, and poor); analyses of overall survival (OS) remain immature. Here, we report post hoc analyses of efficacy from the third interim analysis (data cut-off, April 2020) by the numbers of IMDC risk factors and target tumor sites at baseline., Methods: Efficacy endpoints assessed were PFS, objective response, and best overall response per investigator assessment (RECIST v1.1) and OS. Best percentage change and percentage change from baseline in target tumor size over time during the study were also assessed., Results: In patients with 0, 1, 2, 3, or 4-6 IMDC risk factors, hazard ratios [HRs; 95% confidence interval (CIs)] for OS with avelumab + axitinib versus sunitinib were 0.660 (0.356-1.223), 0.745 (0.524-1.059), 0.973 (0.668-1.417), 0.718 (0.414-1.248), and 0.443 (0.237-0.829), and HRs (95% CIs) for PFS were 0.706 (0.490-1.016), 0.709 (0.540-0.933), 0.711 (0.527-0.960), 0.501 (0.293-0.854), and 0.395 (0.214-0.727), respectively. In patients with 1, 2, 3, or ≥4 target tumor sites, HRs (95% CIs) for OS with avelumab + axitinib versus sunitinib were 0.912 (0.640-1.299), 0.715 (0.507-1.006), 0.679 (0.442-1.044), and 0.747 (0.346-1.615), and HRs (95% CIs) for PFS were 0.706 (0.548-0.911), 0.552 (0.422-0.723), 0.856 (0.589-1.244), and 0.662 (0.329-1.332), respectively. Across all subgroups, analyses of objective response rate and complete response rate favored avelumab + axitinib versus sunitinib, and a greater proportion of patients treated with avelumab + axitinib had tumor shrinkage., Conclusions: In post hoc analyses, first-line treatment with avelumab + axitinib was generally associated with efficacy benefits versus treatment with sunitinib in patients with advanced renal cell carcinoma across subgroups defined by different numbers of IMDC risk factors or target tumor sites., Competing Interests: Disclosure YT has participated in consulting or advisory roles for Eisai, Merck Sharp & Dohme (MSD), and Ono Pharmaceutical; has received honoraria from Astellas Pharma, Bristol Myers Squibb Japan, Chugai Pharma, Novartis, Ono Pharmaceutical, and Pfizer; and has received research funding from Astellas Pharma, AstraZeneca, Chugai Pharma, Eisai, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Takeda. RJM has participated in consulting or advisory roles for AstraZeneca, Aveo, Calithera Biosciences, Eisai, Exelixis, Genentech/Roche, Incyte, Pfizer, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; has received travel, accommodations, and expenses from Bristol Myers Squibb; and has received research funding from Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Novartis, Pfizer, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. TKC reports institutional and personal, paid and/or unpaid support for research, advisory boards, consultancy, and honoraria from Aravive, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, CME events (Peerview, OncLive, MJH and others), Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, MSD, NiKang, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, and Up-To-Date, outside the submitted work; reports institutional patents filed on molecular alterations and immunotherapy response/toxicity, and circulating tumor DNA; reports equity Osel, Pionyr, Precede Bio, and Tempest; has served in committees for ACCRU, ASCO/ESMO, GU Steering Committee, KidneyCan, and NCCN; reports that medical writing and editorial assistance support may have been funded by communications companies in part; has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components; reports that the institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter; and is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, and Loker Pinard Funds for Kidney Cancer Research at DFCI. BIR has participated in consulting or advisory roles for 3D Medicines, Aravive, Arrowhead Pharmaceuticals, Aveo, Bristol Myers Squibb, Corvus Pharmaceuticals, Eisai, GlaxoSmithKline, Pfizer, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Shionogi, Surface Oncology, and Synthorx; reports leadership with MJH Life Sciences; has received travel, accommodations, and expenses from Bristol Myers Squibb, Pfizer, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; reports stock and other ownership interests from PTC Therapeutics; and has received research funding from Aravive, Arrowhead Pharmaceuticals, AstraZeneca/MedImmune, Bristol Myers Squibb, Dragonfly Therapeutics, Immunomedics, Incyte, Exelixis, Pfizer, Roche/Genentech, Seagen, Surface Oncology, Taris, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. HM has received honoraria, consulting or advisory fees, and research funding from Pfizer. MO has participated in consulting or advisory roles for Bayer; has received honoraria from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb Japan, Chugai Pharma, Janssen, MSD, Novartis, Ono Pharmaceutical, Pfizer, Sanofi, and Takeda; and has received research funding from Astellas Pharma. LA has participated in consulting or advisory roles for Astellas Pharma, AstraZeneca, Bellerophon Therapeutics, Bristol Myers Squibb, Corvus Pharmaceuticals, Eisai, Janssen, Ipsen, Merck, MSD, Novartis, Pfizer, and Roche; has received travel, accommodations, and expenses from Bristol Myers Squibb and MSD; and has received research funding from Bristol Myers Squibb. MA is an employee of Pfizer R&D Japan. YU is an employee of Pfizer R&D Japan and holds stock in Pfizer. JW is an employee and reports stock and other ownership interest with Pfizer. AdiP reports employment, stock, and other ownership interest with Pfizer, and has received honoraria from Pfizer. MS has participated in consulting or advisory roles for Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, MSD, and Roche; has received travel, accommodations, and expenses from Bristol Myers Squibb, Ipsen, and Roche; and has received honoraria from Alkermes, Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, Janssen Oncology, and MSD., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Limited information is currently available on the efficacy and safety of axitinib for metastatic renal cell carcinoma (mRCC) patients with renal impairment. Therefore, the present study investigated the efficacy and toxicity of axitinib in patients with chronic kidney disease., Methods: Post-hoc analyses were performed on a Japanese multicenter cohort study of 477 mRCC patients who received axitinib followed by 1 or 2 regimens of systemic antiangiogenic therapy between January 2012 and December 2016. Differences in clinical characteristics and the efficacy and safety of axitinib were assessed based on pretreatment renal function., Results: Patients were categorized into the following 5 renal function groups according to baseline renal function: estimated glomerular filtration rate (eGFR) ≥60 ml/min (n = 133), 45 ml/min ≤eGFR <60 ml/min (n = 153), 30 ml/min ≤eGFR< 45 ml/min (n = 130), eGFR <30 ml/min (n = 45), and dialysis (n = 16). Median progression-free survival (PFS) (95% confidence interval [CI]) in the 5 groups was 11 (8-16), 14 (11-19), 14 (10-19), 12 (8-24), and 6 (3-NR) months, respectively (p = 0.781). After adjustments for treatment-related confounders, the renal function group was not a significant prognostic factor for PFS. Objective response rates in the 5 groups were 22%, 23%, 23%, 18%, 20%, and 38%, respectively (p = 0.468). Regarding adverse events of all grades, hypertension (p = 0.0006) and renal and urinary disorders (p < 0.0001) were more frequently observed in the eGFR <30 ml/min group than in the other groups., Conclusions: Since renal function at the initiation of treatment with axitinib does not adversely affect the efficacy of VEGF-TKI therapy, clinicians do not need to avoid its administration to mRCC patients with impaired renal function in consideration of the risk of progression to end-stage renal disease., Competing Interests: Declaration of Competing Interest Takahiro Osawa has received honoraria from Takeda. Masatoshi Eto received honoraria for lectures from ONO, BMS, Pfizer, Novartis, MSD, and Chugai, and for research funding from ONO, Pfizer, Chugai, BMS, Eisai, Bayer, and MSD. Hiroyuki Nishiyama has received honoraria from Ono and Chugai, research funds from Ono, Takeda, and Astellas, and reports scholarship endowments from MSD, Astellas, AstraZeneca, and Chugai. Takahiro Kimura received honoraria from Astellas, AstraZeneca, Bayer, Janssen, and Sanofi. Akira Yokomizo received honoraria from Pfizer and MSD. Nobuo Shinohara has received honoraria from Bayer, Ono, and Astellas and reports institutional research funding from Ono, Takeda, Sanofi, Taiho, and Astellas. Yoichi M. Ito is a statistical advisor for Nipro Corporation and an IDMC member for clinical trials of Janssen Pharmaceutical K.K. The other authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Disadvantages of systemically administered immunomodulatory anti-tumor therapies include poor efficacy and high toxicity. Direct intratumoral injection of a drug is often associated with rapid efflux from the site of administration, thus reducing local exposure and therapeutic efficacy, while potentially increasing systemic adverse events. To address this, a sustained release prodrug technology was developed using a transient conjugation (TransCon TM ) technology to provide long-term high local drug exposure after injection in the tumor while minimizing systemic exposure. TransCon technology for systemic delivery is clinically validated, with multiple compounds in late-stage clinical development and approval of a once-weekly growth hormone for pediatric growth hormone deficiency. As a further application of this technology, this report describes the design, preparation, and functional characterization of hydrogel microspheres as insoluble, yet degradable carrier system. Microspheres were obtained after reaction of PEG-based polyamine dendrimers and bifunctional crosslinkers. Resiquimod, a TLR7/8 agonist, and axitinib, a vascular endothelial growth factor tyrosine kinase inhibitor, were chosen as anti-cancer drugs. The drugs were covalently attached to the carrier by linkers, which released the drugs under physiological conditions. Essentially all resiquimod or axitinib was released over weeks before physical degradation of the hydrogel microsphere was observed. In summary, TransCon Hydrogel technology allows localized sustained-release drug delivery for cancer therapy enabling high local drug concentrations while at the same time ensuring low systemic drug exposure over weeks with a single injection, which may improve the therapeutic index and improve efficacy, while minimizing systemic adverse events. A hydrogel prodrug of resiquimod, TransCon TLR7/8 agonist, is currently being investigated in clinical trials of patients with solid tumors (NCT04799054)., Competing Interests: Declaration of interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kennett Sprogoe reports a relationship with Ascendis Pharma that includes: employment. Torben Lessmann reports a relationship with Ascendis Pharma that includes: employment. Seth A. Jones reports a relationship with Ascendis Pharma that includes: employment. Tobias Voigt reports a relationship with Ascendis Pharma that includes: employment. Samuel Weisbrod reports a relationship with Ascendis Pharma that includes: employment. Oliver Kracker reports a relationship with Ascendis Pharma that includes: employment. Steffen Winter reports a relationship with Ascendis Pharma that includes: employment. Luis Alejandro Zuniga reports a relationship with Ascendis Pharma that includes: employment. Sebastian Stark reports a relationship with Ascendis Pharma that includes: employment. Nicola Bisek reports a relationship with Ascendis Pharma that includes: employment. Kennett Sprogoe has patent pending to Ascendis Pharma A/S. Torben Lessmann has patent pending to Ascendis Pharma A/S. Samuel Weisbrod has patent pending to Ascendis Pharma A/S. Nicola Bisek has patent pending to Ascendis Pharma A/S. Sebastian Stark has patent pending to Ascendis Pharma A/S. Tobias Voigt has patent pending to Ascendis Pharma A/S., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The larval skeleton of the sea urchin Lytechinus variegatus is an ideal model system for studying skeletal patterning; however, our understanding of the etiology of skeletal patterning in sea urchin larvae is limited due to the lack of approaches to live-image skeleton formation. Calcium-binding fluorochromes have been used to study the temporal dynamics of bone growth and healing. To date, only calcein green has been used in sea urchin larvae to fluorescently label the larval skeleton. Here, we optimize labeling protocols for two additional calcium-binding fluorochromes: xylenol orange and calcein blue- and demonstrate that these fluorochromes can be used individually or in nested pulse-chase experiments to understand the temporal dynamics of skeletogenesis and patterning. Using a pulse-chase approach, we show that the initiation of skeletogenesis begins around 15 ​h post fertilization. We also assess the timing of triradiate formation in embryos treated with a range of patterning perturbagens and demonstrate that triradiate formation is delayed and asynchronous in embryos ventralized via treatment with either nickel or chlorate. Finally, we measure the extent of fluorochrome incorporation in triple-labeled embryos to determine the elongation rate of numerous skeletal elements throughout early skeletal patterning and compare this to the rate of skeletal growth in embryos treated with axitinib to inhibit VEGFR. We find that skeletal elements elongate much more slowly in axitinib-treated embryos, and that axitinib treatment is sufficient to induce abnormal orientation of the triradiates., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Combination immune checkpoint inhibitors (ICI) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-R-TKI), including pembrolizumab/axitinib, are approved for first-line treatment of metastatic renal cell carcinoma (mRCC). Pembrolizumab/axitinib is associated with superior progression free survival (PFS), objective response rate (ORR), and overall survival over sunitinib. However, to date, the activity and safety of pembrolizumab/axitinib in later lines of therapy has not been reported., Materials and Methods: Clinical data of consecutive patients receiving pembrolizumab/axitinib in the second-line or beyond for mRCC at Yale-New Haven Hospital were retrospectively collected. Best objective response was assessed using RECIST 1.1 criteria. Kaplan-Meier function was used to analyze survival., Results: Thirty-eight patients were included. Median age was 64, 92.1% had clear cell mRCC, 18.4% had sarcomatoid dedifferentiation; 94.7% had prior ICI and 39.5% had prior VEGF-R-TKI. Pembrolizumab/axitinib was administered as second-line therapy in 21 (55.5%) patients, third-line in 5 (13.2%) and beyond in 12 (30.2%). Adverse events (AEs) occurred in 86.8% of patients. Grade 3-4 AEs attributed to pembrolizumab and axitinib were seen in 18.4% and 6.4% of patients, respectively. No grade 5 AEs occurred. At a median follow up of 17.1 months, median PFS was 9.7 months (95% CI, 4.1-15.3). Amongst 36 response evaluable patients, the ORR was 25.0% (all partial) and disease control rate (including stable disease for at least 6 months) was 66.6%. The most frequent treatment sequence was first-line nivolumab/ipilimumab followed by second-line pembrolizumab/axitinib (n = 17, 44.7%); among this cohort, median PFS with pembrolizumab/axitinib was 11.1 (95% CI, 8.4-13.7) months, with an ORR of 31.4%., Conclusion: Combination pembrolizumab/axitinib among previously treated mRCC patients has activity, with AE rates comparable to those reported in the first line. Prospective studies evaluating ICI-VEGF-R-TKI combinations beyond first-line are warranted to identify the most beneficial treatment sequencing in mRCC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To clarify the impact of body mass index (BMI) on treatment outcomes including survival, tumor response, and adverse events (AEs) in patients with advanced renal cell carcinoma (RCC) or urothelial carcinoma (UC) treated with immune checkpoint inhibitors (ICIs) in an Asian population., Methods: We retrospectively evaluated 309 patients with advanced RCC or UC who received ICIs between September 2016 and July 2021. The patients were divided into high- (i.e., ≥25 kg/m 2 ) and low-BMI (<25 kg/m 2 ) groups according to the BMI at the time of treatment initiation., Results: Overall, 57 patients (18.4%) were classified into the high-BMI group. In RCC patients treated with ICIs as first-line therapy or UC treated with pembrolizumab, progression-free survival (PFS) (p = 0.309; p = 0.842), overall survival (OS) (p = 0.701; p = 0.983), and objective response rate (ORR) (p = 0.163; p = 0.553) were comparable between the high- and low-BMI groups. In RCC patients treated with nivolumab monotherapy as later-line therapy, OS (p = 0.101) and ORR (p = 0.102) were comparable, but PFS was significantly longer in the high-BMI group (p = 0.0272). Further, multivariate analysis showed that BMI was not an independent factor of PFS or OS in all the treatment groups (any, p>0.05). As for AE profiles, in nivolumab monotherapy, the rate was significantly higher in the high-BMI group (p = 0.0203), whereas in the other two treatments, the rate was comparable., Conclusions: BMI was not associated with survival or response rates of advanced RCC or UC patients treated with ICIs in an Asian population. AEs might frequently develop in high-BMI patients with RCC in nivolumab monotherapy., (Copyright © 2022. Published by Elsevier Inc.)

Background: Whether pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes exist in gastric cancer (GC) remains unclear., Methods: Seven independent cohorts including a total of 1901 GC patients were enrolled in our research. TCGA (n = 371) and GSE84437 (n = 433) were combined into one cohort (n = 804) to screen for prognosis-related PAN genes using a univariate Cox regression analysis. The R package "ConsensusClusterPlus" was applied to conduct a clustering analysis of the combination set based on prognosis-related PAN genes. The R package "limma" was used for the identification of differentially expressed genes (DEGs) between different PAN clusters (FDR <0.05 and |logFC|>1). The combined cohort was randomly divided into a training group (n = 484) and a test group (n = 320) at a ratio of 6:4 to establish and verify the prognostic model. A univariate Cox regression analysis, least absolute shrinkage and selection operator method (LASSO) regression analysis, and multivariate Cox regression analysis were used for the identification of prognostic genes and the construction of risk scores. Another five independent cohorts (GSE62254, n = 300; GSE15459, n = 191; GSE26901, n = 109; GSE26253, n = 432; and GSE13861, n = 65) were used for external validation to verify the accuracy and stability of the prognostic signature., Results: The internal and external validation demonstrated that the 5-gene risk score (LOXL4, SLCO2A1, CST2, PDK4, and MMP11) was an effective instrument for the prognostic risk classification of GC patients. The overall survival (OS) and relapse-free survival (RFS) in the high-risk group were significantly lower than those in the low-risk group and were accompanied by a larger proportion of macrophage and regulatory T cell infiltration. The low-risk group had a good prognosis, with a high tumor mutation burden (TMB), strong cytolytic activity, and a higher proportion of activated CD4 T cell infiltration. In addition, compared with the low-risk group, the cancer-related pathways in the high-risk group were overactivated, and the function of DNA damage repair (DDR) was significantly weakened. Regarding drug sensitivity, the high-risk group was more suitable for targeted drugs, such as axitinib, lapatinib, and nilotinib. The low-risk group was more sensitive to chemotherapy, such as cisplatin, gemcitabine, and vinorelbine., Conclusion: A universally applicable prognostic signature of GC is proposed in this research based on pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: There are known correlations between axitinib exposure and treatment response. The aim of the article was to study relationships between the axitinib steady-state trough concentration and the treatment efficacy and toxicity., Patients and Methods: 35 patients (24 men and 11 women), treated or initiating treatment with axitinib, were included in the study over the period 2016-2019. Blood samples were collected following 2 weeks of treatment (in patients who initiated the therapy) and at the end of Cycles 1, 2, and 3 thereafter (in the entire study population). For concentration measurements, high-performance liquid chromatography - mass spectrometry (HPLC-MS) was applied. Treatment efficacy was assessed according to the RECIST 1.1 criteria. Therapy toxicity was evaluated according to the CTCAE criteria., Results: A statistically significant relationship between the first measured axitinib trough concentration (C trough first ) value and treatment response (P = .004) as well as the median progression-free survival (mPFS) (P = .003) was observed. The association between axitinib C trough first and the median overall survival (mOS) was not statistically significant (P = .142). A statistically significant relationship was observed between the mean trough concentration from 3-month observation (C trough 1-3m ) and treatment response (P = .008) as well as mPFS (P = .001), without a significant relationship for mOS (P = .097). At least grade 3 adverse reactions were meaningfully associated with C trough first (P = .012) and C trough 1-3m (P = .003)., Conclusion: There are significant relationships between axitinib C trough and treatment response, PFS, and grade ≥ 3 toxicity. The data collected may be used to determine indications for axitinib therapy monitoring based on C trough measurements., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified., Patients and Methods: Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs. disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed., Results: In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data., Conclusions: This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cabozantinib, a potent multityrosine kinases inhibitor (TKI), has demonstrated overall survival (OS) benefit over everolimus in patients previously treated with VEGFR TKI for metastatic Renal Cell Carcinoma (mRCC). The efficacy of systemic treatments after cabozantinib failure has not been investigated., Materials and Methods: We conducted a retrospective study on patients receiving systemic treatment after cabozantinib failure in heavily pretreated patient with mRCC. We assessed Time to Treatment Failure (TTF), OS and objective response rate (ORR)., Results: Among 150 patients treated with cabozantinib in our institution, 56 (37.3%) received subsequent systemic therapy and were eligible for the analysis. IMDC prognostic group was good, intermediate and poor in 11 (19.6%), 24 (42.9%) and 11 (19.6%) patients, respectively. Cabozantinib was administered mainly as a second (41.1%), or third (33.9%) line treatment. axitinib or immune-checkpoint inhibitors were the subsequent treatment in 18 (34.8%) patients for each everolimus (n:16, 28.6%), other angiogenesis inhibitors (n:4, 7.1%) TTF and OS from subsequent systemic therapy after cabozantinib failure were 2.8 months (95%CI 1.9-3.7) and 7.7 months (95%CI 4.4-10.8), respectively. ORR was 8.7% and 2 patients with axitinib and 2 patients treated with Immune checkpoint inhibitors achieved a partial response., Conclusion: Overall, activity of systemic therapies after cabozantinib was limited., (Copyright © 2021. Published by Elsevier Inc.)

In this study, a novel, fast, selective, and sensitive molecularly imprinted polymer (MIP)-based electrochemical sensor was developed to determine axitinib (AXI) at low concentrations in pharmaceutical dosage forms and human serum. The newly developed MIP-based sensor (MIP@o-PD/GCE) was designed through electropolymerization of functional monomer o-phenylenediamine (o-PD) in the presence of a template molecule AXI, on a glassy carbon electrode (GCE) using cyclic voltammetry. Differential pulse voltammetry and electrochemical impedance spectroscopy (EIS) techniques were employed for removal and rebinding processes, optimization of conditions, as well as for performance evaluation of MIP@o-PD/GCE using [Fe(CN) 6 ] 3-/4- as the redox probe. Under the optimum experimental conditions, MIP@o-PD/GCE shows a linear response toward AXI in a range of 1 × 10 -13  M - 1 × 10 -12  M. The limit of the detection value of MIP@o-PD/GCE was found as 0.027 pM while the limit of the quantification was obtained as 0.089 pM, respectively. To demonstrate the applicability and validity of the developed sensor, it was successfully applied to tablet dosage form and human serum sample. The selectivity of the sensor was qualified by comparing the binding of AXI, erlotinib, dasatinib, nilotinib, and imatinib, which are similarly structured and in the same group of anticancer drugs. MIP@o-PD/GCE sensor showed a significant selectivity toward AXI. The non-imprinted polymer (NIP) based GCE was prepared and used to control the analytical performance of the MIP-based electrochemical sensor., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: There now exist several viable first-line treatment options for metastatic renal cell carcinoma, making the choice of initial therapy difficult. Considering metrics other than patient factors may be necessary to select the most appropriate therapy. We aimed to assess the cost-effectiveness of the three combination therapies currently approved in treatment-naïve advanced or metastatic renal cell carcinoma-nivolumab + ipilimumab (NI), pembrolizumab + axitinib (PA), and avelumab + axitinib (AA)-from a US payer perspective., Patients and Methods: Our analysis was performed based on previously obtained data derived from progression-free survival and overall survival curves from CheckMate 214, KEYNOTE 426, and JAVELIN Renal 101., Results: The total costs of each treatment were found to be $437,556.12 for NI, $450,597.15 for PA, and $542,882.34 for AA, with quality-adjusted life-year (QALY) values of 4.04, 3.77, and 2.95 for each combination, respectively. The incremental cost-effectiveness ratio (ICER) of NI versus PA was ($47,504.73/QALY); for NI versus AA, it was ($96,533.11/QALY); for PA versus AA, it was ($113,015.87/QALY). Net health benefit scaled against a willingness-to-pay threshold of $150,000 per QALY was positive for NI versus PA at 0.36 and versus AA at 1.79, and this index was also positive for PA versus AA at 1.43, indicating that the additional value of these therapies versus their alternatives is greater than the extra cost., Conclusion: NI was found to be the most cost-effective treatment option compared with the other considered therapies. PA was found to be cost effective compared to AA. When patient factors such as social issues and pre-existing conditions do not dictate their first-line therapy, clinicians may use this additional information to make financially conscious choices., (Copyright © 2021. Published by Elsevier Inc.)

Background: The ATLAS trial, investigating adjuvant axitinib versus placebo in renal cell carcinoma (RCC), was stopped for futility at a preplanned interim analysis. We report subgroup outcome analyses by ethnicity, time on treatment, dose modification and toxicity., Patients and Methods: Patient demographics, baseline characteristics, treatment duration and exposure and safety were analysed for Asian versus non-Asian patients treated with axitinib versus placebo. Disease-free survival (DFS) was analysed by ethnicity, treatment duration (≥1 versus <1 year), dose modification and adverse event (AE) grade., Results: No DFS benefit was observed for Asian {hazard ratio (HR) 0.883 [95% confidence interval (CI) 0.638-1.220]} or non-Asian [HR 0.828 (95% CI 0.490-1.400)] patients treated with axitinib or placebo. Fewer Asian versus non-Asian patients were in the highest-risk group in axitinib (51.9% versus 72.3%) or placebo (51.5% versus 66.0%) arm. Highest-risk patients in both subgroups had no DFS benefit with either treatment. More axitinib-treated Asian versus non-Asian patients had dose reductions due to AEs (58.8% versus 46.0%; P = 0.028). Asian patients experienced more nasopharyngitis but less fatigue or asthenia than non-Asians. Among Asian patients, proteinuria, hypothyroidism, nasopharyngitis, and hypertension were more common in Japanese patients than Korean patients and more common in Korean patients than Chinese patients. Patients receiving axitinib >1 year versus ≤1 year did not have different DFS: HR 0.572 (95% CI 0.247-1.327); P = 0.1874. Compared with patients on stable axitinib dose, DFS was longer in patients with dose reduction [HR 0.458 (95% CI 0.305-0.687); P = 0.0001], whereas DFS was not different in those with dose escalation [HR 1.936 (95% CI 0.937-3.997); P = 0.0685]. DFS was not different in patients experiencing grade ≥2 versus <2 AEs within 6 months of initiating axitinib: HR 0.885 (95% CI 0.419-1.869); P = 0.7488., Conclusions: Asian versus non-Asian subgroup analysis revealed differences in AE experience and drug exposure. There were no DFS differences based on ethnicity or treatment duration, but axitinib dose reduction led to longer DFS., Competing Interests: Disclosure DIQ has provided advisory board services for Pfizer, Bayer, Novartis, Bristol-Myers Squibb, Merck, Exelixis, Genentech, Roche, AstraZeneca and Astellas. CFN has consulted for and/or participated in speakers bureau for Boston Scientific, Janssen, Ferring and Astellas, and has received research funding for Ferring, Astellas, Janssen and Olympus. ME has received honoraria from Bristol-Myers Squibb, Pfizer, Novartis and Ono Pharmaceuticals. EG has received honoraria for ad boards, meetings and/or lectures from Pfizer, Bristol-Myers Squibb, IPSEN, Roche, Eisai, EUSA Pharma, Merck, Sanofi-Genzyme, Advanced Accelerator Applications, Novartis, Pierre Fabre, Lexicon and Celgene; and received unrestricted research grants from Pfizer, AstraZeneca, MTEM/Threshold, Roche, IPSEN and Lexicon. RL is an employee of SFJ Pharmaceuticals. MGG received honoraria from and provided advisory board services to Bristol-Myers Squibb, Ipsen, MSD, Novartis, Pfizer and Roche. BR and MNT are employees of and hold stock in Pfizer. All other authors have declared no conflicts of interest. Data sharing Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (i) for indications that have been approved in the US and/or EU or (ii) in programs that have been terminated (i.e., development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Among patients with advanced renal cell carcinoma (RCC), those with sarcomatoid histology (sRCC) have the poorest prognosis. This analysis assessed the efficacy of avelumab plus axitinib versus sunitinib in patients with treatment-naive advanced sRCC., Methods: The randomized, open-label, multicenter, phase III JAVELIN Renal 101 trial (NCT02684006) enrolled patients with treatment-naive advanced RCC. Patients were randomized 1 : 1 to receive either avelumab plus axitinib or sunitinib following standard doses and schedules. Assessments in this post hoc analysis of patients with sRCC included efficacy (including progression-free survival) and biomarker analyses., Results: A total of 108 patients had sarcomatoid histology and were included in this post hoc analysis; 47 patients in the avelumab plus axitinib arm and 61 in the sunitinib arm. Patients in the avelumab plus axitinib arm had improved progression-free survival [stratified hazard ratio, 0.57 (95% confidence interval, 0.325-1.003)] and a higher objective response rate (46.8% versus 21.3%; complete response in 4.3% versus 0%) versus those in the sunitinib arm. Correlative gene expression analyses of patients with sRCC showed enrichment of gene pathway scores for cancer-associated fibroblasts and regulatory T cells, CD274 and CD8A expression, and tumors with The Cancer Genome Atlas m3 classification., Conclusions: In this subgroup analysis of JAVELIN Renal 101, patients with sRCC in the avelumab plus axitinib arm had improved efficacy outcomes versus those in the sunitinib arm. Correlative analyses provide insight into this subtype of RCC and suggest that avelumab plus axitinib may increase the chance of overcoming the aggressive features of sRCC., Competing Interests: Disclosure TKC reports grants received from Pfizer during the conduct of the study; personal fees received from Agensys, Alexion, Alligent, American Society of Clinical Oncology, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Celldex, Cerulean, Clinical Care Options, Corvus, Dana-Farber Cancer Institute, EMD Serono, Inc., Eisai, Exelixis, Foundation Medicine, Genentech/Roche, GSK, Harborside Press, Heron, Ipsen, Kidney Cancer Association, Kidney Cancer Journal, Lpath, Lancet Oncology, Lilly, Merck & Co., Michael J. Hennessy Associates, National Comprehensive Cancer Network, Navinata Health, New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus Laboratories, Sanofi, Seattle Genetics/Astellas, and UpToDate outside the conduct of the study; grants received from AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Cerulean, Corvus, Eisai, Exelixis, Foundation Medicine, Genentech/Roche, GSK, Ipsen, Merck & Co., Novartis, Peloton Therapeutics, Pfizer, Prometheus Laboratories, Takeda, and TRACON outside the conduct of the study; and medical writing and editorial assistance provided by ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel, funded by pharmaceutical companies. JL reports personal fees from Eisai, EUSA Pharma, GSK, Kymab, Pierre Fabre, Roche/Genentech, and Secarna and grants and personal fees from Bristol Myers Squibb, Merck & Co., Novartis, and Pfizer outside the submitted work. SP reports personal fees from Astellas Pharma and Novartis and personal fees and grants from Medivation. RJM reports serving as a consultant or advisor for and research funding from Pfizer, Novartis, Eisai, and Genentech/Roche, serving as a consultant or advisor for Exelixis, Lilly, Merck & Co., and Incyte, and receiving travel, accommodation, and expenses and research funding from Bristol Myers Squibb outside the submitted work. BIR reports grants and personal fees from AVEO Oncology, Bristol Myers Squibb, Genentech/Roche, Merck & Co., and Pfizer; grants from AstraZeneca; and personal fees from 3D Medicines, Alkermes, Arravive, Inc., Compugen, Corvus Pharmaceuticals, Exelixis, Merck & Co., Novartis, Peloton, Surface Oncology, and Synthorx. BV reports grants and personal fees from Bristol Myers Squibb, personal fees from Merck & Co. and Pfizer, and grants from Merck & Co. during the conduct of the study; and personal fees from EUSA Pharma, Ipsen, and Janssen outside the submitted work. BA reports personal fees from Amgen and Ferring, grants and personal fees from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck & Co., Pfizer, Roche, and Sanofi, and grants from Ipsen outside the submitted work. GG reports receiving travel, accommodation, and expenses from Astellas, Bristol Myers Squibb, Ipsen, Janssen Oncology, and Pfizer. MAB reports grants from AstraZeneca, Bayer, Bristol Myers Squibb, Genentech/Roche, Incyte, Peleton Therapeutics, Pfizer, and TRACON; personal fees from EMD Serono, Inc., Exelixis, Genomic Health, and Sanofi; and grants and personal fees from Nektar. AC reports employment at Pfizer at the time when the study was conducted. SH, KAC, XJM, MM, PBR, BH, AdiP report employment at Pfizer. LA reports consulting fees compensated to their institution from Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus Pharmaceuticals, Exelixis, Ipsen, Merck KGaA, Merck & Co., Novartis, Peloton Therapeutics, Roche, and Pfizer outside the submitted work. HM has declared no conflicts of interest. Data sharing Upon request, and subject to certain criteria, conditions, and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (i) for indications that have been approved in the USA and/or EU or (ii) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The therapeutic landscape in the treatment of advanced/metastatic renal cell cancer has evolved over the last 2 years with the advent of immune checkpoint inhibitors. In 2018 and 2019, marketing authorisations valid throughout the European Union were issued for nivolumab and ipilimumab dual checkpoint inhibition and pembrolizumab or avelumab in combination with the tyrosine kinase inhibitor axitinib. These applications presented numerous regulatory challenges.In this paper, we summarise the main regulatory considerations, originating from the assessment of the dossiers submitted from the applicants for the three combinations. The regulatory issues are grouped in four sections: clinical pharmacology, efficacy, biomarkers and safety. In each section, we describe the issues raised during the regulatory evaluation performed by the Committee for Medicinal Products for Human Use (CHMP) assessors. The CHMP assessments determine whether the medicines concerned meet the necessary quality, safety and efficacy requirements, and whether the benefit-risk balance is positive.In summary, although the overall benefit-risk was considered positive for the three combinations, the immaturity of the outcome data and the absence of long-term safety data remain issues to be addressed. Postauthorisation efficacy studies have been required to confirm the effects of the new combinations., Competing Interests: Competing interests: LM reported personal fees from Pfizer., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis., Patients and Methods: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population., Results: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]., Conclusion: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature., Clinical Trial Number: NCT02684006., Competing Interests: Disclosure TKC reports the following: Research (institutional and personal): AstraZeneca, Alexion, Bayer, Bristol-Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda. Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OncLive, PeerView, and PER), Research to Practice, Lpath, Kidney Cancer Journal, Clinical Care Options, PlatformQ, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, New England Journal of Medicine, The Lancet Oncology, Heron Therapeutics, Lilly. Consulting or Advisory Role: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest. Stock ownership: Pionyr, Tempest. Other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of Medical Staff at Dana-Farber, member of NCCN Kidney Panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee. Patents, royalties or other intellectual properties: International Patent Application No. PCT/US2018/12209, entitled ‘PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response’, filed 3 January 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed 11 January 2017; International Patent Application No. PCT/US2018/058430, entitled ‘Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy’, filed 31 October 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed 3 November 2017. Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack). RJM reports personal fees and other from Pfizer during the conduct of the study; personal fees and other from Genentech/Roche, personal fees from Incyte, other from Bristol-Myers Squibb, personal fees and other from Novartis, personal fees and other from Exelixis, personal fees and other from Eisai, personal fees from Merck, outside the submitted work. BIR reports grants and personal fees from Pfizer during the conduct of the study, grants and personal fees from Merck (MSD), grants and personal fees from Bristol-Myers Squibb, personal fees from Novartis, grants and personal fees from GNE/Roche, personal fees from Exelixis, personal fees from Peloton, outside the submitted work. JH reports grants and personal fees from Bristol-Myers Squibb, MSD, Novartis, and Neon Therapeutics; personal fees from Pfizer, Roche/Genentech, Bayer, Immunocore, Seattle Genetics, Gadeta B.V., Celsius Therapeutics, and AstraZeneca/MedImmune, outside the submitted work. MTC reports personal fees from Eisai, grants and personal fees from EMD Serono, grants from Pfizer, personal fees from Genentech and AstraZeneca, grants from Exelixis and Janssen, other from Bristol-Myers Squibb, Roche, and Merck, outside the submitted work. BV reports personal fees from Bristol-Myers Squibb, personal fees and nonfinancial support from Merck Serono Dohme (MSD), personal fees from EUSA Pharma, personal fees and nonfinancial support from Ipsen, during the conduct of the study. CK reports personal fees from Pfizer, Bristol-Myers Squibb, Eisai, Ipsen, Astellas, and EMD Serono, outside the submitted work. GG-M and MU have nothing to disclose. JLL reports grants, personal fees, and other from Pfizer Korea and Ipsen Korea, personal fees and other from Janssen and Sanofi Aventis, personal fees from Novartis Korea, and personal fees and other from Astellas Korea and Bristol-Myers Squibb Korea, outside the submitted work. M-OG reports grants and personal fees from Novartis and Bristol-Myers Squibb, personal fees from Pfizer, Bayer HealthCare, Astellas, Intuitive Surgical, Sanofi Aventis, Hexal, APOGEPHA, Amgen, AstraZeneca, MSD, Janssen Cilag, Ono Pharma, Ipsen Pharma, Medac, and Merck, outside the submitted work. HG reports personal fees from Bristol-Myers Squibb, Astellas, Pfizer, AstraZeneca, Ipsen, Roche, and MSD, outside the submitted work. MS reports grants, personal fees, and nonfinancial support from Pfizer; personal fees and nonfinancial support from Roche; and personal fees from Novartis, Bristol-Myers Squibb, Ipsen, Exelixis, Eisai, Astellas, and EUSA Pharma, outside the submitted work. JL reports grants and personal fees from Achilles Therapeutics, MSD, Bristol-Myers Squibb, Nektar, Novartis, Pfizer, Roche/Genentech, and Immunocore; personal fees from AstraZeneca, Boston Biomedical, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Pierre Fabre, Secarna, Vitaccess, and Covance; and grants from Aveo and Pharmacyclics, outside the submitted work. MBA reports personal fees from Pfizer, Bristol-Myers Squibb, Merck, Roche, Exelixis, Eisai, Novartis, Alexion, Boehringer Ingelheim, Nektar, and X4 Pharmaceuticals, outside the submitted work. SKP has received honoraria from Astellas Pharma, Medivation, and Novartis; and fees for a consulting or advisory role from Aveo, Bristol-Myers Squibb, Exelixis, Genentech, Myriad Pharmaceuticals, Novartis, and Pfizer. JW, MM, SK, PC, AC, CF, BH, and AdP are employees of Pfizer. LA reports personal fees from Bristol-Myers Squibb, Pfizer, Ipsen, Peloton Therapeutics, Roche, MSD, and Novartis, outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors and vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors are the most commonly used medications in metastatic renal cell carcinoma (mRCC). Recently, large clinical trials have shown favorable outcomes in patients treated with combined immune checkpoint plus VEGFR inhibition compared with VEGFR inhibition alone. However, the benefit among favorable risk (based on International Metastatic Renal Cell Carcinoma Database Consortium score) and elderly (age > 65 years) patients was not clear, leading to a discrepancy between United States Food and Drug Administration and European Association of Urology recommendations., Materials and Methods: We searched available literature for phase III randomized clinical trials evaluating the efficacy of combining immunotherapy plus VEGF/VEGFR inhibitors versus standard of care in patients with previously untreated mRCC. Combinations that were included in United States Food and Drug Administration recommendations or European Association of Urology guidelines were used for analysis. We performed a meta-analysis with a random effects model to evaluate the efficacy of immunotherapy-VEGFR inhibitor combinations compared with sunitinib in favorable risk and elderly patients., Results: Our analysis demonstrated that progression-free survival (PFS) was significantly prolonged with combination therapy compared with sunitinib in patients with age > 65 years (hazard ratio, 0.66; 95% confidence interval, 0.52-0.84; P = .001). The PFS in favorable risk disease was improved with combination therapy compared with sunitinib, but the difference was not statistically significant (hazard ratio, 0.68; 95% confidence interval, 0.46-1.01; P = .055)., Conclusion: Our meta-analysis strengthens the trend of beneficial effect in prolonging PFS in both subgroups compared with each trial alone, indicating that favorable risk and elderly patients with mRCC likely benefit from combining programmed cell death 1 or programmed cell death-ligand 1 and VEGFR inhibition., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The epidemic of loperamide abuse and misuse in the patients for the alternative to opioids has become an increasing worldwide concern and has led to considerations about the potential for drug-drug interactions between loperamide and other combined drugs, especially inhibitors of cytochrome P450 (CYP450) enzymes, such as axitinib. This study assessed the effects of axitinib on the metabolism of loperamide and its main metabolite N-demethylated loperamide in rats and in rat liver microsomes (RLM), human liver microsomes (HLM) and recombinant human CYP3A4*1. The concentrations of both compounds were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The exposures (AUC (0-t) , AUC (0-∞) and C max ) of loperamide and N-demethylated loperamide showed a conspicuous increase when loperamide was co-administered with axitinib. The T max of loperamide increased while CLz/F decreased under the influence of axitinib. In vitro, axitinib inhibited loperamide metabolism with the IC 50 of 18.34 μM for RLM, 1.705 μM for HLM and 1.604 μM for CYP3A4*1, and it was confirmed as a non-competitive inhibitor in all enzymes. Taken together, the results indicated that axitinib had an obvious inhibitory impact on loperamide metabolism both in vivo and in vitro. Thus, more attention should be paid to the concurrent use of loperamide and axitinib to reduce the risk of unexpected clinical outcomes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Metastatic Renal Cell Carcinoma: HOW TO CHOOSE THE APPROPRIATE SECOND-LINE TREATMENT?: The treatment of advanced or metastatic renal cell cancer (RCC) has dramatically improved in the past ten years. In the second-line setting, for patients who progressed on prior antiangiogenic therapy (mainly the VEGFR tyrosine kinase inhibitors (TKI) sunitinib or pazopanib), axitinib and everolimus have been recommended. Since 2015, other drugs have proven their efficacy and are currently considered the standard of care: cabozantinib (TKI that targets VEGFR, MET and AXL) and nivolumab (first anti-PD-1 check point inhibitor). Lenvatinib has also demonstrated promising results in association with everolimus, but this combination is not available in France. The optimal treatment choice for a given patient is challenging for the clinician when facing multiple options. In this article, we review the efficacy, safety and quality of life results of the main pivotal clinical studies involving advanced or metastatic RCC in the second-line setting, to help clinicians in selecting the most appropriate treatment. Beyond that, it is important to define all the sequencing strategy for patients to successively receive all the drugs that have demonstrated an increase in overall survival., (© 2018 Société Française du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Introduction: The AXIS trial established axitinib as a standard of care treatment for patients with metastatic renal cell carcinoma (mRCC) after failure of a prior tyrosine kinase inhibitor. Axitinib dosing begins at 5  mg twice daily, with escalation of doses to 7  and 10  mg after consecutive 2-week intervals if tolerated (as per the drug label). Given clinical concerns about drug-related toxicity, we have used a pragmatic strategy where dose escalations were made only after disease progression or where rapid responses were clinically required., Methods: We performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for >2 weeks at Addenbrooke's Hospital, Cambridge, UK, over a 37 -month period to determine the clinical and radiological effects of dose escalations made according to the above strategy., Results: 42 patients fitting these criteria were identified, 29 having ≥1  dose escalation event (DEE). 60 DEEs were identified (median of two per patient), and the objective radiological consequences of 53 DEEs could be evaluated. The disease control rate (partial response or stable disease) after the first DEE instituted for disease progression was similar to that after the second DEE (68.8% vs 70%). 56.6 % of all DEEs and 63.6 % of DEEs made as a result of disease progression resulted in disease control. The median OS from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 16.5 months for the entire cohort. The mean dose (for all patients) at 90 days after starting axitinib was 5.92  mg., Conclusion: These data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and this may be a preferred option in patients in whom there are particular concerns about drug-related toxicity, quality of life optimisation or healthcare-associated costs., Competing Interests: Competing interests: AM is employed by AstraZeneca. KF has received honoraria for advisory board activities from Esai, Ipsen, Roche and Novartis, and speaker fees from Bristol Myers Squibb and Pfizer. TE is employed by AstraZeneca and has received honoraria for consultancy and advisory board activities from GSK, Pfizer, Roche, Novartis and Bristol Myers Squibb.

Introduction: The aim of this study was to evaluate the efficacy and safety of maintenance therapy with axitinib versus placebo following induction therapy in patients with metastatic colorectal cancer (mCRC)., Patients and Methods: In this double-blinded, phase II trial, patients with mCRC who had not progressed after 6 to 8 months of first-line chemotherapy were randomized to receive axitinib (5 mg twice a day) (arm A) or placebo (arm B)., Results: Forty-nine patients were included: 25 in arm A and 24 in arm B. The median follow-up was 26.07 months (95% confidence interval [CI], 18.44-31.73 months). Progression-free survival (PFS) rate at 6 months was 40.00% (95% CI, 21.28%-58.12%) in the axitinib arm versus 8.33% (95% CI, 1.44%-23.30%) in the placebo arm (P = .0141). The median PFS was statistically significantly longer in the axitinib group than in the placebo group (4.96 vs. 3.16 months; hazard ratio, 0.46; 95% CI, 0.25-0.86; P = .0116). Median overall survival was also longer in the axitinib arm but did not reach statistical significance (27.61 vs. 19.99 months; hazard ratio, 0.68; 95% CI, 0.31-1.48; P = .3279). Grade 3 to 4 treatment-related toxicities were experienced by 7 patients (28%) in cohort A and 1 patient (4%) in cohort B (P = .0488). The most frequent grade 3 to 4 treatment-related toxicities were hypertension, diarrhea, and asthenia. There were no toxic deaths. The study was prematurely closed because of slow recruitment., Conclusions: In our study, maintenance treatment with axitinib monotherapy showed a significant increase in PFS and a good safety profile. Axitinib should be further explored as a possible option for first-line chemotherapy maintenance treatment in patients with mCRC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A method based on micellar liquid chromatography to quantify the tyrosine kinase inhibitors axitinib, lapatinib and afatinib in plasma is reported. The sample pretreatment was a simple 1/5-dilution in a pure micellar solution, filtration and direct injection, without requiring extraction or purification steps. The three drugs were resolved from the matrix in 17min, using an aqueous solution of 0.07M sodium dodecyl sulfate - 6.0% 1-pentanol, buffered at pH7 with 0.01M phosphate salt as mobile phase, running under isocratic mode at 1mL/min through a C18 column. The detection was performed by absorbance at 260nm. An accurate mathematical relationship was established between the retention factor of each drug and the surfactant/organic solvent concentration in the mobile phase, achieved with a limited number of experiments, in order to optimize these factors. A binding behavior of the analytes face to the micelles was found out. The method was successfully validated by the guidelines of the European Medicines Agency in terms of: selectivity, linearity (r 2 >0.9995), calibration range (0.5 to 10mg/L), limit of detection (0.2mg/L), carry-over effect, accuracy (-8.1 to +6.9%), precision (<13.8%), dilution integrity, matrix effect, stability and robustness. The procedure was found reliable, practical, economic, accessible, short-time, easy-to-handle, inexpensive, environmental-friendly, safe, useful for the analysis of many samples per day. Finally, the method was applied to the analysis of incurred, using quality control samples in the same analytical run, with adequate results. Therefore, it can be implementable for routine analysis in clinical laboratories., (Copyright © 2018 Elsevier B.V. All rights reserved.)