Oral Tyrosine Kinase Inhibitor Research Articles

A prospective, non-interventional study among patients diagnosed with locally advanced or metastatic non–small-cell lung cancer to assess the adherence to oral antineoplastic therapy from data collected through patient-reported questionnaires and tablets count in Spain: LOADH study.

e21101 Background: Oral treatments (OT) available in non-small cell lung cancer (NSCLC) directed at different targets are more effective and have a more favorable safety profile than traditional chemotherapy (CT). However, adherence is a challenge as it could affect the therapeutic outcome of patients (pt). The LOADH study aims to assess adherence from tablets count in pt with NSCLC treated with tyrosine kinase inhibitors (TKIs), as well as to evaluate the influence of pt and treatment characteristics on adherence, evaluate correlation between adherence and progression free survival (PFS) and to detect opportunities for improvement of the pharmaceutical intervention. Methods: Prospective, multicenter, observational study in which 6 Spanish hospitals participated. Adult pt diagnosed with NSCLC receiving or starting treatment with orally administered TKI, prescribed by the oncologist according to standard clinical practice, were included. Pt information was collected at the screening visit and at monthly visits during three consecutive months by virtual or face-to-face pharmaceutical care, during which a count of dispensed and unused tablets was also made. Adherence was calculated as: (N of tablets dispensed – N of unused tablets / N of days in treatment * N of tablets prescribed to be taken per day)*100 The cut-off point for adequate adherence was > 80%. The Chi-square test was used to compare adherence between groups. Results: A total of 99 pt were included, of which 95 were valid for the analysis. Mean age was 66 years (SD 13.1; 46.3% ≤65), 66.3% female, 57.9% non-smokers, 90.5% with metastases; 69.5% received TKI-EGFR, 28.4% ALK inhibitors and 2.1% others. ECOG 0: 51.6%; ECOG 1: 42.1%; ECOG ≥2: 6.3%. Adherence was > 80% in 85.3% of pt. Factors that are related to better adherence are ECOG (0: 91.8%; 1: 82.5%; ≥2: 50%; P = 0.020) previous CT (yes: 61.5%; no: 85.7%; P < 0.001) and Initiation of OT prior to the study (yes: 86.7%; no: 75.0%; P < 0.001). Median PFS from start of treatment was higher in adherent pt: 45.6 vs 18.2 months; P = 0.043; in a sensitivity analysis from start of study, PFS was also higher: 18.9 vs 6.5 months; P = 0.007. Although no statistically significant differences were found, conciliation, review and education are the pharmaceutical interventions that have more influence on adherence (percentage of adherent pt with vs without intervention: 95.7% vs 81.8%, 89.2% vs 82.7% and 87.7% vs 81.3% respectively). Conclusions: The percentage of pt with NSCLC adherent to oral TKIs in Spain is high. Previous CT, ECOG and having started OT before the study are correlated with adherence. Adherence is correlated with a better PFS. The interventions that seem to have the most impact on pt adherence are conciliation, education and review.

Evaluating patient adherence and persistence to first-line tyrosine-kinase inhibitors for metastatic renal cell carcinoma.

e18856 Background: Tyrosine kinase inhibitors (TKIs) have been approved in treating advanced renal cell carcinoma (RCC) since 2005. More recently, combination therapy with an immune checkpoint inhibitor (ICI) and a kinase inhibitor (TKI) is considered standard of care in the first-line setting of metastatic RCC. While oral neoplastic therapies such as TKIs promote patient autonomy, these therapies pose unique challenges including ensuring patients take medications as indicated (i.e., adherence) and for the recommended duration (i.e., persistence). Persistence and adherence data from prescription dispensing and refill patterns are important to health care providers, systems, and payers in order to assess and/or optimize the therapeutic goal(s) of anticancer treatment. Therefore, we sought to explore adherence and persistence of first-line TKIs when used in combination with ICIs for treating metastatic RCC. Methods: Adults with metastatic RCC who received at least two prescriptions for FDA-approved TKIs used in combination with ICIs between April 29, 2019 and August 29,2022 were identified at University of California Irvine Medical Center. Adherence was determined by calculating the Medication Possession Ratio (MPR) and the Proportion of Days Covered (PDC). TKI persistence was evaluated using the Kaplan-Meier method. Also evaluated was the average length of therapy. We examined additional dispensing and refill pattern indicators, including the monthly total number of prescriptions filled. Results: A total of 66 individuals and 849 prescriptions were discovered. The mean duration of treatment for all patients was 237 days, and the median duration was 201 days (Table 1). The mean persistence was 303 days, whereas the median persistence was 233 days. Over 180 days, the median MPR was 83%, whereas the median PDC was 72%. The median variable PDC was 86%, while the median variable MPR was 105%. September was historically the month with the lowest prescription counts (16 +/- 2). Conclusions: We observed a significantly longer median duration of oral TKIs therapy (201 days) in an academic medical center than the national average ( < 100 days). This analysis of real-world data reveals that lengthier treatment durations for TKI+ICI combinations are feasible. Further research is warranted to identify possible factors such as clinical monitoring or adverse effect management that may prolong adherence and persistence. [Table: see text]

The multikinase inhibitor axitinib in the treatment of advanced hepatocellular carcinoma: the current clinical applications and the molecular mechanisms.

Advanced hepatocellular carcinoma (HCC) is a formidable public health problem with limited curable treatment options. Axitinib, an oral tyrosine kinase inhibitor, is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptor (VEGFR) 1, 2, and 3. This anti-angiogenic drug was found to have promising activity in various solid tumors, including advanced HCC. At present, however, there is no relevant review article that summarizes the exact roles of axitinib in advanced HCC. In this review, 24 eligible studies (seven studies in the ClinicalTrials, eight experimental studies, and nine clinical trials) were included for further evaluation. The included randomized or single-arm phase II trials indicated that axitinib could not prolong the overall survival compared to the placebo for the treatment of advanced HCC, but improvements in progression free survival and time to tumor progression were observed. Experimental studies showed that the biochemical effects of axitinib in HCC might be regulated by its associated genes and affected signaling cascades (e.g. VEGFR2/PAK1, CYP1A2, CaMKII/ERK, Akt/mTor, and miR-509-3p/PDGFRA). FDA approved sorafenib combined with nivolumab (an inhibitor of PD-1/PD-L1) as the first line regimen for the treatment of advanced HCC. Since both axitinib and sorafenib are tyrosine kinase inhibitors as well as the VEGFR inhibitors, axitinib combined with anti-PDL-1/PD-1 antibodies may also exhibit tremendous potential in anti-tumoral effects for advanced HCC. The present review highlights the current clinical applications and the molecular mechanisms of axitinib in advanced HCC. To move toward clinical applications by combining axitinib and other treatments in advanced HCC, more studies are still warranted in the near future.

Modulation of tumor immune microenvironment by TAS-115, a multi-receptor tyrosine kinase inhibitor, promotes antitumor immunity and contributes anti-PD-1 antibody therapy

TAS-115 is an oral multi-receptor tyrosine kinase inhibitor that strongly inhibits kinases implicated in antitumor immunity, such as colony stimulating factor 1 receptor and vascular endothelial growth factor receptor. Because these kinases are associated with the modulation of immune pathways, we investigated the immunomodulatory activity of TAS-115. An in vitro cytokine assay revealed that TAS-115 upregulated interferon γ (IFNγ) and interleukin-2 secretion by T cells, suggesting that TAS-115 activated T cells. Gene expression analysis suggested that TAS-115 promoted M1 macrophage differentiation. In in vivo experiments, although TAS-115 exerted a moderate antitumor effect in the MC38 mouse colorectal cancer model under immunodeficient conditions, this effect was enhanced under immunocompetent conditions. Furthermore, combination of TAS-115 and anti-PD-1 antibody exhibited greater antitumor activity than either treatment alone. Flow cytometry analysis showed the increase in IFNγ- and granzyme B (Gzmb)-secreting tumor-infiltrating T cells by TAS-115 treatment. The combination treatment further increased the percentage of Gzmb+CD8+ T cells and decreased the percentage of macrophages compared with either treatment alone. These results highlight the potential therapeutic effect of TAS-115 in combination with PD-1 blockade, mediated via activation of antitumor immunity by TAS-115.

Afatinib for the Treatment of NSCLC with Uncommon EGFR Mutations: A Narrative Review.

Afatinib, the world's first irreversible ErbB family (containing four different cancer cell epidermal growth factor receptors, including EGFR, HER2, ErbB3, and ErbB4) inhibitor, is a second-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It can be used as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with an EGFR-sensitive mutation or for patients with locally advanced or metastatic squamous lung cancer whose disease progresses during or after platinum-containing chemotherapy. Currently, with the use of third-generation EGFR-TKIs, afatinib is no longer clinically indicated as the first choice for patients with NSCLC who have EGFR-sensitive mutations. However, afatinib showed a considerable inhibitory effect in NSCLC patients with uncommon EGFR mutations (G719X, S768I, and L861Q) according to a combined post hoc analysis of the LUX-Lung2/3/6 trials. With the development of genetic testing technology, the detection rate of uncommon EGFR mutations is increasing. The aim of this paper is to describe in detail the sensitivity of rare EGFR mutations to afatinib and to provide information and a reference for those suffering from advanced NSCLC who have uncommon EGFR mutations.

Randomized phase II BGOG/ENGOT-cx1 study of paclitaxel-carboplatin with or without nintedanib in first-line recurrent or advanced cervical cancer

ObjectiveNintedanib is an oral tyrosine kinase inhibitor targeting, among others, vascular endothelial growth factor receptor. The aim was to establish the role of nintedanib in addition to paclitaxel and carboplatin in first-line recurrent/metastatic cervical cancer. MethodsDouble-blind phase II randomized study in patients with first-line recurrent or primary advanced (FIGO stage IVB) cervical cancer. Patients received carboplatin-paclitaxel with oral nintedanib 200 mg BID/placebo. The primary endpoint was progression-free survival (PFS) at 1.5 years and α = 0.15, β = 80%, one sided. Results120 patients (62 N, 58C) were randomized. Median follow-up was 35 months. Baseline characteristics were similar in both groups (total population: squamous cell carcinoma 62%, prior radiotherapy 64%, primary advanced 25%, recurrent 75%). The primary endpoint was met with a PFS at 1.5 years of 15.1% versus 12.8% in favor of the nintedanib arm (p = 0.057). Median overall survival (OS) was 21.7 and 16.4 months for N and C, respectively. Confirmed RECIST response rate was 48% for N and 39% for C. No new adverse events were noted for N. However, N was associated with numerically more serious adverse events for anemia and febrile neutropenia. Global health status during and at the end of the study was similar in both arms. ConclusionThe study met its primary endpoint with a prolonged PFS in the N arm. No new safety signals were observed.

Studies on the inhibitory effect of isavuconazole on flumatinib metabolism in vitro and in vivo.

As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib. Many patients experience aspergillosis infection and they may start using isavuconazole, which is an inhibitor of CYP3A4. However, there is no study on their interaction in vitro and in vivo. In the present study, the concentrations of flumatinib and its major metabolite M1 were rapidly determined using an stable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The half-maximal inhibitory concentration (IC50) was 6.66μM in human liver microsomes (HLM), while 0.62μM in rat liver microsomes (RLM) and 2.90μM in recombinant human CYP3A4 (rCYP3A4). Furthermore, the mechanisms of inhibition of flumatinib in human liver microsomes, rat liver microsomes and rCYP3A4 by isavuconazole were mixed. Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism. In pharmacokinetic experiments of rats, it was observed that isavuconazole could greatly change the pharmacokinetic parameters of flumatinib, including AUC(0-t), AUC(0-∞), Cmax and CLz/F, but had no effect on the metabolism of M1. According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications.

Upregulation of CSNK1A1 induced by ITGB5 confers to hepatocellular carcinoma resistance to sorafenib in vivo by disrupting the EPS15/EGFR complex

Oral multitarget tyrosine kinase inhibitors (TKIs), such as sorafenib, which suppress tumor cell proliferation and tumor angiogenesis, have been approved to treat patients with hepatocellular carcinoma (HCC). Of note, only approximately 30% of patients can benefit from TKIs, and this population usually acquires drug resistance within 6 months. In this study, we intended to explore the mechanism associated with regulating the sensitivity of HCC to TKIs. We revealed that integrin subunit β 5 (ITGB5) is abnormally expressed in HCC and contributes to decreased the sensitivity of HCC to sorafenib. Mechanistically, unbiased mass spectrometry analysis using ITGB5 antibodies revealed that ITGB5 interacts with EPS15 to prevent the degradation of EGFR in HCC cells, which activates AKT-mTOR signaling and the MAPK pathway to reduce the sensitivity of HCC cells to sorafenib. In addition, mass spectrometry analysis showed that CSNK1A1 binds to ITGB5 in HCC cells. Further study indicated that ITGB5 increased the protein level of CSNK1A1 through the EGFR-AKT-mTOR pathway in HCC. Upregulated CSNK1A1 phosphorylates ITGB5 to enhance the interaction between ITGB5 and EPS15 and activate EGFR in HCC cells. Thus, we identified a positive feedback loop between ITGB5-EPS15-EGFR-CSNK1A1 in HCC cells. This finding provides a theoretical basis for the future development of therapeutic strategies to improve the anti-HCC efficacy of sorafenib.

Efficacy of salvage therapies after failure of adjuvant anti-PD-1 monotherapy for melanoma in the Chinese population: a multi-institutional cohort study

SummaryThe majority of melanoma patients experience relapse during adjuvant therapy or after the end of therapy. Sixty-one patients from 3 melanoma centres who experienced recurrence and received adjuvant pembrolizumab for resected stage III/IV melanoma were enrolled. Disease characteristics, recurrence characteristics, subsequent management and outcomes were retrospectively analysed. Sixty-one patients were enrolled in this study. The median time to first relapse from the commencement of adjuvant pembrolizumab was 8 months (1–22 months). The first recurrences were locoregional alone in 25 patients (41%), distant alone in 29 (47.5%) and concurrent locoregional and distant relapse in 7 (11.5%). At the first recurrence, 4 patients (80%) who underwent resection alone experienced further relapse of disease. Three (60%) patients who were treated with adjuvant pembrolizumab following surgery, 2 (100%) patients who were treated with adjuvant chemotherapy, 2 (66.7%) patients who were treated with adjuvant chemotherapy and pembrolizumab combined and 3 (100%) patients who were treated with adjuvant radiotherapy and pembrolizumab combined had further recurrence. Of the three patients treated with adjuvant BRAF/MEKi following the first relapse, none had yet recurred. Of the 8 patients treated with pembrolizumab alone, only one patient (12.5%) who recurred after ceasing adjuvant PD1 had a partial response. The overall response rate to BRAF/MEKi was 75%, 3/4; to pembrolizumab in combination with an oral multitargeted receptor tyrosine kinase inhibitor, it was 22.2%, 2/9; to chemotherapeutic agents alone, it was 33.3%, 1/3; and to chemotherapeutic agents combined with pembrolizumab, it was 37.5%, 3/8. The patient treated with imatinib had progressive disease after 3 months of treatment. Of the 6 patients who received temozolomide combined with pembrolizumab, 3 (3/6, 50%) had a partial response. The median OS of the patients who relapsed locoregionally only was longer than that of the patients who relapsed distally at the first recurrence (35 months and 14 months, respectively; P < 0.01). The outcomes of the patients with disease recurrence during or after the completion of 1 year of adjuvant anti-PD1 therapy were poor despite multimodality treatment.

A single-arm phase II clinical trial of anlotinib combined with chemotherapy for the treatment of metastatic triple-negative breast cancer.

Anlotinib is a novel oral small-molecule tyrosine kinase inhibitor (TKI), which can inhibit angiogenesis. The purpose of this study was to evaluate the efficacy and safety of anlotinib combined with chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). This phase II clinical trial included 40 patients with metastatic TNBC who had previously received anthracycline and/or taxane treatment. All patients received anlotinib combined with chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and safety. During May 1, 2019 and April 30, 2022, there were 40 patients enrolled in this study. The median PFS and median OS were 8.8 months (95% confidence interval [CI] 6.5-11.1 months) and 19.0 months (95% CI, 12.1-25.9 months), respectively. The ORR, CBR and DCR were 40.0% (16/40), 85.0% (34/40) and 95.0% (38/40), respectively. Cox univariate and multivariate analyses demonstrated that having more than 3 metastatic sites (p = 0.001; p = 0.020) was an independent and meaningful unfavorable prognostic factor for PFS. 37.5% of patients had grade 3 to 4 treatment-related adverse events (TRAEs). The grade 3 to 4 TRAEs included neutropenia (22.5%), leukopenia (20.0%), secondary hypertension (10.0%), hand-foot syndrome (5.0%), vomiting (5.0%), proteinuria (5.0%) and thrombocytopenia (2.5%). None of the patients withdrew from the study or died due to TRAEs. In this single-arm study, the treatment of metastatic TNBC with anlotinib combined with chemotherapy showed certain efficacy, and its toxicity was acceptable.

L-carnitine prevents lenvatinib-induced muscle toxicity without impairment of the anti-angiogenic efficacy.

Lenvatinib is an oral tyrosine kinase inhibitor that acts on multiple receptors involved in angiogenesis. Lenvatinib is a standard agent for the treatment of several types of advanced cancers; however, it frequently causes muscle-related adverse reactions. Our previous study revealed that lenvatinib treatment reduced carnitine content and the expression of carnitine-related and oxidative phosphorylation (OXPHOS) proteins in the skeletal muscle of rats. Therefore, this study aimed to evaluate the effects of L-carnitine on myotoxic and anti-angiogenic actions of lenvatinib. Co-administration of L-carnitine in rats treated with lenvatinib for 2weeks completely prevented the decrease in carnitine content and expression levels of carnitine-related and OXPHOS proteins, including carnitine/organic cation transporter 2, in the skeletal muscle. Moreover, L-carnitine counteracted lenvatinib-induced protein synthesis inhibition, mitochondrial dysfunction, and cell toxicity in C2C12 myocytes. In contrast, L-carnitine had no influence on either lenvatinib-induced inhibition of vascular endothelial growth factor receptor 2 phosphorylation in human umbilical vein endothelial cells or angiogenesis in endothelial tube formation and mouse aortic ring assays. These results suggest that L-carnitine supplementation could prevent lenvatinib-induced muscle toxicity without diminishing its antineoplastic activity, although further clinical studies are needed to validate these findings.

Analysis of intracellular tyrosine phosphorylation in circulating neutrophils as a rapid assay for the in vivo effect of oral tyrosine kinase inhibitors.

Tyrosine kinases are crucial signaling components of diverse biological processes and are major therapeutic targets in various malignancies and immune-mediated disorders. A critical step of development of novel tyrosine kinase inhibitors is the transition from the confirmation of the in vitro effects of drug candidates to the analysis of their in vivo efficacy. To facilitate this transition, we have developed a rapid in vivo assay for the analysis of the effect of oral tyrosine kinase inhibitors on basal tyrosine phosphorylation of circulating mouse neutrophils. The assay uses a single drop of peripheral blood without sacrificing the mice. Flow cytometry using intracellular staining by fluorescently labeled anti-phosphotyrosine antibodies revealed robust basal tyrosine phosphorylation in resting circulating neutrophils. This signal was abrogated by the use of isotype control antibodies or by pre-saturation of the anti-phosphotyrosine antibodies with soluble phosphotyrosine amino acids or tyrosine-phosphorylated peptides. Basal tyrosine phosphorylation was dramatically reduced in neutrophils of triple knockout mice lacking the Src-family tyrosine kinases Hck, Fgr, and Lyn. Neutrophil tyrosine phosphorylation was also abrogated by oral administration of the Abl/Src-family inhibitor dasatinib, a clinically used anti-leukemic agent. Detailed dose-response and kinetic studies revealed half-maximal reduction of neutrophil tyrosine phosphorylation by 2.9mg/kg dasatinib, with maximal reduction observed 2h after inhibitor administration. Taken together, our assay allows highly efficient analysis of the in vivo effect of orally administered tyrosine kinase inhibitors, and may be used as a suitable alternative to other existing approaches.

Abstract 1097: Surufatinib improved the radiation sensitivity of biliary cancer growth by reprograming of TAM and anti-angiogenesis

Abstract Background: Patients with Biliary tract cancer (BTC) have poor clinical outcomes. Radiation therapy is an adjunct strategy throughout biliary tract cancer treatment. The aim of the study was to explore the efficacy and mechanism of the radiosensitization of surufatinib(SF), an oral tyrosine kinase inhibitor with anti-angiogenic and immunomodulatory activities. Methods: The NOZ and TFK1 human BTC cell lines were treated with SF and/or radiation. Effects on cell viability and cell cycle progression were measured by CCK8, a clonogenic survival assay, and flow cytometry. Finally, the in vivo effect on the growth of NOZ xenografts was assessed in nude mice. F4/80, CD206, Ki67 and CD31 expression were employed in tumor samples. Results: SF inhibited the proliferation and enhanced the radiosensitivity in NOZ and TFK1 cells lines. SF combined with radiation increased cell cycle arrest in the G2/M phase compared to the other treatments in the NOZ cell line (P&amp;lt;0.05). Similarly, cell cycle arrest occurred in the TFK1 cell line, (P&amp;lt;0.05). In vivo, SF plus radiation significantly inhibited the tumor growth compared to either agent independently. Conclusions: SF significantly increased the radiosensitivity of NOZ and TFK1 cells in vitro and in vivo. Radiation combined with SF inhibited tumor proliferation, increased apoptosis, prolonged G2/M arrest. SF decreased the number of blood vessels and reprogrammed the macrophages from M2 to M1. These data support the clinical trials of biologically targeted and conventional therapies in the treatment of cancer. Citation Format: Hong Ma, Ai Huang, Yong Xiao, Jing Yao, Ningyu Wang, Xiangping Mei, Shaoshi Wen, Xing Lv. Surufatinib improved the radiation sensitivity of biliary cancer growth by reprograming of TAM and anti-angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1097.

Abstract 4014: Comparative biochemical kinase activity analysis identifies rivoceranib as the most selective VEGFR-2 inhibitor compared with other TKIs with known activity against VEGFR-2

Abstract Introduction: Vascular endothelial growth factor receptor 2 (VEGFR-2) is a key regulator of tumor angiogenesis that is highly expressed in several tumor types and is a known target for anti-cancer therapy. Yet the clinical use of VEGFR-2 inhibitors has been challenged by limited efficacy and various side effects, potentially due to the low selectivity of these TKIs for VEGFR-2. Thus, potent VEGFR-2 inhibitors with improved selectivity are needed. Rivoceranib is an oral tyrosine kinase inhibitor (TKI) that potently and selectively inhibits VEGFR-2. A comparison of the potency and selectivity of VEGFR-2 inhibitors can provide a rationale for selecting a specific TKI for anticancer therapy in the clinic. Methods: Binding of rivoceranib to VEGFR-2 was determined on a Biacore T200. The affinity constant (KD) was derived from the association and dissociation rate constants. Inhibitory potency of rivoceranib and 10 FDA-approved reference inhibitors on kinase enzyme activity was determined using mobility shift assays (MSA) or immobilized metal ion affinity particle (IMAP) assays. The half-maximum inhibitory activity (IC50) of the 11 inhibitors on VEGFR-2 was determined in 10-point dose-response curves. The selectivity of the inhibitors was determined on 270 wild-type kinases at a fixed concentration of each inhibitor. Rivoceranib was tested at 10- and 100-times IC50 (160 nmol/L and 1.6 µmol/L). Reference inhibitors were tested at 1 µmol/L (35 to 1056-times IC50). Results: Rivoceranib had a KD of 3 nmol/L on VEGFR-2. In enzyme activity assays, rivoceranib had intermediate potency compared with the 10 reference inhibitors, with a VEGFR-2 kinase inhibition IC50 value of 16 nmol/L. Analysis of the residual activity of the panel of 270 kinases in the presence of rivoceranib or the reference inhibitors showed wide variation in selectivity for VEGFR-2, with rivoceranib identified as the most selective inhibitor (activity of 16 additional kinases inhibited by &amp;gt;50% at 1.6 µmol/L). Tivozanib, the most potent VEGFR-2 inhibitor, displayed greater than 50% inhibitory activity against more than 70 additional kinases. Sunitinib was identified as the least selective inhibitor included in this study, inhibiting 125 additional kinases by &amp;gt;50%. Conclusion: Variations in selectivity among TKIs with similar anti-VEGFR-2 potency can help explain differences in their clinical toxicity profiles, which may be partially due to variant inhibitory effects against TKIs other than VEGFR-2. This comparative biochemical analysis highlights the potential for rivoceranib to address clinical limitations associated with the poor selectivity of currently available VEGFR-2 inhibitors. Rivoceranib is under ongoing investigation as monotherapy and in combination with chemotherapy in various tumor types. Citation Format: Seong Jang, Bill Strickland, Lynda Finis, Jeffrey J. Koojiman, Janneke J. Melis, Guido J. Zaman, Jan V. Tornout. Comparative biochemical kinase activity analysis identifies rivoceranib as the most selective VEGFR-2 inhibitor compared with other TKIs with known activity against VEGFR-2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4014.

Insight into intermolecular binding mechanism of apatinib mesylate and human alpha-1-acid glycoprotein: combined multi-spectroscopic approaches with in silico

Apatinib mesylate (APM), an oral tyrosine kinase inhibitor, has a good anti-tumor activity in the treatment of various cancers, particularly in advanced non-small cell lung cancer. In this study, the intermolecular binding mechanism between APM and human alpha-1-acid glycoprotein (HAG) was investigated by combining multi-spectroscopic approaches with in silico techniques. The findings revealed that APM gave rise to the fluorescence quenching of HAG by forming a ground-state complex between APM and HAG with a stoichiometric ratio of 1:1, and APM has a moderate affinity for HAG as the binding constant of APM and HAG of approximately 105 M−1, which was larger than the APM-HAG complex. The findings from thermodynamic parameter analysis indicated that the dominant driving forces for the formation of the APM-HAG complex were van der Waals forces, hydrogen bonding and hydrophobic interactions, which were also verified with site-probe studies and molecular docking. The findings from in silico study indicated that APM inserted into the opening of the hydrophobic cavity of HAG, leads to a slight conformational change in the HAG, which was verified by circular dichroism (CD) measurements, that was, the beta sheet level of HAG decreased. Additionally, the results of synchronous and 3D fluorescence spectroscopies confirmed the decline in hydrophobicity of the microenvironment around Trp and Tyr residues. Moreover, some common metal ions such as Cu2+, Mg2+, Fe3+, Ca2+, and Zn2+ could cause the alteration in the binding constant of APM with HAG, leading to the change in the efficacy of APM. It will be expected that these study findings are to provide useful information for further understanding pharmacokinetic and structural modifications of APM. Communicated by Ramaswamy H. Sarma

Antifibrotic mechanism of avitinib in bleomycin-induced pulmonary fibrosis in mice

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by alveolar epithelial cell injury and lung fibroblast overactivation. At present, only two drugs are approved by the FDA for the treatment of IPF, including the synthetic pyridinone drug, pirfenidone, and the tyrosine kinase inhibitor, nintedanib. Avitinib (AVB) is a novel oral and potent third-generation tyrosine kinase inhibitor for treating non-small cell lung cancer (NSCLC). However, the role of avitinib in pulmonary fibrosis has not yet been established. In the present study, we used in vivo and in vitro models to evaluate the role of avitinib in pulmonary fibrosis. In vivo experiments first verified that avitinib significantly alleviated bleomycin-induced pulmonary fibrosis in mice. Further in vitro molecular studies indicated that avitinib inhibited myofibroblast activation, migration and extracellular matrix (ECM) production in NIH-3T3 cells, mainly by inhibiting the TGF-β1/Smad3 signalling pathways. The cellular experiments also indicated that avitinib improved alveolar epithelial cell injury in A549 cells. In conclusion, the present findings demonstrated that avitinib attenuates bleomycin-induced pulmonary fibrosis in mice by inhibiting alveolar epithelial cell injury and myofibroblast activation.

Poziotinib in Treatment-Naive NSCLC Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4)

IntroductionERBB2 or HER2 alterations are found in approximately 2% to 5% of NSCLCs; most are exon 20 insertion mutations. The efficacy and safety of poziotinib, an oral tyrosine kinase inhibitor, were assessed in patients with treatment-naive NSCLC whose tumors harbor HER2 exon 20 insertions. MethodsZENITH20 is an open-label, multicohort, multicenter, global, phase 2 trial. ZENITH20-C4 enrolled treatment-naive patients with NSCLC with tumors harboring HER2 exon 20 insertions. Poziotinib was administered 16 mg once daily (QD) or 8 mg twice daily (BID). The primary end point was objective response rate (ORR) by independent central review. Secondary and exploratory end points included disease control rate, duration of response, progression-free survival, and safety. ResultsA total of 80 patients (16 mg QD, n = 47; 8 mg BID, n = 33) were treated in ZENITH20-C4. ORR was 39% (95% confidence interval [CI]: 28%–50%; 31 of 80), with a disease control rate of 73% (95% CI: 61%–82%; 58 of 80); 80% of the patients experienced tumor reduction. Median duration of response was 5.7 (95% CI: 4.6–11.9) months, and median progression-free survival was 5.6 (95% CI: 5.4–7.3) months. The most common grade 3 treatment-related adverse events were rash (QD, 45%; BID, 39%), stomatitis (QD, 21%; BID, 15%), and diarrhea (QD, 15%; BID, 21%). Among all subtypes of HER2 exon 20 insertions, seven patients (9%) harboring tumors with G778_P780dupGSP had the best clinical outcomes (ORR, 71%). ConclusionsPoziotinib was found to have clinically meaningful efficacy with a manageable toxicity profile for patients with treatment-naive NSCLC harboring HER2 exon 20 mutations.

The efficacy and safety of apatinib plus capecitabine in platinum-refractory metastatic and/or recurrent nasopharyngeal carcinoma: a prospective, phase II trial

BackgroundPrevious studies have shown that monotherapy with apatinib, an oral tyrosine kinase inhibitor, has promising efficacy for treating recurrent or metastatic (RM) nasopharyngeal carcinoma (NPC) patients. In this study, we aimed to assess the efficacy and safety of apatinib combined with capecitabine as a second-line therapy or beyond for treating RM-NPC patients who failed the first-line platinum-based chemotherapy.MethodsIn this single-arm, phase II study, we enrolled RM-NPC patients who had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The sample size was determined using Simon’s two-stage design. All patients were administered with apatinib 500 mg once daily and capecitabine 1000 mg/m2 twice per day on days 1–14 of each 21-day cycle. The primary endpoint was the objective response rate (ORR), and the secondary endpoints comprised disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety.ResultsWe enrolled 64 patients from September 2018 to August 2020. The ORR and DCR were 39.1% (95% CI, 27.1–52.1) and 85.9% (95% CI, 75.0–93.4), respectively. The median DoR was 14.4 months (95% CI, 7.8–21.0). As of April 20, 2021, the median follow-up duration was 12.0 months. The median PFS was 7.5 months (95% CI, 5.0–10.0) and the median OS was 15.7 months (95% CI, 11.3–20.1). The most common toxicities of any grade were anemia (75.0%), hand-foot syndrome (65.6%), and proteinuria (64.0%). Grade 3–4 toxicities were observed in 36 (56.3%) patients, with hypertension (14.1%), mucositis (12.4%), and fatigue (10.9%) most commonly observed.ConclusionsApatinib plus capecitabine shows promising efficacy as a second-line treatment option in pretreated platinum-refractory RM-NPC patients. Dose selection of this combination needs further investigation considering the toxicity.Trial registrationChi-CTR1800017229.

Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib plus Osimertinib in an EGFR Mutation-Positive, MET-Amplified Non-Small Cell Lung Cancer Model.

Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor (TKI) recommended as first-line treatment for patients with locally advanced/metastatic EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). However, MET amplification/overexpression is a common acquired osimertinib resistance mechanism. Savolitinib is an oral, potent, and highly selective MET-TKI; preliminary data suggest that combining osimertinib with savolitinib may overcome MET-driven resistance. A patient-derived xenograft (PDX) mouse model with EGFRm, MET-amplified NSCLC was tested with a fixed osimertinib dose [10 mg/kg for exposures equivalent to (≈)80 mg], combined with doses of savolitinib (0-15 mg/kg, ≈0-600 mg once daily), both with 1-aminobenzotriazole (to better match clinical half-life). After 20 days of oral dosing, samples were taken at various time points to follow the time course of drug exposure in addition to phosphorylated MET and EGFR (pMET and pEGFR) change. Population pharmacokinetics, savolitinib concentration versus percentage inhibition from baseline in pMET, and the relationship between pMET and tumor growth inhibition (TGI) were also modeled. As single agents, savolitinib (15 mg/kg) showed significant antitumor activity, reaching ∼84% TGI, and osimertinib (10 mg/kg) showed no significant antitumor activity (34% TGI, P > 0.05 vs. vehicle). Upon combination, at a fixed dose of osimertinib, significant savolitinib dose-related antitumor activity was shown, ranging from 81% TGI (0.3 mg/kg) to 84% tumor regression (15 mg/kg). Pharmacokinetic-pharmacodynamic modeling showed that the maximum inhibition of both pEGFR and pMET increased with increasing savolitinib doses. Savolitinib demonstrated exposure-related combination antitumor activity when combined with osimertinib in the EGFRm MET-amplified NSCLC PDX model.

Abstract P1-12-11: Real-world incidence and management of diarrhea secondary to pyrotinib in patients with HER-2 positive breast cancer

Abstract Objective: Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase inhibitor, showed promising efficacy and manageable safety profiles in the treatment of HER-2 positive breast cancer. Diarrhea is the most common adverse event associated with pyrotinib. This study aimed to evaluate the incidence and management of diarrhea secondary to pyrotinib in Chinese patients with HER-2 positive breast cancer. Methods: In this prospective real-world study, consecutive patients aged over 18 with HER-2 positive breast cancer and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2 who planned to receive pyrotinib-based regimens for at least 21 days were included. Pyrotinib-treated patients and those with preexisting gastrointestinal conditions were excluded. There were no planned management strategy or primary prophylaxis for diarrhea, while loperamide, montmorillonite powder or Golden Bifid (a live combined Bifidobacterium, Lactobacillus and Streptococcus Thermophilus tablet) were recommended. Treatment was given in accordance with routine clinical practice by investigators. For patients developed grade 3 or higher diarrhea, pyrotinib was suspended until the diarrhea improving to grade 1 or less, and secondary prophylaxis (such as loperamide, loperamide plus montmorillonite powder, or loperamide plus Golden Bifid) was administrated before pyrotinib resumption. The baseline characteristics of patients and details of diarrhea (onset time, duration, severity according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.03, treatment and prognosis) were collected. Results: Between August, 2020 and April, 2022, a total of 107 eligible patients were included, with a median age of 54 (range: 25-81) years old. Most patients (93.5%) had an ECOG PS of 0-1, and 51 patients (47.7%) were hormone receptor positive. A total of 46 patients (43.0%) received pyrotinib in the early stage and 61 (57.0%) in the advanced stage. Sixty-nine cases (64.5%) used pyrotinib-containing combination therapy (including 40 combined with capecitabine, 13 combined with trastuzumab, and 16 combined with other regimens), and 38 (35.5%) received pyrotinib alone. Ninety-eight cases (91.6%) reported diarrhea of any grade. Grade 1, 2 and 3 diarrhea occurred in 78 (72.9%), 9 (8.4%) and 11 (10.3%) patients, respectively. The median time to first onset of diarrhea of any grade was 2.5 (1-12) days, and the duration of first onset was 4 (1-24) days. The cumulative duration of diarrhea was 10 (1-60) days. Sixty-four, two, thirty, two patients used loperamide alone, montmorillonite powder alone, loperamide plus montmorillonite powder and loperamide plus Golden Bifid for the treatment of diarrhea, respectively. Eleven (10.3%) and seven (6.5%) patients experienced pyrotinib dose reduction and pyrotinib discontinuation. For 11 patients suffered grade 3 diarrhea, the median time to first onset of grade 3 diarrhea was 9 (4-14) days. Two, four and five patients administrated loperamide, loperamide plus Golden Bifid and loperamide plus montmorillonite powder as their secondary prophylaxis. Ten of eleven had grade 1 or 2 diarrhea after secondary prophylaxis, while one patient still suffered grade 3 diarrhea. All of them (11/11) held the pyrotinib dose. The incidence rate of constipation of all patients was 3.7%, which did not increase after treatment or secondary prophylaxis for diarrhea. Conclusion: In this study, the majority of patients developed pyrotinib associated diarrhea, and most of them were grade 1. About 10% patients reported grade 3 diarrhea, which can be managed by loperamide-based treatment and secondary prophylaxis. Table 1. Baseline characteristics of patients ECOG PS: Eastern Cooperative Oncology Group performance status; HER-2: human epidermal growth factor receptor 2. Table 2. Summary of patients developed diarrhea Table 3. Summary of patients developed grade 3 diarrhea Citation Format: Hong Liu, Li Ma, Xu Wang, Xinzhong Chang, Qi Yu, Qingfeng Huang, Chunfang Hao, Jun Liu, Jing Zhao, Shufen Li, Zhongsheng Tong, Yehui Shi, Ning Lu, Weipeng Zhao, Tong Wang, Xuchen Cao, Chen Wang, Juntian Liu, Ying Zhao, Lina Zhang, Baoliang Guo, Xin Wang, Xu Di, Chunhui Gao, Zongzhan Liu, Shuo Sun, Linwei Li. Real-world incidence and management of diarrhea secondary to pyrotinib in patients with HER-2 positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-11.