Small Molecule Tyrosine Kinase Inhibitors Research Articles

Abstract PO2-01-04: Efficacy and safety of anti-HER2 therapy in neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis

Abstract Background: Human epidermal growth factor receptor-2 overexpression or gene amplification (HER2+) breast cancer is considered to be a highly aggressive, dangerous and even fatal subtype..In recent years, with the application of large molecule anti-HER2 monoclonal antibody and its biosimilar in neoadjuvant therapy of HER2-positive breast cancer, small molecule tyrosine kinase inhibitors (TKIs) have also performed strong advantages of antineoplastic activity in breast cancer. At present, there is no direct evidence to demonstrate the differences in neoadjuvant efficacy of anti-HER2 monoclonal antibody and tyrosine kinase inhibitors (TKIs) in this subtype of breast cancer.We conducted a preliminary network meta-analysis to explore the difference of efficacy and safety between anti-HER2 monoclonal antibody and TKIs for neoadjuvant therapy in patients with HER2-positive early or locally advanced breast cancer. Method: A systematic literature search in the Cochrane Central Register of Controlled Trials, PubMed, Embase and Web of Science was performed.Randomized or non-randomized controlled studies of neoadjuvant therapy for HER2-positive breast cancer including large molecules trastuzumab, pertuzumab and small molecules TKIs (pyrotinib, lapatinib, nenatinib, etc.) were screened.Studies had to satisfy the following criteria: i) randomized or non-randomized controlled trials, ii) at least one treatment group received an anti-HER2 agent, iii) available information of any efficacy end-point. A network meta-analysis with a frequentist framework using random-effects model was used to pool direct and indirect evidence. Pathologic complete response (pCR) were the efficacy end-points of interest, and selected safety end-points were also analysed. Results: A total of 5885 published manuscripts were identified,and 19 studies including 6517 patients were finally included in our analysis. and 19 different regimens were evaluated. Dual anti-HER2-therapy,trastuzumab with pertuzumab or tyrosine kinase inhibitors, combined with chemotherapy was significantly superior to trastuzumab or TKIs and chemotherapy in terms of pCR(OR=2.20, 95%CI=1.92-2.52).In the comparison of dual-target treatment regiments, the efficacy of pyrotinib plus trastuzumab combined chemotherapy was superior to that of pertuzumab plus trastuzumab combined chemotherapy (OR=1.20, 95%CI=0.85-1.70), but the difference was not statistically significant.In addition, compared with pertuzumab combined with trastuzumab and chemotherapy,there was no significant difference in the efficacy aspect of TKIs combined with trastuzumab and chemotherapy (OR=1.15, 95%CI=0.88-1.51). Conclusion:For the selection of neoadjuvant treatment for HER2-positive early or locally advanced breast cancer, trastuzumab plus pertuzumab combined with chemotherapy is still the preferred strategy at present.As our study showed that pyrotinib combined with trastuzumab and chemotherapy maybe could provide another option for neoadjuvant target therapy for HER2-positive breast cancer. Keywords: breast cancer, HER2-positive, neoadjuvant, network meta-analysis, target therapy. Characteristics of eligible studies. NAC=Neoadjuvant chemotherapy;T=nab-paclitaxel,paclitaxel or Docetaxel;F= fluorouracil;E=epirubicin;A=doxorubicin;C=cyclophosphamide; Cb=carboplatin;tzmb=trastuzumb;pzmb=pertuzumab;Py=pyrotinib;lpnb=lapatinib;Ne=neratinib. Cross-comparison odds ratios (ORs) and their respective 95% CIs for pCR among different experimental arms. CT=chemotherapy;tzmb=trastuzumb;pzmb=pertuzumab;TKI=tyrosine kinase inhibitors;Py=pyrotinib;lpnb=lapatinib;Ne=neratinib. Cross-comparison odds ratios (ORs) and their respective 95% confidence intervals (CIs) for pathologic complete response (pCR) in HR-positive and HR-negative subgroups. CT=chemotherapy;tzmb=trastuzumb;pzmb=pertuzumab;TKI=tyrosine kinase inhibitors;Py=pyrotinib;lpnb=lapatinib;Ne=neratinib. Citation Format: Lu Gan, Fangxuan Li, Jialin Su. Efficacy and safety of anti-HER2 therapy in neoadjuvant therapy for HER2-positive breast cancer: a network meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-04.

Abstract PO1-25-03: Programmed Death-Ligand 1 and Receptor Tyrosine Kinases in Breast Cancer

Abstract Programmed death-ligand 1 (PD-L1) is an immune checkpoint expressed in a wide range of malignancies leading to immune tolerance and cancer cell immune evasion. Receptor tyrosine kinases (RTKs) are key regulators of cancer cell proliferation, survival, and invasion. The Hepatocyte Growth Factor (HGF) receptor, MET, and the Epidermal Growth Factor Receptor (EGFR) are RTKs known for their tumorigenic potential in a variety of human malignancies. This study aimed to evaluate the effect of the small-molecule tyrosine kinase inhibitors (TKIs) on the expression of PD-L1 in breast cancer cells and the effect of their combination with inflammatory cytokines. The study also assessed the association of the expression of the tumoral PD-L1 mRNA with each of MET and EGFR mRNA expression and the tumor features and treatment outcomes in breast cancer patients using the METABRIC dataset publicly available from cBioPortal for Cancer Genomics. The TKIs crizotinib [a MET inhibitor] and gefitinib [an EGFR inhibitor] were used as a single treatment and in combination with the cytokines; tumor necrosis factor-α (TNF-α) or interferon-γ (INF-γ) in MCF7 and MDA-MB-231 breast cancer cells in vitro. The cells were also treated with the mitogens HGF and EGF. The viability of cells after the different treatments was determined using the MTT viability assay. The effects of the combination treatments were analyzed using combination index (CI) analysis. The expression level of PD-L1 in cancer cells was assessed using Western blotting. The combination treatment of crizotinib with TNF-α and INF-γ produced a synergistic growth inhibition of MCF7 and MDA-MB-231 cells with CI values of 0.31 and 0.55, respectively. Alternatively, combined crizotinib and TNF-α produced an antagonist effect on the viability of MCF7 cells (CI=2.49). The combination of gefitinib with TNF-α produced a synergistic growth inhibition in both MCF7 and MDA-MB-231 cells with CI values of 0.39 and 0.78, respectively. Alternatively, gefitinib resulted in an additive effect when combined with INF-γ (CI=0.99) and an antagonistic effect when combined with TNF-α (CI=2.68) in MCF7 and MDA-MB-231 cells, respectively. Treatment with HGF (50 and 100 ng/ml) increased the protein levels of PD-L1 while EGF (50 and 100 ng/ml) reduced its levels in MDA-MB-231 cells. Treatment with the TKIs crizotinib (0.1-4 µM) and gefitinib (1-40 µM) significantly reduced PD-L1 levels in MDA-MB-231 cells compared to vehicle-treated cells. The analysis of the METABRIC dataset revealed that the mRNA expression of PD-L1 was positively correlated with the mRNA expression of the EGFR gene (r= 0.081, p< 0.001) but not the MET gene. A double-high PD-L1/MET expression was significantly associated with younger age at diagnosis, high-grade carcinoma, greater tumor size, hormone receptor-negative status, HER2-positivity, and non-luminal disease compared to patients with a double-low PD-L1/MET expression. Similar findings were reported for patients with a double-high PD-L1/EGFR expression compared to patients with a double-low PD-L1/EGFR expression. Nevertheless, the mRNA expression of the PD-L1, MET, and EGFR genes as well as the co-expression of PD-L1/MET or PD-L1/EGFR genes did not affect the overall survival of breast cancer patients. Collectively, MET and EGFR TKIs could modulate the effects of inflammatory cytokines differently based on the type of cytokine and the molecular subtype of breast cancer cells. The expression of PD-L1 in breast cancer cells was upregulated by HGF while TKIs reduced its expression. The co-expression of the PD-L1 gene with MET and EGFR genes in breast cancer was associated with advanced disease presentation and worse prognosticators in patients. Together, TKIs that target MET or EGFR could be an appealing therapeutic target in breast cancer, particularly in younger patients with the non-luminal disease. Citation Format: Nehad Ayoub, Muhsen Al-Diabat, Moath Al-Shorman, Laith Al-Eitan. Programmed Death-Ligand 1 and Receptor Tyrosine Kinases in Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-25-03.

302 Targeted Inhibition of the Epigenetically Activated miR-483-5p IGF-2 Pathway as a Novel Therapeutic Strategy for Meningioma

INTRODUCTION: Meningioma is the most common primary central nervous system tumor. These are usually treated by surgical resection with curative intent, however gross total resection is not always feasible and there are many cases of recurrent and refractory disease despite adjuvant radiotherapy. Presently, there is no effective pharmacotherapeutic options for these tumors. METHODS: Small RNA sequencing was performed on meningioma tumor samples to study grade-dependent changes in microRNA expression. Gene expression was analyzed by chromatin marks, qRT-PCR and western blot. miRNA modulation, anti-IGF-2 neutralizing antibodies, and inhibitors against IGF1R were evaluated in a tumor-derived primary cultures of meningioma cells. RESULTS: Meningioma tumor samples showed high, grade-dependent expression of miR-483-5p, associated with high mRNA and protein expression of its host gene IGF-2. Inhibition of miR-483-5p reduced the growth of cultured meningioma cells, whereas a miR-483 mimic increased cell proliferation. Similarly, inhibition of this pathway with anti-IGF-2 neutralizing antibodies reduced meningioma cell proliferation. Small molecule tyrosine kinase inhibitor blockade of the IGF-2 receptor (IGF1R) resulted in rapid loss of viability of cultured meningioma tumor-derived cells, suggesting that autocrine IGF-2 feedback is obligatory for meningioma tumor cell survival and growth. The observed IGF1R-inhibitory IC50 for GSK1838705A and Ceritinib in cell-based assays along with the available pharmacokinetics data predicted that effective drug concentration could be achieved in vivo as a new medical treatment of meningioma. CONCLUSIONS: Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a new feasible meningioma treatment target.

The efficiency and safety of low-dose apatinib combined with oral vinorelbine in pretreated HER2-negative metastatic breast cancer.

Apatinib is an oral small-molecule tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptor-2. Oral vinorelbine is a semisynthetic chemotherapeutic agent of vinorelbine alkaloids. Apatinib and oral vinorelbine have been proved to be effective in the treatment of metastatic breast cancer (mBC). At present, several small sample clinical trials have explored the efficacy of apatinib combined with oral vinorelbine in the treatment of mBC. This retrospective study included 100 human epidermal growth factor receptor-2 (HER2)-negative mBC patients who received low-dose apatinib (250 mg orally per day) plus oral vinorelbine until disease progression or intolerance during February 2017 and March 2023. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and safety were analyzed by SPSS 26.0 software and GraphPad Prism 8 software. Cox proportional hazards regression model for univariate and multivariate was used to identify factors significantly related to PFS and OS. The median follow-up time for this study was 38.1 months. Among 100 patients with HER2-negative mBC, 66 were hormone receptor (HR)-positive/HER2-negative and 34 were triple-negative breast cancer (TNBC). The median PFS and OS were 6.0 months (95% CI, 5.2-6.8 months) and 23.0 months (95% CI, 19.9-26.1 months). There were no statistical differences in PFS (p = 0.239) and OS (p = 0.762) between the HR-positive /HER2-negative and TNBC subgroups. The ORR, CBR, and DCR were 21.0%, 58.0%, and 78.0%, respectively. Ninety-five patients (95.0%) experienced varying grades of adverse events (AEs) and 38.0% of patients for Grades 3-4. The most common Grades 3-4 AEs that we observed were neutropenia (30.0%) and leukopenia (25.0%). Low-dose apatinib combined with oral vinorelbine demonstrates potential efficacy and well tolerated for pretreated HER2-negative mBC.

Abstract 5848: Unraveling c-MET targeting resistance mechanisms in gastric cancer via single-cell transcriptome analysis; Novel therapeutic target discovery of ERO1A and VEGFA

Abstract Background: Gastric cancer (GC) is the fifth most prevalent malignant tumor worldwide, and the fourth most common cause of mortality. c-MET has been reported to be associated with poor prognosis in GC. Over the decades, treatment approaches targeting HGF/c-MET have been developed including small molecule tyrosine kinase inhibitors, anti-c-MET and anti-HGF monoclonal antibodies. Unfortunately, the results of previous study support the development of acquired resistance to HGF/c-Met inhibitors. They suggest a possible resistance mechanism involving poor MET-status detection, crosstalk between c-MET and compensatory signaling pathways, the occurrence of acquired a new mutation, however, knowledge regarding the mechanism of c-MET inhibitor is limited.2. Purpose: We identify new markers and mechanisms that induce drug resistance when c-MET-targeted inhibitors are treated in c-MET-amplified GC cell lines in 3D culture, and discover new therapeutic targets for GC via single cell-RNA sequencing analysis.3. Material and Methods: Single cell-RNA sequencing is performed on c-MET amplified GC cell line in the 2D and 3D culture methods according to the presence or absence of c-MET inhibitor treatment. Through DEG and clustering analysis, the candidate genes estimated to impart resistance are selected and verified by qPCR. Through over-expression, induction of resistance for c-MET inhibitor treatment with target gene is evaluated in c-MET amplified GC cell line. c-MET inhibitor selected gene is constructed as a xenograft model to reveal the mechanism of drug resistance. Retrospective analysis confirms the relationship between target gene expression level and the resistance for c-MET inhibitor or other TKI treated patients with GC. 4. Results: Treatment of c-MET-amplified GC cell lines with c-MET inhibitors under the conditions of 2D and 3D cultures confirmed that resistance was induced only in the 3D. We performed a high-precision single cell RNA-Seq analysis of 18056 single cells in total from c-MET amplified GC cell line MKN-45 in 2D/3D culture control as well as corresponding samples with volitinib treatment investigate their gene expression signatures. Fifteen selected candidate genes presumed to induce drug resistance were screened and validated by qPCR, with a total of six genes consistent with the sequencing results. After over-expression of six genes to the c-MET amplified gastric cancer cell line, c-MET inhibitors were treated and cell viability was performed to check for resistance to cell viability. Finally, ERO1A and VEGFA were over-expressed to confirm the resistant for the c-MET inhibitor treatment in vitro and in vivo.5. Discussion: We plan to build a xenograft mouse model with candidate genes such as ERO1a and VEGFA to prove whether the candidate gene overcomes drug resistance when they are on or off. Citation Format: Hajung Kim, Jinhyeon Kim, Seung-Jae Myung, Charny Park, Sun young Kim. Unraveling c-MET targeting resistance mechanisms in gastric cancer via single-cell transcriptome analysis; Novel therapeutic target discovery of ERO1A and VEGFA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5848.

Abstract 5083: Discovery of an asymmetric IgG-like bispecific ADC targeting EGFR/HER3

Abstract Background: The epidermal growth factor receptor (EGFR) family, consisting of EGFR, HER2, HER3, and HER4, plays a critical role in tumorigenesis and tumor progression. Inhibition of ERBBs using either monoclonal antibodies (mAb) or small-molecule tyrosine kinase inhibitors have been approved for use for the treatment of various types of cancers. Despite relative success, many patients acquire resistance to long-term benefit due to alternative compensatory signaling pathways. Accordingly, activating mutations or overexpression of HER3 has been reported in many cancers, such as breast, ovarian, lung, colorectal, melanoma, head and neck, cervical and prostate cancers. Here, we report the discovery of a humanized anti-EGFR x HER3 IgG-like bispecific antibody-drug conjugate (ADC). The ADC takes a asymmetric 1+1 form through HC-HC and HC-LC charge-based heterodimerization, which is then conjugated to a topoisomerase 1 inhibitor (TOP1i) payload via a cleavable linker. The affinity of EGFR and HER3 was optimized to improve the therapeutical window, and has shown potent anti-tumor efficacy in various tumor models with limited toxicity supporting further development in clinic. Methods: An anti-EGFR x HER3 bispecific ADC (PM1300) was generated by introducing unique mutations to the CH1-CL domains of each binding arm to avoid HC-LC mispairing. KIH mutations were also introduced to each CH3 domain to support HC/HC heterodimerization and generate an IgG-like bispecific with one arm binding to EGFR and the other to HER3. TOP1i payload was conjugated to the IgG-like bispecific by the endogenous cysteine residues at DAR 8 via a clearable linker. Results: Through affinity optimization, PM300 was found to preferentially bind to EGFR/HER3 double-positive cells rather than EGFR single-positive cells. PM1300 showed significantly increased internalization and anti-proliferation activity against EGFR/HER3 double-positive cells, with limited activity towards single positive-cells. PM1300 used an optimized linker for better payload release and serum stability. PM1300 induced a potent anti-tumor efficacy in various CDX models representing different EGFR and HER3 expressing levels and mutations. Importantly, PM1300 exhibited a good safety profile in NHP consistent with the optimal affinity for EGFR and HER3. These results demonstrate that PM1300 has a promising efficacy/safety therapeutical window in preclinical models supporting further development in the clinic. Conclusion: A bispecific ADC targeting EGFR x HER3 was discovered, named PM1300, which has an asymmetric 1+1 IgG-like structure and optimized affinity. This allows for preferential binding to EGFR/HER3 double-positive cancer cells, rather than EGFR single-positive cells. This may significantly contribute to minimizing safety risk that is common for EGFR-targeting agents. Citation Format: Liandi Chen, Shaogang Peng, Chao Wang, Xiaoniu Miao, Yao Yan, Jun Xing, Weifeng Huang, Andy Tsun, Yingda Xu, Xiaolin Liu, Yi Luo. Discovery of an asymmetric IgG-like bispecific ADC targeting EGFR/HER3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5083.

Exploring the effect of Wuzhi capsule on the pharmacokinetics of regorafenib and its main metabolites in rat plasma using liquid chromatography-tandem mass spectrometry.

Regorafenib is a small-molecule tyrosine kinase inhibitor with severe hepatotoxicity. It undergoes metabolism mainly by CYP3A4 to generate active metabolites regorafenib-N-oxide (M2) and N-desmethyl-regorafenib-N-oxide (M5). Wuzhi capsule (WZC) is an herbal preparation derived from Schisandra sphenanthera and is potentially used to prevent regorafenib-induced hepatotoxicity. This study aims to explore the effect of WZC on the pharmacokinetics of regorafenib in rats. An efficient and sensitive liquid chromatography-tandem mass spectrometry method was developed to quantitatively determine regorafenib and its main metabolites in rat plasma. The proposed method was applied to the pharmacokinetic study of regorafenib in rats, with or without WZC. Coadministration of regorafenib with WZC resulted in a prolonged mean residence time (MRT) of the parent drug but had no statistically significant difference in other pharmacokinetic parameters. While for the main metabolites of regorafenib, WZC decreased the area under the curve and maximum concentration (Cmax ), delayed the time to reach Cmax , and prolonged the MRT of M2 and M5. These results indicate that WZC delayed and inhibited the metabolism of regorafenib to M2 and M5 by suppressing CYP3A4. Our study provides implications for the rational use of the WZC-regorafenib combination in clinical practice.

A Multifunctional Bimetallic Nanoplatform for Synergic Local Hyperthermia and Chemotherapy Targeting HER2-Positive Breast Cancer.

Anti-HER2 (human epidermal growth factor receptor 2) therapies significantly increase the overall survival of patients with HER2-positive breast cancer. Unfortunately, a large fraction of patients may develop primary or acquired resistance. Further, a multidrug combination used to prevent this in the clinic places a significant burden on patients. To address this issue, this work develops a nanotherapeutic platform that incorporates bimetallic gold-silver hollow nanoshells (AuAg HNSs) with exceptional near-infrared (NIR) absorption capability, the small-molecule tyrosine kinase inhibitor pyrotinib (PYR), and Herceptin (HCT). This platform realizes targeted delivery of multiple therapeutic effects, including chemo-and photothermal activities, oxidative stress, and immune response. In vitro assays reveal that the HCT-modified nanoparticles exhibit specific recognition ability and effective internalization by cells. The released PYR inhibit cell proliferation by downregulating HER2 and its associated pathways. NIR laser application induces a photothermal effect and tumor cell apoptosis, whereas an intracellular reactive oxygen species burst amplifies oxidative stress and triggers cancer cell ferroptosis. Importantly, this multimodal therapy also promotes the upregulation of genes related to TNF and NF-κB signaling pathways, enhancing immune activation and immunogenic cell death. In vivo studies confirm a significant reduction in tumor volume after treatment, substantiating the potential effectiveness of these nanocarriers.

ELK1/MTOR/S6K1 Pathway Contributes to Acquired Resistance to Gefitinib in Non-Small Cell Lung Cancer.

The development of acquired resistance to small molecule tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) signaling has hindered their efficacy in treating non-small cell lung cancer (NSCLC) patients. Our previous study showed that constitutive activation of the 70 kDa ribosomal protein S6 kinase 1 (S6K1) contributes to the acquired resistance to EGFR-TKIs in NSCLC cell lines and xenograft tumors in nude mice. However, the regulatory mechanisms underlying S6K1 constitutive activation in TKI-resistant cancer cells have not yet been explored. In this study, we recapitulated this finding by taking advantage of a gefitinib-resistant patient-derived xenograft (PDX) model established through a number of passages in mice treated with increasing doses of gefitinib. The dissociated primary cells from the resistant PDX tumors (PDX-R) displayed higher levels of phosphor-S6K1 expression and were resistant to gefitinib compared to cells from passage-matched parental PDX tumors (PDX-P). Both genetic and pharmacological inhibition of S6K1 increased sensitivity to gefitinib in PDX-R cells. In addition, both total and phosphorylated mechanistic target of rapamycin kinase (MTOR) levels were upregulated in PDX-R and gefitinib-resistant PC9G cells. Knockdown of MTOR by siRNA decreased the expression levels of total and phosphor-S6K1 and increased sensitivity to gefitinib in PDX-R and PC9G cells. Moreover, a transcription factor ELK1, which has multiple predicted binding sites on the MTOR promoter, was also upregulated in PDX-R and PC9G cells, while the knockdown of ELK1 led to decreased expression of MTOR and S6K1. The chromatin immunoprecipitation (ChIP)-PCR assay showed the direct binding between ELK1 and the MTOR promoter, and the luciferase reporter assay further indicated that ELK1 could upregulate MTOR expression through tuning up its transcription. Silencing ELK1 via siRNA transfection improved the efficacy of gefitinib in PDX-R and PC9G cells. These results support the notion that activation of ELK1/MTOR/S6K1 signaling contributes to acquired resistance to gefitinib in NSCLC. The findings in this study shed new light on the mechanism for acquired EGFR-TKI resistance and provide potential novel strategies by targeting the ELK1/MTOR/S6K1 pathway.

Microvascular rarefaction caused by the NOTCH signaling pathway is a key cause of TKI-apatinib-induced hypertension and cardiac damage.

With the advancement of tumour-targeted therapy technology, the survival of cancer patients has continued to increase, and cardiovascular events have gradually become an important cause of death in cancer patients. This phenomenon occurs due to adverse cardiovascular reactions caused by the cardiovascular toxicity of antitumour therapy. Moreover, the increase in the proportion of elderly patients with cancer and cardiovascular diseases is due to the extension of life expectancy. Hypertension is the most common cardiovascular side effect of small molecule tyrosine kinase inhibitors (TKIs). The increase in blood pressure induced by TKIs and subsequent cardiovascular complications and events affect the survival and quality of life of patients and partly offset the benefits of antitumour therapy. Many studies have confirmed that in the pathogenesis of hypertension, arterioles and capillary thinness are involved in its occurrence and development. Our previous findings showing that apatinib causes microcirculation rarefaction of the superior mesenteric artery and impaired microvascular growth may inspire new therapeutic strategies for treating hypertension. Thus, by restoring microvascular development and branching patterns, total peripheral resistance and blood pressure are reduced. Therefore, exploring the key molecular targets of TKIs that inhibit the expression of angiogenic factors and elucidating the specific molecular mechanism involved are key scientific avenues for effectively promoting endothelial cell angiogenesis and achieving accurate repair of microcirculation injury in hypertension patients.

Glycaemic abnormalities induced by small molecule tryosine kinase inhibitors: a review.

In light of the expected increase in the prevalence of diabetes mellitus due to an aging population, sedentary lifestyles, an increase in obesity, and unhealthy diets, there is a need to identify potential pharmacological agents that can heighten the risk of developing diabetes. Similarly, it is equally important to also identify those agents that show blood glucose-lowering properties. Amongst these agents are tyrosine kinase inhibitors used to treat certain types of cancers. Over the last two decades, there has been an increase in the use of targeted chemotherapy for cancers such as renal cell carcinoma, chronic leukaemia, and gastrointestinal stromal tumours. Small molecule tyrosine kinase inhibitors have been at the forefront of targeted chemotherapy. Studies have shown that small molecule tyrosine kinase inhibitors can alter glycaemic control and glucose metabolism, with some demonstrating hypoglycaemic activities whilst others showing hyperglycaemic properties. The mechanism by which small molecule tyrosine kinase inhibitors cause glycaemic dysregulation is not well understood, therefore, the clinical significance of these chemotherapeutic agents on glucose handling is also poorly documented. In this review, the effort is directed at mapping mechanistic insights into the effect of various small molecule tyrosine kinase inhibitors on glycaemic dysregulation envisaged to provide a deeper understanding of these chemotherapeutic agents on glucose metabolism. Small molecule tyrosine kinase inhibitors may elicit these observed glycaemic effects through preservation of β-cell function, improving insulin sensitivity and insulin secretion. These compounds bind to a spectrum of receptors and proteins implicated in glucose regulation for example, non-receptor tyrosine kinase SRC and ABL. Then receptor tyrosine kinase EGFR, PDGFR, and FGFR.

The inhibitory effect of apatinib on different small cell lung cancer cells and in lung cancer-bearing mice and patients.

To observe the inhibitory effect of the small molecule tyrosine kinase inhibitor apatinib on small cell lung cancer in vitro and vivo. Three small lung cancer cells were selected CCK-8 and monoclonal assay was used to determine the effect of apatinib on proliferation. The effects on cell cycle and apoptosis were detected by flow cytometry and TUNEL. We observed the inhibitory effect of different doses of apatinib on xenograft tumor. The efficacy and safety of apatinib in 20 patients with advanced small cell lung cancer were observed. For small cell lung cancer with high expression of VEGFR2, apatinib has a significant inhibitory effect both in vitro and in vivo. It can play an inhibitory role by promoting apoptosis and cell cycle arrest pathways. For small cell lung cancer with low expression of VEGFR, the inhibitory effect on cells in vitro was not significant. It has certain inhibitory effect on nude mouse transplanted tumor and small cell lung cancer patients, but the effect is weaker than that of animal models and patients with small cell lung cancer cells with high expression of VEGFR2. Apatinib has a significant inhibitory effect on small cell lung cancer with high expression of VEGFR2 and may be a treatment for small cell lung cancer patients.

Camrelizumab combined with apatinib for unresectable, metastatic esophageal squamous cell carcinoma: a single-center, single-arm, prospective study.

The prognosis for esophageal cancer (EC), a common malignant tumor, is poor. The new oral small-molecule tyrosine kinase inhibitor apatinib has shown an excellent therapeutic effect on treating EC. Camrelizumab is a humanized programmed death 1 (PD-1) inhibitor with high affinity. Immune checkpoint inhibitors combined with chemotherapy have become the standard first-line treatment for advanced EC. The new combination strategy of anti-angiogenic therapy combined with immunotherapy has great application prospects in the treatment of tumors. We aimed to assess camrelizumab in combination with apatinib as a new combination regimen for advanced or metastatic esophageal squamous cell carcinoma (ESCC). In this study, we recruited patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, with pathologically confirmed unresectable, locally advanced, locally recurrent, or metastatic ESCC. Each patient received an intravenous infusion of camrelizumab 200 mg and oral administration of apatinib 250 mg once a day, every 21 days, as a cycle until disease progression, intolerance, or death. The primary endpoint was the objective response rate (ORR), while the Kaplan-Meier method and LIFETEST procedure were used to estimate survival functions for overall survival (OS) and progression-free survival (PFS). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used to evaluate adverse events. Between December 1, 2019 and July 31, 2022, 35 patients were enrolled, with 29 patients in the efficacy and safety analysis. The ORR was 34.5%, and the disease control rate (DCR) reached 82.8%. Median OS was 13.8 months (95% CI: 11.2-16.2), and the estimated 6-, 9-, and 12-month OS rates were 85.5% (95% CI: 65.7-94.3%), 80.9% (95% CI: 60.3-91.5%), and 67.0% (95% CI: 43.8-82.4%), respectively. Median PFS was 9.5 months (95% CI: 7.0-13.6). The most prominent grade ≥3 adverse events associated with treatments were alanine aminotransferase (ALT) increase (10.3%), hypertension (10.3%), and reactive cutaneous capillary endothelial proliferation (CCEP) (6.9%), and no deaths occurred due to adverse events. Among patients with advanced or metastatic ESCC, camrelizumab combined with apatinib showed a reasonable remission rate and survival benefit with a manageable safety profile.

Preliminary results of a phase II study of surufatinib plus sintilimab, nab-paclitaxel and gemcitabine (AG) as first-line therapy in patients (pts) with locally advanced or metastatic pancreatic adenocarcinoma (mPDAC).

659 Background: Advanced pancreatic adenocarcinoma (PDAC) had poor survival and limited therapeutic options. Surufatinib is a potent, small-molecule tyrosine kinase inhibitor (TKI), selectively targeting VEGF receptors (VEGFR) 1, 2, and 3, FGFR 1, and CSF-1R. Recent studies showed that small molecule anti-vascular inhibitor combined with a PD-1 inhibitor exhibited encouraging efficacy in PDAC. This study is to assess the efficacy and safety of surufatinib plus sintilimab (an anti-PD-1 antibody),nab-paclitaxel and gemcitabine(AG) as first-line therapy for mPDAC pts. Here we report the preliminary results. Methods: Eligible pts ≥18 years old with histologically confirmed mPDAC, ECOG PS 0-1, with at least one measurable lesion were enrolled. Pts received surufatinib (250mg, orally daily), sintilimab (200mg, I.V., D1, Q3W), nab-paclitaxel (125mg/m2, I.V., D1, D8, Q3W) and gemcitabine (1000mg/m2,I.V.,D1, D8, Q3W). Based on Simon’s Two-stage design, 11 patients would be enrolled in stage 1; if 3 or more responses were observed, the trial would continue to stage 2, and additional 21 patients would be enrolled. The total sample size was 32. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. Results: At cutoff date of Aug 25, 2023, 15 pts were enrolled and received at least one time treatment. Median age was 60 years (range 45-68), male 53.3%, ECOG PS 1 100%, 66.7% of pts had more than 3 sites of metastasis. The most common metastatic sites were lymph nodes (66.7%) and liver (60.0%). 12 pts had received at least one tumor assessment. Six out of 11 evaluable pts responded during stage 1, allowing for enrollment to continue with a planned 21 additional patients in stage 2. Eight pts achieved partial response (PR), 3 pts achieved stable disease (SD), and the confirmed ORR (c-ORR) was 50.0% (6/12) (95% confidence interval [CI]: 21.1-78.9), and the DCR was 91.7% (11/12) (95% CI: 61.5-99.8). The median time to response (TTR) was 2.95 months (95% CI: 2.79-3.06), and median PFS was not reached yet. 15 pts underwent safety evaluation. The most common AEs of all grades were white blood cell count decreased (66.7%), neutrophil count decreased (60.0%), and anemia (53.3%), and grades ≥ 3 were blood cell count decreased (33.3%), neutrophil count decreased (33.3%), and diarrhea (13.3%). Conclusions: Surufatinib plus sintilimab, along with AG showed preliminary anti-tumor activity and manageable toxicity for the 1L treatment of mPDAC. This trial is ongoing and warrants further exploration in mPDAC. Clinical trial information: NCT05481476 .

Fruquintinib with PD-1 inhibitors versus fruquintinib monotherapy in late-line mCRC: A retrospective cohort study based on propensity score matching.

139 Background: Immune checkpoint inhibitors (ICIs) are highly effective in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC). However, the population of MSI-H/dMMR only accounts for 5% of mCRC. And most of the remaining microsatellite stable or proficient mismatch repair (MSS/pMMR) mCRC patients appeared not to benefit from mere immunotherapy. Fruquintinib, as the standard third-line regimen for mCRC, is an oral small-molecule anti-angiogenic tyrosine kinase inhibitor. Studies demonstrated that fruquintinib combined with programmed death receptor-1 (PD-1) inhibitors (FP) can reverse the immunosuppression and achieve promising efficacy. However, due to the lack of the research comparing the efficacy between fruquintinib monotherapy (FM) and FP, it remains unclear if FP can bring extra benefit. Methods: This is a retrospective cohort study conducted in the First Affiliated Hospital of Zhengzhou University. Patients (pts) with MSS/pMMR mCRC who had received at least the 2nd line treatment were eligible. Propensity score (PS) would be calculated to balance the baseline characteristics of two cohorts. Progression-Free survival (PFS) was set as the primary endpoint. The Kaplan–Meier method and Cox proportional hazard model was used to evaluate PFS and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: From Apr 2020 to Jan 2023, 83 eligible pts in total were enrolled. According to the treatment received, 47 and 36 pts were respectively allocated into FP cohort and FM cohort. With a global median follow-up of 16.5 mo, the crude PFS was 6.8 (95% CI: 4.3-11.3) mo in FP cohort vs. 3.9 (3.1-4.7) mo in FM cohort. The HR of FP was 0.58 (95% CI: 0.34-0.98, FM as reference). Multivariate Cox regression showed that the adjusted HR was 0.49 (95% CI: 0.26-0.93), which was adjusted with sex, age greater than 65 yr, ECOG-PS, RAS mutation, BRAF mutation, location of lesion (left or right), surgery history, metastases (liver and lung), prior medication (bevacizumab and cetuximab), and current line (3 or later). With PS, we performed three statistical methods, namely inverse probability weighting, PS matching (the sample size was 37 vs. 29 after matching), and additional adjustment for propensity score with multivariate cox regression. The HR of FP were 0.49 (95% CI: 0.26-0.94), 0.40 (95% CI: 0.21-0.77), and 0.46 (95% CI: 0.24-0.90), respectively. Conclusions: Pts in FP cohort showed a significantly greater PFS than those in FM cohort. And with further analysis, FP indicated robustly lower HRs than FM. Our study suggests FP could provide additional benefits to pts with MSS/pMMR mCRC, and warrants further investigations in a large cohort.

Regorafenib: A comprehensive drug profile.

Regorafenib is a small molecule tyrosine kinase inhibitor administered orally drug, act by inhibiting the activity of the VEGF receptors. It is used for the treatment of patients with metastatic colorectal cancer (CRC), advanced gastrointestinal stromal tumors, and hepatocellular carcinoma. This comprehensive profile on regorafenib includes an original data as well as data collected from the literature on Profiles of Methods of Drug Synthesis, different Physical Drug Profiles, Drug Analytical methods and Pharmacological profile (ADME). This chapter is divided into five main sections: General Description of the drug, Physical Characteristics, Methods of Preparation, Methods of Analysis, Pharmacology and List of References. These main sections are further divided to many sub-titles to cover most aspect of the drug in the light of the available literature. Among these sub-titles are the formulae, Elemental Analysis, physical characteristics which include constant of ionization, solubility, X-ray powder diffraction pattern, TGA, thermal conduct and spectroscopic and stability. Additionally, analytical techniques including Electrochemical, Spectrophotometric and chromatographic methods, ADME profiles and pharmacological effects were also discussed. Furthermore, methods and schemes are outlined for the preparation of the drug substance.

Combined use of Anlotinib with chemotherapy in patients with advanced ovarian cancer: a real-world cohort study and meta-analysis.

Anlotinib is a novel oral small-molecule receptor tyrosine kinase inhibitor. However, the efficacy and safety of its combined use with chemotherapy remain unclear in patients with advanced ovarian cancer. To assess the efficacy and safety of the combined use of Anlotinib with chemotherapy in patients with advanced ovarian cancer. A multi-center retrospective real-world analysis and a meta-analysis. We enrolled patients with advanced ovarian cancer who received a combination therapy of Anlotinib and chemotherapy from 15 medical centers. We also searched electronic databases for studies assessing the efficacy and safety of the combined use of Anlotinib with chemotherapy in patients with ovarian cancer. The outcomes of interest included objective response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS). A total of 71 patients, who were predominantly recurrent cases, were included in the real-world study. The ORR and DCR of the included patients were 40.8% and 76.1%, respectively; and their mPFS was 4.6 months. The log-rank test showed that previous antiangiogenic therapy was related to a longer mPFS (p < 0.05). Five studies in total were eligible for meta-analysis. The random-effects meta-analysis model showed that the ORR, DCR, and mPFS were 33.8% [95% confidence interval (CI) 22.7-44.8% from four studies], 90.6% (95% CI 73.6-99.9% from five studies), and 6.6 months (95% CI 4.9-8.4 months from five studies). The most common adverse events were hand-foot syndrome and hypertension. The combined use of Anlotinib with chemotherapy showed potential in treating patients with advanced ovarian cancer, with a tolerable safety profile.

Comparison of Efficacy and Safety of Imatinib and Dasatinib in the Treatment of Chronic-phase Chronic Myeloid Leukemia

Chronic-phase chronic myeloid leukemia (CML-CP) treatment has significantly improved in recent years. The generational development of small molecule tyrosine kinase inhibitors (TKIs) such as Imatinib and Dasatinib, has revolutionized the treatment of CML. Their mechanisms and efficacy have been clear, but there is no literature review to summarize or comprehensively compare their efficacy and safety. Studies have revealed that second-generation TKI therapy yields noticeably greater response rates than imatinib and there is no marked difference in treatment-related adverse events between the two therapies. According to this direction, A double-therapies analysis was performed to assess the efficacy and tolerability of various front-line treatments for individuals with CML-CP. Both direct and indirect comparisons between the various treatment choices were taken into account in this general analysis. The author took Imatinib and Dasatinib as the main comparison objects and provide a comprehensive assessment of the two available therapies for CML-CP. By comparing the efficacy outcomes and adverse effects (AEs), the study was aimed to identify the treatment options that are both highly effective and well-tolerated for patients in general.

TARGETING EPIDERMAL GROWTH FACTOR RECEPTOR FOR CANCER TREATMENT

The Epidermal Growth Factor Receptor (EGFR) is a pivotal player in cellular signalling pathways and its dysregulation is implicated in various cancers. Targeting EGFR has emerged as a promising strategy for cancer treatment. This abstract provides Comprehensive analysis of EGFR-targeted therapies, including small molecule tyrosine kinase inhibitors and monoclonal antibodies, reveals their efficacy in suppressing aberrant signalling cascades associated with tumor growth. Mechanisms of resistance, biomarkers for patient stratification, and ongoing clinical trials are discussed to highlight the evolving landscape of EGFR-targeted cancer therapies. The multifaceted nature of EGFR signaling necessitates a personalized approach, emphasizing the need for precision medicine to optimize therapeutic outcomes. This abstract encapsulates the significance and challenges of targeting EGFR for cancer treatment, providing a foundation for further research and clinical advancements in the field. KEYWORDS: Epidermal Growth Factor Receptor (EGFR), Cancer Treatment, Tyrosine Kinase Inhibitors, Monoclonal Antibodies, Biomarkers, Precision Medicine

Abstract C036: A Phase 1 Study to assess BDTX-1535, an oral EGFR inhibitor, in patients with Glioblastoma or Non-Small Cell Lung Cancer

Abstract Background: Epidermal growth factor receptor (EGFR) is a potent oncogene commonly altered in non-small cell lung cancer (NSCLC) and glioblastoma (rGBM). For NSCLC, EGFR tyrosine kinase activity can be driven by classical driver, intrinsic driver, and acquired resistance mutations. BDTX-1535 is an orally available, highly potent, brain penetrant, selective, irreversible small molecule tyrosine kinase inhibitor that targets all 3 classes of EGFR mutations. Preclinical data demonstrated the ability of BDTX-1535 to cross the blood-brain barrier and produce sustained inhibition of EGFR signaling. Methods: BDTX-1535-101 (NCT05256290) is a Phase 1, open-label, multicenter study to assess the safety, tolerability, pharmacokinetics (PK), central nervous system (CNS) activity, and preliminary antitumor activity of BDTX-1535 in locally advanced or metastatic NSCLC with or without CNS disease or recurrent GBM (rGBM). The primary objective is to determine the BDTX-1535 recommended Phase 2 dose (RP2D) based on the overall safety, PK, pharmacodynamic, and preliminary antitumor activity. The monotherapy dose escalation portion evaluates BDTX-1535 in patients with locally advanced/metastatic NSCLC harboring intrinsic driver EGFR mutations following standard of care or with acquired resistance EGFR mutations following a 3rd generation EGFR inhibitor in the 1st line setting, in addition to patients with rGBM expressing EGFR alterations who previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). A capsule-to-tablet bridging cohort and a food effect cohort will also be assessed. Following the establishment of a preliminary recommended Phase 2 dose (RP2D), the disease-specific expansion portion of the study will further evaluate the safety, tolerability, and preliminary antitumor effect of BDTX-1535. Cohorts include the following:1) advanced/metastatic NSCLC with intrinsic resistance EGFR mutations following up to 2 lines of therapy, one of which must be an EGFR inhibitor treatment, 2) advanced/metastatic NSCLC with acquired resistance EGFR mutation following a 3rd generation EGFR inhibitor in the first line setting, 3) rGBM with confirmed EGFR alterations with or without amplifications. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M. BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with newly diagnosed GBM harboring EGFR alterations. Enrollment was initiated in 2022 and dose escalation is almost complete. Initiation of the dose expansion cohorts of NSCLC patients with EGFR acquired resistance and intrinsic driver mutations after progression on prior EGFR inhibitor is planned for the second half of 2023. For additional information, please contact ClinicalTrials@bdtx.com. Citation Format: Helena Yu, Melissa Johnson, Jason T Henry, Alex Spira, Ji-Youn Han, Minal Barve, James Battiste, Iyad Alnahhas, DoHyun Nam, Jeffrey Edenfield, Balazs Halmos, Shinkyo Yoon, Tae Min Kim, Sudharshan Eathiraj, Julio Hajdenberg, Sergey Yurasov, Manmeet Ahluwalia, Patrick Wen. A Phase 1 Study to assess BDTX-1535, an oral EGFR inhibitor, in patients with Glioblastoma or Non-Small Cell Lung Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C036.