Oral Tyrosine Kinase Inhibitor Research Articles

Human dermal fibroblast subpopulations and epithelial mesenchymal transition signals in hidradenitis suppurativa tunnels are normalized by spleen tyrosine kinase antagonism in vivo.

Hidradenitis Suppurativa is a chronic inflammatory disease of which the pathogenesis is incompletely understood. Dermal fibroblasts have been previously identified as a major source of inflammatory cytokines, however information pertaining to the characteristics of subpopulations of fibroblasts in HS remains unexplored. Using in silico-deconvolution of whole-tissue RNAseq, Nanostring gene expression panels and confirmatory immunohistochemistry we identified fibroblast subpopulations in HS tissue and their relationship to disease severity and lesion morphology. Gene signatures of SFRP2+ fibroblast subsets were increased in lesional tissue, with gene signatures of SFRP1+ fibroblast subsets decreased. SFRP2+ and CXCL12+ fibroblast numbers, measured by IHC, were increased in HS tissue, with greater numbers associated with epithelialized tunnels and Hurley Stage 3 disease. Pro-inflammatory CXCL12+ fibroblasts were also increased, with reductions in SFRP1+ fibroblasts compared to healthy controls. Evidence of Epithelial Mesenchymal Transition was seen via altered gene expression of SNAI2 and altered protein expression of ZEB1, TWIST1, Snail/Slug, E-Cadherin and N-Cadherin in HS lesional tissue. The greatest dysregulation of EMT associated proteins was seen in biopsies containing epithelialized tunnels. The use of the oral Spleen tyrosine Kinase inhibitor Fostamatinib significantly reduced expression of genes associated with chronic inflammation, fibroblast proliferation and migration suggesting a potential role for targeting fibroblast activity in HS.

The Effects of Rilzabrutinib, an Oral Bruton Tyrosine Kinase Inhibitor, on Bleeding Symptoms and Health-Related Quality of Life in Patients with Immune Thrombocytopenia

Introduction: Patients with immune thrombocytopenia (ITP) have a high incidence of comorbid conditions, elevated risk for bleeding and thrombosis, and reduced health-related quality of life (HRQoL). Rilzabrutinib is a potent oral, reversible inhibitor of Bruton tyrosine kinase with the potential to modulate multiple immunological pathways. In part A of a phase 1/2 study (LUNA 2) of ITP patients, rilzabrutinib treatment led to rapid and durable platelet responses with a favorable safety profile. This abstract reports the effects of rilzabrutinib on bleeding and HRQoL on patients in part B of the LUNA 2 study. Methods: The multicenter, open-label, phase 1/2, part B study evaluated the efficacy and safety of rilzabrutinib 400 mg BID in relapsed ITP (NCT03395210). Adults aged 18-80 y were eligible with ≥2 baseline platelet counts <30x10 9/L no less than 7 days apart in the 15 days before the first dose. Eligible patients were required to have a past response (achievement of platelet count ≥50x10 9/L) to intravenous immunoglobulin (IVIg)/anti-D or corticosteroid (CS) that was not sustained, and have failed ≥1 other ITP therapy (not IVIg or CS). Stable doses of concomitant CS/thrombopoietin receptor agonists (TPO-RA) were allowed with rilzabrutinib. The primary endpoints were safety and durable platelet response defined as platelet counts ≥50x10 9/L on ≥8 of the last 12 weeks of rilzabrutinib without rescue medication. Change from baseline in the ITP Bleeding Scale (IBLS) score (0 none to 2 marked bleeding) was a secondary endpoint to assess bleeding across 9 anatomical sites (8 for male/postmenopausal women). An exploratory HRQoL endpoint evaluated the EuroQol-5 Dimensions 5-Level (EQ-5D-5L) + Visual Analog Scale (EQ-VAS) and ITP Patient Assessment Questionnaire (ITP-PAQ; scores 0 worst to 100 best HRQoL). Results: For 26 enrolled patients with data cut-off of 31Jan2023, 15 patients completed 24 weeks of treatment and 11 discontinued due to lack of response (n=5); adverse events (AEs, n=3); and n=1 each lack of response/AE, noncompliance, and erroneous enrollment. At baseline, patients had a median age of 57 y (range, 20-75) with median platelet count of 13x10 9/L (range, 2-24x10 9/L). Patients had a median duration of ITP of 10.3 y (range, 0.7-48.2) and had received a median of 6 prior unique ITP therapies (range, 3-19; 46% splenectomy). Prior ITP medication included CS (100%), TPO-RA (85%), immunosuppressants or IVIg (81%), and rituximab (50%). During the study, 17 patients (65%) received concomitant non-rescue CS and/or TPO-RA. The median compliance to rilzabrutinib for patients with 24 weeks of treatment was 99%. Nine patients (35%; 95% CI, 17-56%) achieved the primary endpoint of durable platelet response. Treatment-related AEs were mainly grade 1/2, with no treatment-related grade ≥2 bleeding/thrombotic events or infections, serious AEs, or deaths. At baseline, the IBLS average score across sites was a mean of 0.27 (SD, 0.27) and mean change from baseline at week 25 was -0.07 (SD, 0.12). The anatomical site with the highest proportion of patients having a baseline score of 2 was skin (n=7 per medical history, n=6 per physical examination), all of whom had a decrease at 25 weeks. At baseline, median EQ-VAS was 78 (range, 8-100) with a median change from baseline (N=26) to week 25 (n=15) of +7 (range, -5 to 77) indicating an improvement in HRQoL. Median changes in ITP-PAQ domain scores from baseline to week 25 (Figure 1) showed clinically meaningful improvement in women's reproductive health with a 21-point increase (range, 0-38; median baseline: 54); clinically meaningful improvement in fatigue/sleep, activity, and overall HRQoL scales with ~13-point increases (range, -23 to 75; median baseline: 53, 50, and 52, respectively); and improvement in psychological, symptoms, social activity, and bother-physical health domains with 4- to 8-point increases (range, -13 to 56; median baseline: 70, 60, 75, 69, respectively). Fear and work domains had high scores at baseline (≥90) with minimal changes over time. Conclusion: Overall, rilzabrutinib showed durable platelet responses, high compliance, and improvements on HRQoL measures in difficult to treat patients with relapsed ITP. There was no evidence of increased bleeding with rilzabrutinib. Clinically meaningful improvements in HRQoL were observed in multiple individual and overall HRQoL health domains following rilzabrutinib.

Safety and Efficacy of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM): Results from Part 1 of the Phase 2 Apex Trial

Background: Systemic mastocytosis (SM) is a rare disease characterized by the aberrant proliferation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and Mast Cell leukemia (MCL). Bezuclastinib is an oral, potent, and selective tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Preliminary results from the on-going Apex study in patients with AdvSM (NCT04996875) were presented previously (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13). Methods: Apex is a randomized Phase 2, open-label, multicenter trial in adult patients diagnosed with AdvSM per 2022 WHO criteria with a baseline serum tryptase of ≥20 ng/mL. In Part 1, patients were randomized 1:1:1:1 to bezuclastinib 50mg BID, 100mg BID, 200mg BID, or 400mg QD. Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the trial. Data from Part 1 informed dose selection for Part 2 of the trial. The primary efficacy endpoint for this trial is overall response rate (complete response [CR], CR with incomplete hematologic recovery [CRh], partial response [PR] and clinical improvement [CI]) as assessed by a central review committee based on mIWG-MRT-ECNM response criteria. Results: As of April 2023, Part 1 was fully enrolled with 33 AdvSM patients. Patients were randomized to 50mg BID (n=8), 100mg BID (n=8), 200mg BID (n=8), or 400mg QD (n=9). Disease subtypes included ASM (n=7), MCL (n=2), and SM-AHN (n=24); AHN subtypes included CMML (n=18), MDS (n=3), MPN (n=1), and MDS/MPN-U (n=2). The majority of patients were male (64%), ECOG PS 0-1 (82%) and KITD816V positive at baseline (91%). At baseline, 67% of patients were TKI-naïve; 33% had prior midostaurin, and 15% had prior avapritinib. Median (range) BM MC burden, serum tryptase, and KIT D816V VAF at baseline were 30% (5-90), 163 ng/mL (35-1578), and 7% (0-47), respectively. Of the 33 patients enrolled, 25 patients (76%) had C-findings evaluable per mIWG-MRT-ECNM criteria; 20 patients (61%) were positive for SRSF2/ASXL1/RUNX1 mutation which are associated with poor survival in SM. Conclusion: Enrollment in Part 1 of the Apex trial is complete. Patients enrolled in Part 1 of the Apex trial are generally representative of the population of patients with AdvSM based on patient characteristics and markers of disease. Part 1 includes a small subset of patients with prior use of TKIs. Safety, clinical activity, and clinical objective response for all patients in Part 1 will be presented.

Chemotherapy-Sparing Induction Followed By Consolidation and Maintenance with Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy for Newly-Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Primary Endpoint Results from the Blissphall Study

Background: Oral ABL-targeted kinase inhibitors (TKIs) have transformed treatment of BCR::ABL+ (Philadelphia chromosome-positive, Ph+) acute lymphoblastic leukemia (ALL). Induction (IND) w/ corticosteroids (CS) and dasatinib (DAS) alone results in morphologic complete response (mCR) rates approaching 100% but low rates of measurable residual disease (MRD) negativity; addition of intensive chemotherapy to TKIs adds risks of myelosuppression. DAS + the CD3/CD19 bispecific T-cell engager blinatumomab (BLIN) is effective consolidation (CONSOL) for Ph+ ALL, though ABL kinase mutations conferring resistance can arise early in therapy (Foà, NEJM, 2020). We designed a phase II study of BLIN as part of a chemotherapy sparing strategy in pts w/ Ph+ ALL (BLISSPHALL), introducing BLIN as early as 6 weeks into treatment for pts in mCR, w/ aim of expediting MRD clearance and suppressing resistant clones early in disease course, and including a maintenance (MAINT) phase of BLIN + TKI for pts in molecular response. Methods: We conducted a multicenter trial of TKI + CS IND and TKI + BLIN CONSOL + MAINT in adults (≥18 yrs) w/ newly-diagnosed (ND) Ph+ ALL (NCT04329325). Study schema is depicted in Figure 1. Pts received CS pre-phase w/ prednisone (PRED) or dexamethasone (DEX) followed by modified GIMEMA LAL1205 IND (DEX + DAS 140 mg/d w/ DAS dose adjustments or TKI change per protocol) w/ intrathecal methotrexate (IT MTX) d22, 43 and bone marrow (BM) MRD assessments including FACS and BCR::ABL1 PCR. Pts in mCR on d43 could proceed to CONSOL w/ 3 cycles (C) of TKI + BLIN 28 mcg/d IVCI, d1-28, w/ 14d off BLIN between cycles and BM MRD assessment/IT MTX after each cycle. TKI was given continuously including between BLIN cycles. Pts in protocol-defined complete molecular response (CMR; MRD negative by FACS and no detectable BCR::ABL1 transcripts) after CONSOL could proceed to MAINT (C4-7 BLIN + TKI, 28d off between cycles). The primary objective is to determine the proportion of evaluable pts achieving CMR by the end of CONSOL (≤ 3C BLIN + TKI). Secondary objectives include safety/toxicity of BLIN + DAS, duration of CMR, incidence of relapse, event-free/overall survival. Toxicities were defined by CTCAE v5.0. Results: 17 pts enrolled (12 women, 5 men) w/ median age 50 yrs (range 22-87); BCR::ABL1 transcript type p190 (n=15) or p210 (n=2). Median follow-up 11.7 months (range 3-24). All began DAS 140 mg/d as initial TKI; 4 changed TKI for DAS intolerance per protocol (bosutinib, n=2; ponatinib [PON], n=2) and remained on study; TKI was changed to PON in 1 other pt to optimize BCR::ABL1 transcript suppression pre-allogeneic transplant (alloHCT) and that pt was withdrawn from study. Two had interruption or delay of BLIN due to toxicity (grade [G] 3 transaminase elevation, n=1; G2 cytokine release syndrome, n=1); BLIN was resumed in both. Figure 2 lists nonhematologic adverse effects (AEs) seen in ≥2 pts at least possibly related to TKI or BLIN while on study. One pt developed G3 pancreatitis after DAS was changed to PON; TKI was changed back to DAS. There were no G4-5 AEs. All pts (100%) achieved mCR during IND (median d22). Ten achieved CMR to date (5 during IND, 5 during CONSOL) and 6 did not achieve CMR; determination pending in 1 pt. By FACS, 16/17 achieved BM MRD negativity; 13/14 evaluable pts had no evidence of malignant clonal IgH rearrangement (IgHR) by next generation sequencing (NGS). Notably, 3 pts w/ persistent low-level BCR::ABL1 transcripts had no evidence of malignant clonal IgHR by NGS but were withdrawn post-CONSOL as protocol required BCR::ABL1 PCR negativity to proceed to MAINT. Two pts relapsed, both after achieving CMR (one declined CONSOL and self-discontinued TKI; one had extramedullary (EM) relapse w/ ABL T315I mutation). Four pts underwent alloHCT in CR1 (rising MRD levels on study leading to change in therapy, n=1; persistent BCR::ABL1 PCR positivity, n=2; IKZF1 plus phenotype, n=1); one underwent alloHCT in CR2 following EM relapse. Conclusions: DAS + CS IND w/ addition of BLIN to TKI in mCR leads to high rates of deep molecular response w/ low risk of early relapse and low rates of severe regimen-related toxicity in pts w/ ND Ph+ ALL. Use of PON (vs DAS) as initial TKI w/ BLIN may further suppress resistant clones. Further f/u is needed to confirm durability of CMR w/ BLIN + TKI CONSOL ± MAINT in absence of alloHCT and whether pts w/ persistent BCR::ABL1 PCR positivity and no malignant clonal IgHR by NGS exhibit similar outcomes to those in CMR.

Research Progress on Mechanism and Management of Adverse Drug Reactions of Anlotinib.

Anti-angiogenesis therapy plays a vital role in the treatment of tumors, with anlotinib as its representative targeted drug. Anlotinib is a novel oral tyrosine kinase inhibitor (TKI) with inhibitory effects on tumor growth tumor angiogenesis. In Phase III clinical trials, anlotinib demonstrated better overall survival and progression-free survival than placebo in patients with advanced non-small cell lung cancer (NSCLC), and was approved for the first time as a third-line treatment for refractory advanced NSCLC. Going far beyond that, anlotinib has shown encouraging results in a variety of malignancies, including medullary thyroid carcinoma, renal cell carcinoma, gastric cancer and esophageal squamous cell carcinoma. Nevertheless, anlotinib has been subject to some controversy in terms of adverse events due to its widespread use. In this review, the mechanism of action, pharmacokinetic characteristics, adverse reactions in clinical use and management of anlotinib were summarized.

Neuropsychiatric adverse drug reactions with oral tyrosine kinase inhibitors in metastatic colorectal cancer: an analysis from the FDA Adverse Event Reporting System.

New oral tyrosine kinase inhibitors (TKIs) are approved for metastatic colorectal cancer (mCRC). The aim of this study was to assess the neuropsychiatric adverse drug reactions (ADRs) of these drugs reported in the FDA Adverse Event Reporting System (FAERS) database. All reports with regorafenib (REG) and encorafenib (ENC) as the primary suspect, and reported in the FAERS between 2012 and 2022, were collected. A descriptive and disproportionality analyses were conducted. Out of 4,984 cases, 1,357 (30.2%) reported at least one neuropsychiatric ADR. New potential signals for REG included neuropathy peripheral (n = 265; reporting odds ratio, ROR = 19.48, 95% confidence interval, CI 95% = 17.52-22.47; information component, IC = 2.89, IC025-IC075=2.77-3.02), hyperesthesia (n = 18; ROR = 12.56, CI 95% = 7.90-19.96; IC = 2.25, IC025-IC075=1.79-2.72), taste disorder (n = 41; ROR = 9.91, CI 95% = 7.29-13.49; IC = 2.18, IC025-IC075=1.88-2.49), poor quality sleep (n = 18; ROR = 6.56, CI 95% = 4.13-10.42; IC = 1.74, IC025-IC075=1.27-2.20), altered state of consciousness (n = 15; ROR = 5.50, CI 95% = 3.31-9.14; IC = 1.57, IC025-IC075=1.06-2.07), depressed mood (n = 13; ROR = 1.85, CI 95% = 1.07-3.19; IC = 0.58, IC025-IC075=0.04-1.13) and insomnia (n = 63; ROR = 1.48, CI 95% = 1.15-1.89; IC = 0.38, IC025-IC075=0.13-0.63). For ENC comprised depressed mood (n = 4; ROR = 5.75, CI 95% = 2.15-15.39; IC = 1.74, IC025-IC075=0.76-2.73) and cognitive disorders (n = 3; ROR = 4.71, CI 95% = 1.51-14.66; IC = 1.54, IC025-IC075=0.41-2.68). This study identified new unknown potential neuropsychiatric ADRs. Further investigations are required to better define the neurotoxicity of TKIs in mCRC patients.

Longitudinal x-ray based lung function measurement for monitoring Nintedanib treatment response in a mouse model of lung fibrosis

Lung fibrosis (LF) is a chronic progressive, incurable, and debilitating condition of the lung, which is associated with different lung disease. Treatment options are still sparse. Nintedanib, an oral tyrosine kinase inhibitor, significantly slows the LF progression. However, there is a strong need of further research and the development of novel therapies. In this study, we used a correlative set-up that combines X-ray based lung function (XLF) with microCT and whole body plethysmography (WBP) for a comprehensive functional and structural evaluation of lung fibrosis (LF) as well as for monitoring response to orally administered Nintedanib in the mouse model of bleomycin induced LF. The decline in lung function as early as one week after intratracheal bleomycin instillation was reliably detected by XLF, revealing the lowest decay rate in the LF mice compared to healthy ones. Simultaneously performed microCT and WBP measurements corroborated XLF findings by exhibiting reduced lung volume V^{insp}_{mu CT} and tidal volume TV_{WBP}. In LF mice XLF also revealed profound improvement in lung function one week after Nintedanib treatment. This positive response to Nintedanib therapy was further substantiated by microCT and WBP measurements which also showed significantly improved V^{insp}_{mu CT} and TV_{WBP} in the Nintedanib treated mice. By comparing the XLF data to structural features assessing the extent of fibrosis obtained by ex-vivo high-resolution synchrotron radiation-based imaging and classical histology we demonstrate that: (1) a simple low dose x-ray measurement like XLF is sensitive enough to pick up treatment response, (2) Nintedanib treatment successfully improved lung function in a bleomycin induced LF mouse model and (3) differences between the fully restored lung function and the partially reduced fibrotic burden compared to healthy and untreated mice. The presented analysis pipeline underlines the importance of a combined functional and anatomical readout to reliably measure treatment response and could easily be adapted to other preclinical lung disease models.

Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial

Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC. Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P= 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death. Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population.

Chinese expert guidance on overall application of lenvatinib in hepatocellular carcinoma

Lenvatinib mesylate is an oral receptor tyrosine kinase inhibitor against targets of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor α, stem cell growth factor receptor, and rearranged during transfection, et al. Lenvatinib has been approved by the National Medical Products Administration of China on September 4, 2018, for the first-line treatment of patients with unresectable hepatocellular carcinoma who have not received systematic treatment before. Up to February 2023, Lenvatinib has been listed in China for more than 4 years, accumulating a series of post-marketing clinical research evidences. Based on the clinical practice before and after the launch of lenvatinib and referring to the clinical experience of other anti-angiogenesis inhibitors, domestic multidisciplinary experts and scholars adopt the Delphi method to formulate the Chinese Expert Guidance on Overall Application of Lenvatinib in Hepatocellular Carcinoma after repeated discussions and revisions, in order to provide reference for reasonable and effective clinical application of lenvatinib for clinicians.

Dose-sparing effect of lapatinib co-administered with a high-fat enteral nutrition emulsion: preclinical pharmacokinetic study.

Lapatinib is an oral small-molecule tyrosine kinase inhibitor indicated for advanced or metastatic HER2-positive breast cancer. In order to reduce the treatment cost, a high-fat enteral nutrition emulsion TPF-T was selected as a dose-sparing agent for lapatinib-based therapies. This study aimed to investigate the effect of TPF-T on lapatinib pharmacokinetics. First, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to quantitatively evaluate lapatinib in rabbit plasma. The method was fully validated according to the China Pharmacopoeia 2020 guidance. Rabbits and rats were chosen as the animal models due to their low and high bile flows, respectively. The proposed LC-MS/MS method was applied to pharmacokinetic studies of lapatinib, with or without TPF-T, in rabbit and rat plasma. The LC-MS/MS method revealed high sensitivity and excellent efficiency. In the rabbit model, co-administration with TPF-T resulted in a 32.2% increase in lapatinib exposure. In the rat model, TPF-T had minimal influence on the lapatinib exposure. In both models, TPF-T was observed to significantly elevate lapatinib concentration in the absorption phase. Co-administration with TPF-T had a moderate effect on increasing exposure to lapatinib. Dose sparing using a high-fat liquid diet is potentially feasible for lapatinib-based therapies.

The involvement of hepatic cytochrome P450s in the cytotoxicity of lapatinib.

Lapatinib, an oral tyrosine kinase inhibitor used as a first-line treatment for HER2-positive breast cancer, has been reported to be associated with hepatotoxicity; however, the underlying mechanisms remain unclear. In this study, we report that lapatinib causes cytotoxicity in multiple types of hepatic cells, including primary human hepatocytes, HepaRG cells, and HepG2 cells. A 24-h treatment with lapatinib induced cell cycle disturbances, apoptosis, and DNA damage, and decreased the protein levels of topoisomerase in HepG2 cells. We investigated the role of cytochrome P450 (CYP)-mediated metabolism in lapatinib-induced cytotoxicity using our previously established HepG2 cell lines, which express each of 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrate that lapatinib is metabolized by CYP1A1, 3A4, 3A5, and 3A7. Among these, lapatinib-induced cytotoxicity and DNA damage were attenuated in cells overexpressing CYP3A5 or 3A7. Additionally, we measured the production of three primary metabolites of lapatinib (O-dealkylated lapatinib, N-dealkylated lapatinib, and N-hydroxy lapatinib) in CYP1A1-, 3A4-, 3A5-, and 3A7-overexpressing HepG2 cells. We compared the cytotoxicity of lapatinib and its 3 metabolites in primary human hepatocytes, HepaRG cells, and HepG2 cells and demonstrated that N-dealkylated lapatinib is more toxic than the parent drug and the other metabolites. Taken together, our results indicate that lapatinib-induced cytotoxicity involves multiple mechanisms, such as apoptosis and DNA damage; that N-dealkylated lapatinib is a toxic metabolite contributing to the toxic effect of lapatinib; and that CYP3A5- and 3A7-mediated metabolism plays a role in attenuating the cytotoxicity of lapatinib.

OC 65.1 Long-Term Efficacy and Safety with Oral Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Immune Thrombocytopenia

OC 65.1 Long-Term Efficacy and Safety with Oral Bruton Tyrosine Kinase Inhibitor Rilzabrutinib in Patients with Immune Thrombocytopenia

Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy

We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology. Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P< 0.05). There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted.

Liquid biopsy kinetics and detection of ERBB2 amplification/HER2-positivity in refractory hepatocellular carcinoma

Hepatocellular Carcinoma (HCC) is the most common primary liver carcinoma, accounting for 75–85% of all cases. For patients with advanced unresectable and/or metastatic HCC, treatment options primarily include immunotherapy combinations and/or oral tyrosine kinase inhibitors. For patients with alpha-fetoprotein (AFP) levels above 400 ng/ml, ramucirumab, an anti-VEGF agent, is also approved in the second-line setting. However, none of these therapies are based on a specific molecular marker and the role of molecular testing is limited. In fact, HCC is unique in the sense that a biopsy may not be pursued if imaging findings are classic for HCC, in the appropriate clinical context. Herein, we report a case of a patient with metastatic HCC and a huge disease burden where a circulating tumor DNA (ctDNA) liquid biopsy done as part of our standard of care serendipitously revealed a very high ERBB2 copy number amplification (>78). This was corroborated by HER2 immunohistochemical staining, which demonstrated strong diffuse membranous HER2 3+ expression; tissue next-generation sequencing also identified an ERBB2 unadjusted copy number gain of 183. Furthermore, we were able to demonstrate the feasibility of using both ctDNA and circulating tumor cells (CTCs) to determine the heterogeneity of HER2 and response to dual HER2 blockade trastuzumab/pertuzumab (MyPathway regimen). In addition to the utility of liquid biopsies increasing opportunities for precision medicine, this n-of-1 precision medicine case illustrates and reiterates the need for comprehensive panel-based NGS testing that employs both DNA/RNA for all patients with advanced or metastatic cancers. It also supports the agnostic potential of ERBB2/HER2 as an actionable marker.

Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD

BackgroundAbout 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile.MethodsIn this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization.The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders.Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument.ConclusionCurrently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety.Ethics and disseminationEthical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.Trial registrationClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.

Nintedanib inhibits normal human vitreous-induced epithelial-mesenchymal transition in human retinal pigment epithelial cells

PurposeIn this study, we aim to investigate the potential of nintedanib as a therapeutic approach to proliferative vitreoretinopathy (PVR), which is the leading cause of failure in retinal detachment repair. PVR is characterized by the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, and understanding the effects of nintedanib on EMT in the normal human vitreous (HV)-induced RPE cells is crucial. MethodsOur research focuses on assessing the impact of nintedanib on HV-induced EMT in human retinal pigment epithelial (ARPE-19) cells in vitro. We employed various techniques, including quantitative real-time PCR (qPCR), western blot analysis, and immunofluorescence staining, to evaluate the mRNA and protein expression of EMT biomarkers in HV-induced ARPE-19 cells. Additionally, we measured the proliferation of RPE cells using cell counting, CCK-8, and Ki-67 assays. Migration was assessed through wound healing and transwell migration assays, while contraction was determined using a collagen gel contraction assay. Morphological changes were examined using phase-contrast microscopy. ResultsOur results demonstrate that nintedanib selectively attenuates the upregulation of mesenchymal markers in HV-induced ARPE-19 cells, at both the mRNA and protein levels. Furthermore, nintedanib effectively suppresses the HV-induced proliferation, migration, and contraction of ARPE-19 cells, while maintaining the cells' basal activity. These findings strongly suggest that nintedanib exhibits protective effects against EMT in ARPE-19 cells and could be a promising therapeutic option for PVR. ConclusionsBy elucidating the anti-EMT effects of nintedanib in HV-induced RPE cells, our study highlights the potential of this oral triple tyrosine kinase inhibitor in the treatment of PVR. These findings contribute to the growing body of research aimed at developing novel strategies to prevent and manage PVR, ultimately improving the success rates of retinal detachment repair.

Therapeutic Drug Monitoring of Imatinib and N-Desmethyl Imatinib in Chronic Myeloid Leukemia Patients Using LC-MS/MS in a Cohort Study.

Imatinib is an oral tyrosine kinase inhibitor (TKI) and first-line therapy for patients with chronic myeloid leukemia (CML). There is a positive correlation between serum imatinib concentrations and treatment response. However, the specific relationship between the blood concentration of imatinib and its influencing factors remains unclear. This study collected basic information from 102 patients using imatinib as first-line treatment for CML. Further, we analyzed the individual differences in imatinib concentration and explored its influencing factors. Through intra-day and inter-day precision studies, we found that the precision for the imatinib assay methodology was within ±13% and that the recovery rate was above 85%. There is notable individual variation in the blood concentration of imatinib; the recommended treatment concentration is 860-1500ng/mL, with only 41.40% of patients achieving this concentration. Also, there was a negative correlation between age and imatinib trough concentration (Ctrough ), as is observed between age and N-desmethyl imatinib. Moreover, compared with the adolescent group, the serum imatinib Ctrough for groups aged 17-47 and 48-68years was significantly reduced. Further analysis shows that imatinib Ctrough values reaching therapeutic concentrations (59%) increased dramatically for patients with CML aged 17-47years. Moreover, groups dosed with 400mg/day resulted in therapeutic imatinib concentrations for 68% of patients with CML, which was the best performance. The established method was validated, with acceptable accuracy, precision, linearity, and stability, as required, and then successfully applied to the therapeutic drug monitoring of imatinib. Age, dose, and metabolites can influence the imatinib concentration and its therapeutic effect in patients with CML.

Management of upper gastrointestinal bleeding in advanced hepatocellular carcinoma with portal hypertension and variceal bleeding during receiving tyrosine kinase inhibitors therapy: Beyond and known frontiers

AbstractHepatocellular carcinoma (HCC) poses a significant global burden, with most patients being diagnosed at an advanced stage, leading to poor prognosis due to the lack of systemic treatment. The approval of oral tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, and anti‐angiogenic agents has rapidly expanded the treatment prospects for HCC. However, the use of these drugs has also increased the incidence of portal hypertension (PHT) and upper gastrointestinal variceal bleeding in HCC patients. The diagnosis, screening, emergency treatment, and secondary prevention of upper gastrointestinal variceal rebleeding in advanced HCC patients undergoing oral TKIs therapy have become clinically urgent and critical issues. This review provides an overview of the existing understanding regarding the uses and limitations of transjugular intrahepatic portosystemic shunt (TIPS) insertion for managing HCC in cirrhosis patients with PHT and variceal hemorrhage. Additionally, it explores the potential of TIPS in managing acute upper gastrointestinal bleeding and preventing rebleeding in advanced HCC patients undergoing TKIs therapy. The placement of TIPS within the treatment hierarchy is determined by the specific clinical environment and the individual attributes of the patient.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

A Systematic Review and Meta-Analysis: Safety and Efficacy of Cediranib in the Treatment of Cancer Patients

Objective. Tyrosine kinase inhibitors are exciting new anticancer strategies. As one of the most promising oral tyrosine kinase inhibitors, cediranib has been proven effective in treating various solid malignant tumors. This study aimed to evaluate the efficacy and safety of cediranib in cancer patients. Methods. A comprehensive literature review was conducted for phase II and phase III randomized controlled trials (RCTs) up to June 31, 2021, using databases from PubMed, Cochrane Library, Embase, and Web of Science. Relevant clinical trials reporting the efficacy and toxicity characteristics of cediranib in cancer patients were analyzed using Stata 15.1. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system was used to assess the strength of the evidence. Results. The systematic review yielded 14 eligible trials, comprising 4,387 patients with solid malignant tumors. The analysis results of RCTs showed that the cediranib-containing group had a significantly better PFS than the control group (HR: 0.75; 95% CI 0.69–0.82; P &lt; 0.001), and the pooled OS of the cediranib-containing group was significantly higher than that of the control group (HR: 0.91; 95% CI 0.84–1.00; P = 0.041). The sensitivity analysis revealed that the pooled HR was stable and excluding a single study had no effect on the significance of the pooled HR. In addition, the meta-analysis passed Begg’s and Egger’s tests, indicating no publication bias. Regarding safety, the most common adverse events were diarrhea, nausea, hypertension, fatigue, sensory neuropathy, dyspnea, vomiting, headache, neutropenia, thrombocytopenia, and leukopenia. Conclusion. Cediranib treatment responds better than noncediranib therapy but can increase the risk of specific treatment-related toxicities.