Sorafenib Research Articles

Clinical impact of the changes of muscle volume during various systemic therapies in patients with unresectable hepatocellular carcinoma.

e16177 Background: Sarcopenia is associated with clinical outcomes in cirrhosis and hepatocellular carcinoma (HCC). However, the clinical impact of muscle volume during systemic therapy is unknown. We investigated the changes in muscle volume during various systemic therapies for HCC. Methods: The patients with unresectable HCC (u-HCC) treated with a molecular targeted agent as initial systemic therapy were included. The skeletal muscle mass index (SMI) was calculated from the skeletal muscle area at the L3 level of the lumbar vertebrae using computed tomography. Sarcopenia was defined as an L3 SMI value≦42 cm2/m2 for men and 38 cm2/m2 for women. ΔSMI was defined as the difference between baseline and 6-14 weeks after the administration of the agent. Results: A total of 174 patients was analyzed. The 1st-line agent was sorafenib (SOR) (n = 89), lenvatinib (LEN)(n = 58), and atezolizumab plus bevacizumab (ATE+BEV) (n = 27). In three groups, ATE+BEV group had significantly fewer discontinuation due to adverse events. (ATE+BEV 6 cases, LEN 31 cases, SOR 32 cases, p = 0.014). The median PFS was 4.1, 3.0, and 6.1 months in SOR, LEN, and ATE+BEV. The median Δ In patients treated with ATE+BEV, pretreatment sarcopenia was not associated with OS and PFS, while the patients with a SMI decrease (at 6-14W, n = 12) had significantly shorter PFS than the patients without a SMI decrease (n = 15) (p = 0.026). The best radiological response based on RECIST ver1.1 in ATE+BEV was CR (n = 2), PR(n = 6), SD(n = 15), and PD (n = 3). The patients without a SMI decrease tended to have better disease control rate than patients with a SMI decrease (100% vs. 75%, p = 0.08). There were no significant differences in age, etiology, ALBI score, BCLC stage, and pretreatment AFP between the patients with and without a SMI decrease. The significant factor associated with PFS after the administration of ATE+BEV as 1st-line was a decrease of SMI (HR9.44, 95% CI 1.04-85.6, p = 0.046). In patients treated with SOR and LEN, pretreatment sarcopenia and SMI decrease were not significantly associated with OS and PFS. Conclusions: The decrease of muscle volume at 6-14W was significantly associated with PFS in patients treated with ATE+BEV, while pretreatment sarcopenia was not a significant factor. Monitoring muscle volume during immunotherapy would be useful in clinical practice.

Maturation of overall survival (OS) in TIVO-3 with long-term follow-up.

4557 Background: Maturity of survival data is a consideration in the value assessment and confident clinical application of oncology drugs based on trial evidence. TIVO-3 supported FDA-approval of tivozanib (TIVO) in relapsed/refractory (R/R) advanced RCC, meeting the primary endpoint of significantly improved PFS over sorafenib (SOR) (HR: 0.73, 95% CI, 0.56-0.95). Long-term follow-up analyses demonstrate that the PFS rate at 3-years with TIVO is >5x higher than with SOR (12% vs 2%, respectively), yet a significant OS benefit for TIVO has not been observed to date. Here we report the contribution of event accumulation and data maturation on the stability of KM survival estimates. Methods: Intent-to-treat analyses of Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for OS in the TIVO-3 trial at prespecified (2-years after last-patient-in [LPI]; ≥251 events) and exploratory extended follow-up timepoints (≥270 events; database closure). Patients were followed for survival until death, consent withdrawal, or loss to follow-up. Results: 350 patients were randomized 1:1 to TIVO (n=175) or SOR (n=175). 2-years post LPI and a mean follow-up of 17.9 months (data cut-off August 2019), 65% of patients experienced an event (HR: 0.99, 95% CI, 0.76-1.29). Subsequent analyses are reported at 20.3 (May 2020), 21.9 (January 2021), and 22.8 (May 2021) months follow-up. Accumulation of events and HR over time is shown in the Table. After almost 23 months of follow-up and realization of 80% of events, OS HR has decreased to below 0.90, in favor of TIVO. Conclusions: Serial OS analyses using KM estimates are subject to increased curve reliability with decreased censoring and limited residual patients at risk for death. Long-term follow-up of TIVO-3 suggests early and consistent PFS benefit with TIVO over SOR is associated with an OS HR decline over-time with more events. Clinical trial information: NCT02627963. [Table: see text]

PLGA-graphene quantum dot nanocomposites targeted against αvβ3 integrin receptor for sorafenib delivery in angiogenesis.

Angiogenesis is a vital step in many severe diseases such as cancer, diabetic retinopathy, and rheumatoid arthritis. Sorafenib (SFB), a multi-tyrosine kinase inhibitor, has recently been shown to inhibit tumor progression and suppress angiogenesis. Its narrow therapeutic window, however, has limited its clinical application and therapeutic efficacy. Accordingly, in this study, a nanocomposite formulation comprising of graphene quantum dots (GQDs) and poly (D, l-lactide-co-glycolide) (PLGA) nanoparticles was functionalized with an integrin-targeting ligand (RGD peptide) to improve SFB delivery for the treatment of angiogenesis. Physicochemical and biological properties of the targeted nanocomposite were evaluated in terms of chemical structure, morphology, particle size, zeta potential, photoluminescence, and cell toxicity. The loading capacity of the nanocomposite was optimized at different drug-to-PLGA ratios. Drug release behavior was also investigated at 37°C in pH=7.4. The SFB-to-PLGA ratio of 1:3 was selected as the optimum condition which resulted in the encapsulation efficiency and encapsulation capacity of 68.93±1.39 and 18.77±0.46, respectively. Photoluminescence properties of GQD in nanocomposite were used to track the delivery system. The results indicated that conjugating targeting ligand could enhance cellular uptake of nanocomposite in cells overexpressing integrin receptors. In vivo anti-angiogenesis activity of targeted nanocomposite was investigated in chick chorioallantoic membrane (CAM). The findings showed that SFB loaded in the targeted nanocomposite reduced VEGF secretion in vitro and its anti-angiogenic effect surpass free SFB. Thanks to its unique therapeutic and bioimaging properties, the developed nanocomposite could be an effective drug delivery system for poorly water-soluble therapeutic agents.

Clinical outcomes associated with tislelizumab in patients (pts) with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (SOR) or lenvatinib (LEN) in RATIONALE-208.

4072 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). At the time of this study, SOR and LEN were recommended first-line treatments for pts with advanced HCC and continue to have an important role in the first-line treatment of HCC despite the recent approval of new immuno-oncology-based combinations (atezolizumab and bevacizumab) in some regions. We report the clinical outcomes of pts with advanced HCC who were previously treated with SOR/LEN. Methods: Pts who had received ≥ 1 prior line of systemic therapy for advanced HCC received tislelizumab 200 mg intravenously once every three weeks. Objective response rate (ORR) by independent review committee (IRC) (ORRIRC), duration of response by IRC (DORIRC), progression-free survival by IRC (PFSIRC), overall survival (OS), and safety were evaluated in pts who had been previously treated with SOR/LEN. Results: As of February 2020, 249 pts were enrolled and 235 pts had received prior treatment with SOR/LEN, of whom 126 and 109 pts had received 1 or ≥ 2 prior lines of systemic therapy, respectively. At study entry, 211 (89.8%) pts had BCLC stage C and 187 (79.6%) pts had extrahepatic spread. Median follow-up duration for pts previously treated with SOR/LEN was 12.5 months and ORRIRC was 13.6% (95% CI: 9.5, 18.7), including 2 complete responses and 30 partial responses. Median DORIRC was not reached. Median PFSIRC and OS of pts previously treated with SOR/LEN was 2.7 months (95% CI: 1.6, 2.8) and 13.5 months (95% CI: 10.9, 15.8), respectively. Tislelizumab was generally well tolerated in pts previously treated with SOR/LEN (Table), and the most common treatment-emergent adverse events were increased aspartate aminotransferase (n=70; 28.1%) and alanine aminotransferase (n=52; 20.9%). Conclusions: Tislelizumab was investigated beyond the first-line setting, as effective second- and third-line treatment options are limited for pts with advanced HCC and there is an unmet medical need. This analysis indicates that tislelizumab is clinically active and well tolerated in pts with advanced HCC who have received prior systemic treatment with SOR/LEN. Clinical trial information: NCT03419897. [Table: see text]

Selenium nanoparticles overcomes sorafenib resistance in thioacetamide induced hepatocellular carcinoma in rats by modulation of mTOR, NF-κB pathways and LncRNA-AF085935/GPC3 axis

AimsThe first-line treatment for advanced hepatocellular carcinoma (HCC) is the multikinase inhibitor sorafenib (SOR). Sofafenib resistance is linked to protein kinase B/ mammalian target of rapamycin (AKT/mTOR) and nuclear factor kappa B (NF-κB) activation, apoptosis inhibition and oxidative stress. This study investigated selenium nanoparticles (SeNps) to overcome SOR resistance in thioacetamide (TAA) induced HCC in rats. Materials and methodsTAA (200 mg/kg/twice weekly, i.p.) was administered for 16 weeks to induce HCC.s. Rats were treated with oral SOR (10 mg/Kg daily), selenium, and SeNps (5 mg/kg three times/week) alone or in combination, for two weeks. Apoptosis, proliferation, angiogenesis, metastasis and drug resistance were assessed. Cleaved caspase 3 (C. CASP3), mTOR, and NF-κB were determined by western blotting. Expression of p53 gene and long-noncoding RNA-AF085935 was determined by qRT-PCR. Expression of B- Cell Leukemia/Lymphoma 2 (Bcl2), Bcl associated X protein (Bax)and glypican 3 (GPC3) was determined by enzyme-linked immunosorbent assay. Liver functions, antioxidant capacity, histopathology and CD34 immunohistochemistry were performed. Key findingsSOR/SeNps reversed TAA-induced HCC in rats, through reduction of oxidative stress, activation of p53, Bax and CASP3, and inhibition of Bcl2. SOR/SeNps ameliorated the HCC-induced effect on cell proliferation and drug resistance by targeting mTOR and NF-κB pathways. SOR/SeNps decreased CD34 immunostaining indicating a decrease in angiogenesis and metastasis. SOR/SeNps regulated HCC epigenetically through the lncRNA-AF085935/GPC3 axis. SignificanceSOR/SeNps are a promising combination for tumor suppression and overcoming sorafenib resistance in HCC by modulating apoptosis, AKT/mTOR and NF-κB pathways, as well as CD34 and lncRNA-AF085935/GPC3 axis.

Layered Double Hydroxides-Loaded Sorafenib Inhibit Hepatic Stellate Cells Proliferation and Activation In Vitro and Reduce Fibrosis In Vivo.

A core feature of liver fibrosis is the activation of hepatic stellate cells (HSCs), which are transformed into myofibroblasts and lead to the accumulation of extracellular matrix (ECM) proteins. In this study, we combined in vitro cellular efficacy with in vivo antifibrosis performance to evaluate the outcome of sorafenib (SRF) loaded layered double hydroxide (LDH) nanocomposite (LDH-SRF) on HSCs. The cellular uptake test has revealed that sorafenib encapsulated LDH nanoparticles were efficiently internalized by the HSC-T6 cells, synergistically inducing apoptosis of hepatic stellate cells. Moreover, the apoptosis rate and the migration inhibition rate induced by LDHs-SRF were 2.5 and 1.7 times that of SRF. Western Blot showed that the TGF-β1/Smad/EMT and AKT signaling pathway was significantly inhibited in HSC-T6 cells treated with LDHs-SRF. For the in vivo experiment, LDHs-SRF were administered to rat models of CCl4-induced liver fibrosis. H&E, masson and sirius red staining showed that LDHs-SRF could significantly reduce inflammatory infiltrate and collagen fiber deposition and immunohistochemical results found that LDHs-SRF treatment significantly inhibited the protein expressions of α-SMA in the liver, these results suggesting that LDHs-SRF exhibited better anti-fibrotic effect than SRF alone and significantly inhibited the proliferation and activation of rat hepatic stellate cells and collagen fiber synthesis.

Design and Evaluation of Sorafenib Tosylate Nanoparticles Including Assessment of IC50 Values using PC Cell Lines

Introduction: Sorafenib tosylate is an anticancer drug used for treatment of pancreatic cancer. In the present research work, Sorafenib tosylate is converted to nanoparticles with an aim to assess its anticancer activity with reduced concentration expecting less side effects of the parent drug.
 Objective: The aim of the present research work is preparation of nanoparticles of Sorafenib tosylate, evaluation at in-vitro level and to carry out promising nanoparticles for anti cancer activity for treatment of pancreatic cancer by MTT Assay method using PC cell lines including comparison of IC50 values of sorafenib tosylate nanoparticles and pure drug
 Methodology: The nanoparticles of sorafenib were prepared by salting out method using Eudragit S-100, sodium CMC and Zinc sulphate. Eight formulations were tried using varied drug to polymer ratios.
 Results: The promising formulation produced with drug to polymer ratio of 1:2 has particle size of 231.6nm and highest dissolution rate 76.2± 0.35% in 60 min and 82.5% in 90 min. These nanoparticles assessed by MTT assay method revealed reasonably reduced IC50 value of 0.848±0.217 compared to 1.92±0.14 in case of pure sorafenib tosylate.
 Conclusion: Sorafenib tosylate nanoparticles can be produced successfully by salting out method using drug to polymer (Sorafenib tosylate: Eudragit L-100) ratio of 1:3 by salting out method to possess ideal drug release characteristics. IC50 values of nanoparticles of sorafenib tosylate are reasonably reduced compared to pure drugs indicating very chances of reduced side effects with nanoparticles to treat pancreatic cancer effectively with reduced side effects.

Ginsenoside Rg3 and sorafenib combination therapy relieves the hepatocellular carcinomaprogression through regulating the HK2-mediated glycolysis and PI3K/Akt signaling pathway

ABSTRACT Hepatocellular carcinoma (HCC) is the most common pathological type of primary hepatic carcinoma. This study investigated the effects of ginsenoside Rg3 (Rg3) and sorafenib (SFN) combination therapy on HCC progression. The HCC-related data were obtained from TCGA database, and the data of HK2 mRNA, clinicopathological features, and survival outcomes were extracted using R Programming 4.0. The human hepatoma cell lines HepG2 and Bel7404 were used. Cell viability was tested using the MTT assay. Glucose consumption and lactate levels of HCC cells were detected using the corresponding kits. Western blotting was used to determine the protein expression of HK2, PI3K, and Akt. HK2 was overexpressed in patients with HCC. Compared with patients with overexpressed HK2, those with low levels of HK2 achieved a longer survival time. In addition, the Rg3 and SFN combination therapy significantly reduced cell viability, glucose consumption, lactate levels, and protein expression of HK2, PI3K, and Akt in HCC cells. Additionally, the Rg3 and SFN combination therapy exhibited a better effect than the single drug group. Inhibition of the PI3K/Akt signaling pathway or exogenous lactate intervention reversed the effects of Rg3 and SFN combination therapy in HCC cells. In conclusion, Rg3 has a synergistic effect on the sensitivity of HepG2 and Bel7404 hepatoma cells to SFN, which is related to HK2-mediated glycolysis and the PI3K/Akt signaling pathway.

A novel polymer integrated Vertically-Oriented reduced graphene oxide sheets supported over palladium nanoparticles based sensor for Real-Time monitoring of Sorafenib; a Multi-kinase inhibitor in complex biological samples

Herein, we report a facile preparation of vertically oriented reduced graphene oxide sheets (VrGO) supported on a palladium nanoparticles-decorated graphite electrode. The electrode is fabricated by a simple two electrodeposition steps method. The designed electrode BEFD&VrGO@PdNPs successfully provides an open structure of rGO layer exposing palladium nanoparticles (PdNPs) to the solution, leading to formation of a uniform distributed vertically oriented rGO (VrGO) due to the high surface area of palladium-decorated PGE substrate. The fabricated electrode was successfully used for determination of sorafenib (SOR); an anti-cancer drug. Using square wave voltammetric method (SWV), the fabricated electrochemical sensor succeeds to monitor the electro-oxidation of SOR with a low limit of detection of 9.9 x10−10 M and ultrahigh sensitivity of 237 µA nM−1cm−2 over a linear concentration range of 3–120 10−9 M with an excellent correlation coefficient. Additionally, the performance of the modified electrode has been successfully tested by real-time monitoring of SOR in pharmaceutical tablets, human plasma, and human urine without any interference from complex matrices.

Validated UV-Vis spectrophotometric method for the estimation of Sorafenib Tosylate in bulk and nanoparticles

It was noticed from the standard databases such as Scopus, PubMed, ScienceDirect, etc. that a limited UV-Vis spectrophotometric method has been reported for estimating Sorafenib (SOR), but no sophisticated analytical methods have been ever reported in any database for estimating SOR in nanoparticles. The present research involved the establishment of an economic, accurate, robust, and precise analytical method for the quantitative determination of SOR in bulk and nanoparticles utilizing a new validated spectrophotometric method. The spectrophotometric analysis was carried out using double-beam ultraviolet-visible spectrophotometer was employed in developing a new method using methanol and water at a ratio of 80:20 v/v and λmax of 265 nm. The technique was verified using the Q2A and Q2B guidelines of ICH. The newly developed UV-Vis method had desired linearity over the range of 2-12 μg/mL; along with excellent precision, accuracy, ruggedness, and robustness characteristics as observed from % RSD values of less than 2. The present study concluded that the developed UV-Vis method has desired linearity, precision, accuracy, ruggedness, and robustness, and will serve as an excellent technique for the determination of sorafenib in both bulk and nanoparticles without the interference of commonly used chemicals or solvents.

Folate-targeted co-delivery polymersomes for efficient photo-chemo-antiangiogenic therapy against breast cancer and in vivo evaluation via OCTA/NIRF dual-modal imaging

Intelligent nanoplatform that combines multimodal imaging and therapeutic effects holds great promise for precise and efficient cancer therapy. Herein, folate-targeted polymersomes with stimuli-responsiveness were fabricated and evaluated by near-infrared fluorescence (NIRF) and optical coherence tomography angiography (OCTA) dual-imaging for photo-chemo-antiangiogenic therapy against cancer. The folate-targeted polymersomes (FA-MIT-SIPS) not only integrated ammonium bicarbonate (ABC) and mitoxantrone (MIT) into their hydrophilic cavity but also encapsulated indocyanine green (ICG) and sorafenib (SOR) within their hydrophobic layer. NIRF imaging demonstrated that FA-MIT-SIPS effectively accumulated and retained in the tumors. Upon 808 nm laser irradiation, the ICG produced hyperthermia and reactive oxygen species (ROS) for efficient photothermal and photodynamic therapy. In addition, the decomposition of ABC in responsive to acidic tumor environment and ICG-induced hyperthermia accelerated drug release. The released MIT accumulated in nucleus to inhibit DNA synthesis, while the released SOR destructed tumor vascularization. Notably, OCTA imaging was applied to observe the tumor blood flow upon the combination therapy, demonstrating that FA-MIT-SIPS obviously decreased the vessels area density. Moreover, the synergistic photo-chemo-antiangiogenic therapy of FA-MIT-SIPS achieved excellent antitumor effect with 40% of the 4T1 tumor-bearing mice being completely cured without recurrence. The multifunctional polymersomes provide a promising dual-modal imaging-evaluated synergistic strategy for tumor therapy.

Glutathione Depletion‐Induced Activation of Dimersomes for Potentiating the Ferroptosis and Immunotherapy of “Cold” Tumor

AbstractThe abundant glutathione (GSH) in “cold” tumors weakens ferroptosis therapy and the immune response. Inspired by lipids, we fabricated cinnamaldehyde dimers (CDC) into lipid‐like materials to form dimersomes capable of depleting GSH and delivering therapeutics to potentiate the ferroptosis and immunotherapy of breast cancer. The dimersomes exhibited superior storage stability for over one year. After reaching the tumor, they quickly underwent breakage in the cytosol owing to the conjugation of hydrophilic GSH on CDC by Michael addition, which not only triggered the drug release and fluorescence switch “ON”, but also led to the depletion of intracellular GSH. Ferroptosis was significantly enhanced after combination with sorafenib (SRF) and elicited a robust immune response in vivo by promoting the maturation of dendritic cells and the priming of CD8+ T cells. As a result, the CDC@SRF dimersomes cured breast cancer in all the mice after four doses of administration.

Glutathione Depletion-Induced Activation of Dimersomes for Potentiating the Ferroptosis and Immunotherapy of "Cold" Tumor.

The abundant glutathione (GSH) in "cold" tumors weakens ferroptosis therapy and the immune response. Inspired by lipids, we fabricated cinnamaldehyde dimers (CDC) into lipid-like materials to form dimersomes capable of depleting GSH and delivering therapeutics to potentiate the ferroptosis and immunotherapy of breast cancer. The dimersomes exhibited superior storage stability for over one year. After reaching the tumor, they quickly underwent breakage in the cytosol owing to the conjugation of hydrophilic GSH on CDC by Michael addition, which not only triggered the drug release and fluorescence switch "ON", but also led to the depletion of intracellular GSH. Ferroptosis was significantly enhanced after combination with sorafenib (SRF) and elicited a robust immune response in vivo by promoting the maturation of dendritic cells and the priming of CD8+ T cells. As a result, the CDC@SRF dimersomes cured breast cancer in all the mice after four doses of administration.

Enhancing the Anticancer Activity of Sorafenib through Its Combination with a Nitric Oxide Photodelivering β-Cyclodextrin Polymer.

In this contribution, we report a strategy to enhance the therapeutic action of the chemotherapeutic Sorafenib (SRB) through its combination with a multifunctional β-cyclodextrin-based polymer able to deliver nitric oxide (NO) and emit green fluorescence upon visible light excitation (PolyCDNO). The basically water-insoluble SRB is effectively encapsulated in the polymeric host (1 mg mL−1) up to a concentration of 18 μg mL−1. The resulting host-guest supramolecular complex is able to release SRB in sink conditions and to preserve very well the photophysical and photochemical properties of the free PolyCDNO, as demonstrated by the similar values of the NO release and fluorescence emission quantum efficiencies found. The complex PolyCDNO/SRB internalizes in HEP-G2 hepatocarcinoma, MCF-7 breast cancer and ACHN kidney adenocarcinoma cells, localizing in all cases mainly at the cytoplasmic level. Biological experiments have been performed at SRB concentrations below the IC50 and with light doses producing NO at nontoxic concentrations. The results demonstrate exceptional mortality levels for PolyCDNO/SRB upon visible light irradiation in all the different cell lines tested, indicating a clear synergistic action between the chemotherapeutic drug and the NO. These findings can open up exciting avenues to potentiate the anticancer action of SRB and, in principle, to reduce its side effects through its use at low dosages when in combination with the photo-regulated release of NO.

Sorafenib-loaded nanostructured lipid carriers for topical ocular therapy of corneal neovascularization: development, in-vitro and in vivo study

Sorafenib (SRB), a multikinase inhibitor, is effective in reducing experimental corneal neovascularization (CNV) after oral administration; however, its therapeutic use in ocular surface disorders is restricted due to poor solubility and limited bioavailability. This study aimed to develop and optimize SRB-loaded nanostructured lipid carriers (SRB-NLCs) for topical ocular delivery by a central composite design response surface methodology (CCD-RSM). It was spherical and uniform in morphology with an average particle size of 111.87 ± 0.93 nm and a narrow size distribution. The in vitro drug release from the released SRB-NLC formulation was well fitted to Korsmeyer Peppas release kinetics. The cell counting kit-8 (CCK-8) cell viability assay demonstrated that SRB-NLC was not obviously cytotoxic to human corneal epithelial cells (HCECs). An in vivo ocular irritation test showed that SRB-NLC was well tolerated by rabbit eyes. Ocular pharmacokinetics revealed 6.79-fold and 1.24-fold increase in the area under concentration-time curves (AUC0-12h) over 12 h in rabbit cornea and conjunctiva, respectively, treated with one dose of SRB-NLC compared with those treated with SRB suspension. Moreover, SRB-NLC (0.05% SRB) and dexamethasone (0.025%) similarly suppressed corneal neovascularization in mice. In conclusion, the optimized SRB-NLC formulation demonstrated excellent physicochemical properties and good tolerance, sustained release, and enhanced ocular bioavailability. It is safe and potentially effective for the treatment of corneal neovascularization.

LC-MS/MS monitoring of the colorectal carcinoma cellular uptake and entrapment of sorafenib and its N-oxide active metabolite

Sorafenib (SOR) is a multikinase inhibitor with a mild activity against colorectal cancer cells due to multi-drug resistance mechanisms. Potentiated SOR activity was expected upon combination with some ginger derived compounds due to their interference with intracellular drug metabolism. Studying such combination necessitates the development of a sensitive validated LC-MS/MS method for the determination of intra and extracellular concentration of SOR and its N-oxide metabolite (SNX) in colorectal cancer cells. SOR, SNX and the internal standard (diclofenac sodium) were efficiently separated on Eclipse plus C18 column (3.0 ×150 mm, 5 µm) using isocratic elution with acetonitrile and 0.01 M ammonium formate aqueous solution containing 0.1% formic acid (69:31, v/v). Sample pretreatment using solid phase extraction was optimized and the mean percent recoveries were more than 97.01% for both analytes. Detection was conducted at positive ion multiple reaction monitoring (MRM) mode and the monitored mass transitions were 465.2 → 252.2 for SOR and 481.1 → 286.0 for SNX. The method was linear over the range 0.25 – 200.00 ng/mL (r2 ≥ 0.9992) for SOR and 0.10 – 125.00 ng/mL (r2 ≥ 0.9990) for SNX in both intra and extracellular matrices. The lower limits of quantification (LLOQ) were 0.25 and 0.10 ng/mL for SOR and SNX, respectively. Accuracies were within 94.25 – 109.45% and precision CV values did not exceed 7.63%. The method was able to monitor the cellular uptake and entrapment of both analytes and to prove the positive effect of the ginger derived compounds on SOR activity.

Long-term PFS from TIVO-3: Tivozanib (TIVO) versus sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC.

362 Background: The TIVO-3 trial supported FDA-approval of TIVO in R/R advanced RCC, demonstrating significantly improved PFS over SOR in the primary independent review committee [IRC] analysis (HR: 0.672, 95% CI: 0.52-0.87). Long-term survival without disease progression (LT-PFS) is a clinically meaningful outcome among patients with R/R mRCC and ≥2 lines of prior therapy. We assessed the proportion of TIVO-3 patients living progression-free with R/R mRCC at 6-month intervals up to 4 years post-initiation of TIVO or SOR. Methods: Exploratory analysis of LT-PFS was calculated using investigator-assessment [INV] with a data cut-off of May 24, 2021. PFS hazard ratio and landmark values of LT-PFS at 6, 12, 18, 24, 30, 36, 42 and 48 months are reported. Results include the ITT population, with censoring for missing assessments and discontinuation without PD. Cox proportional hazards and log-rank statistics were used to estimate the HR and 95% CI for INV-PFS; odds ratios (ORs) are reported for landmark timepoints up to 36-months. LT-PFS across prespecified subgroups were analyzed descriptively. Results: 350 patients were randomized to TIVO (n=175) or SOR (n=175). INV PFS was superior with TIVO vs SOR (HR: 0.624, 95% CI: 0.49-0.79). Landmark LT-PFS rates up to 48-months are consistently higher with TIVO vs SOR, with 12% vs 2% and 7.6% vs 0% at 3- and 4-years, respectively (Table). Despite low numbers of patients at risk with extended follow-up, subgroups with ≥15% LT-PFS at 3-years include IMDC favorable risk, female gender, ECOG PS0, age ≥65 years, and region NA – all confined to the TIVO arm. Conclusions: INV PFS with long-term follow-up is consistent with primary IRC PFS. Patients treated with TIVO were up to 5X more likely to experience LT-PFS compared to SOR. A clinically relevant minority of patients are alive and progression-free on TIVO at 3- and 4-years. Clinical trial information: NCT02627963. [Table: see text]

A multicenter, observational, phase 4 study (STELLAR) to evaluate the safety and tolerability of lenvatinib (LEN) in patients with advanced or unresectable hepatocellular carcinoma (uHCC).

TPS485 Background: HCC is a leading cause of cancer-related deaths worldwide. LEN is now a first-line treatment option for patients with uHCC, based on the REFLECT study in which LEN was established as noninferior to sorafenib (SOR) for overall survival (OS); LEN also demonstrated statistically significant and clinically meaningful improvements in progression-free survival, time-to-progression, and objective response rate vs SOR. The safety profile of LEN was consistent with its known side-effect profile. This postauthorization safety study aims to better characterize the safety of LEN, including hepatotoxicity, in real-life conditions in a Western population. Methods: This prospective, open-label, observational study (NCT04763408) will enroll patients with advanced or uHCC in routine clinical practice whom the treating physician has decided to treat with LEN (n = 500) or SOR (n = 500) according to the product labels. Enrollment is planned for 60 sites across Europe, Australia, USA, and Russia. The primary endpoint is the safety of LEN (hepatic-related toxicity and overall safety profile with regard to serious adverse events, grade ≥3 adverse events, and dose modifications and discontinuations due to adverse events). Secondary endpoints include treatment patterns (duration of treatment, incidence of dose interruptions and dose reductions, relative dose intensity, and subsequent treatments) and OS with LEN. Similar efficacy and safety data will be collected with SOR as an internal control for the population. Additionally, associations will be explored between patients’ baseline characteristics and treatment decisions as well as clinical and safety outcomes. Visits will be scheduled according to routine practice. Patients will be followed from initiation of treatment until the end of observation (whichever occurs first: withdrawal of consent, loss to follow-up, death, or end of the study [ie, 6 months after the last patient is enrolled]). Safety will be collected from initiation of LEN or SOR until the earlier of: 28 days after LEN/SOR discontinuation or the end of observation for patients who did not discontinue. Patients will be followed for survival and subsequent anticancer treatments until the end of observation, irrespective of length of treatment. Clinical trial information: NCT04763408.

A retrospective single centre study exploring the efficacy of sequential tyrosine kinase inhibitors (TKI) in patients with hepatocellular cancer.

443 A retrospective single centre study exploring the efficacy of sequential tyrosine-kinase inhibitors (TKI) for patients with hepatocellular carcinoma. Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. In the UK patients with advanced or intermediate disease despite locoregional treatments are offered a tyrosine-kinase inhibitor (TKI). Sorafenib (SOR) remains the approved first-line choice, with lenvatinib (LEN) and regorafenib (REG) used as either alternative first line or second line therapies, respectively. Previous studies have shown increased overall survival when comparing a single drug to placebo; however few have studied outcomes for patients treated with one or more TKIs. Methods: Data was collected from patients who received TKI therapy for HCC between January, 2016 and September, 2020, within the Barts Health NHS Trust, London. The Electronic Medical Record system was used to gather information pertaining to treatment. The non-parametric Pearson correlation coefficient was calculated using IBM SPSS software to explore the duration of TKI therapy and overall survival. Results: 64 patients were included in the cohort, 17% (n=11) female, 83% (n=53) were male. Median age was 68 years (range 38 - 92 years) and median survival from diagnosis was 18 months (range 4 - 106 months). 51 patients received one TKI, 12 patients received two and 1 patient received three sequential TKIs There was no significant correlation between the number of cycles of SOR or LEN received and overall survival ( p = 0.387), but there was a statistically significant correlation in the group of patients who received SOR and then REG (rs = 0.973, p = 0.000). There was also a statistically significant correlation (rs = 0.360, p = 0.004) between the cumulative number of cycles of TKI treatment and overall survival for all patients (i.e. SOR only, LEN only and those who received more than one TKI). Conclusions: Our analysis suggests that across the cohort, a longer duration of TKI treatment (measured in cycles) may be associated with increased overall survival for patients with advanced HCC. Further data is required to explore the impact on quality of life during therapy. [Table: see text]

Clinical outcomes associated with tislelizumab in patients (pts) with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (SOR) or lenvatinib (LEN) in RATIONALE-208.

420 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well tolerated in pts with previously treated advanced HCC in the phase 2 RATIONALE-208 study (NCT03419897). At the time of this study, SOR and LEN were recommended first-line treatments for pts with advanced HCC and continue to have an important role in the first-line treatment of HCC despite the recent approval of new immuno-oncology-based combinations (atezolizumab and bevacizumab) in some regions. We report the clinical outcomes of pts with advanced HCC who were previously treated with SOR/LEN. Methods: Pts who had received ≥1 prior line of systemic therapy for advanced HCC received tislelizumab 200 mg intravenously once every three weeks. Objective response rate (ORR) by independent review committee (IRC) (ORRIRC), duration of response by IRC (DORIRC), progression-free survival by IRC (PFSIRC), overall survival (OS), and safety were evaluated in pts who had been previously treated with SOR/LEN. Results: As of February 2020, 249 pts were enrolled and 235 pts had received prior treatment with SOR/LEN, of whom 126 and 109 pts had received 1 or ≥ 2 prior lines of systemic therapy, respectively. At study entry, 211 (89.8%) pts had BCLC stage C and 187 (79.6%) pts had extrahepatic spread. Median follow-up duration for pts previously treated with SOR/LEN was 12.5 months and ORRIRC was 13.6% (95% CI: 9.5, 18.7), including 2 complete responses and 30 partial responses. Median DORIRC was not reached. Median PFSIRC and OS of pts previously treated with SOR/LEN was 2.7 months (95% CI: 1.6, 2.8) and 13.5 months (95% CI: 10.9, 15.8), respectively. Tislelizumab was generally well tolerated in pts previously treated with SOR/LEN (Table), and the most common treatment-emergent adverse events were increased aspartate aminotransferase (n=70; 28.1%) and alanine aminotransferase (n=52; 20.9%). Conclusions: Tislelizumab was investigated beyond the first-line setting, as effective second- and third-line treatment options are limited for pts with advanced HCC and there is an unmet medical need. This analysis indicates that tislelizumab is clinically active and well tolerated in pts with advanced HCC who have received prior systemic treatment with SOR/LEN. Clinical trial information: NCT03419897. [Table: see text]