Small Molecule Tyrosine Kinase Inhibitors Research Articles

From Anti-HER-2 to Anti-HER-2-CAR-T Cells: An Evolutionary Immunotherapy Approach for Gastric Cancer

Current Therapeutic modalities provide no survival advantage to gastric cancer (GC) patients. Targeting the human epidermal growth factor receptor-2 (HER-2) is a viable therapeutic strategy against advanced HER-2 positive GC. Antibody-drug conjugates, small-molecule tyrosine kinase inhibitors (TKIs), and bispecific antibodies are emerging as novel drug forms that may abrogate the resistance to HER-2-specific drugs and monoclonal antibodies. Chimeric antigen receptor-modified T cells (CAR-T) targeting HER-2 have shown considerable therapeutic potential in GC and other solid tumors. However, due to the high heterogeneity along with the complex tumor microenvironment (TME) of GC that often leads to immune escape, the immunological treatment of GC still faces many challenges. Here, we reviewed and discussed the current progress in the research of anti-HER-2-CAR-T cell immunotherapy against GC.

Apatinib Through Activating the RhoA/ROCK Signaling Pathway to Cause Dysfunction of Vascular Smooth Muscle Cells.

Vascular smooth muscle cells (VSMCs) are associated with differentiated, organized, and contractile phenotype under the effect of various types of physiological conditions those are associated with migratory, proliferative, and synthetic phenotype under the effect of various types of stimuli, which dysfunction drives many cardiovascular diseases. Abnormal cell proliferation and invasion of VSMCs are among the primary causes of hypertension. Apatinib is a small-molecule tyrosine kinase inhibitor (TKI) that highly selectively binds to and strongly inhibits VEGFR-2. Previous studies have confirmed that the TKIs can raise blood pressure through RhoA/ROCK pathway. LARG is a key gene in the RhoA/ROCK pathway and plays a critical role in the continuous vasoconstriction function because it regulates part of signal transduction in VSMCs. In this study, an in vitro experiment was conducted to observe that apatinib caused dysfunction of MOVAS cells through the RhoA/ROCK signalling pathway and Y27632, a nonspecific ROCK inhibitor, and knockout of LARG gene can improve the proliferation, antiapoptosis, oxidative stress, and mitochondrial autophagy of apatinib-induced MOVAS cells. These findings suggest that activation of the RhoA/ROCK signalling pathway could be the underlying mechanism of apatinib-induced dysfunction of MOVAS cells, while ROCK inhibitor and knockout of LARG gene have potential therapeutic value.

Infigratinib for cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a serious and often fatal cancer of the bile ducts of the liver with a 5-year survival rate of 5-15%. At the time of diagnosis, most patients present with advanced or metastatic CCA, which is an aggressive malignancy with a poor prognosis. The standard of care for patients with locally advanced or metastatic CCA includes systemic chemotherapy with gemcitabine and cisplatin. Recently, research in the molecular basis of cancer has led to the discovery of underlying gene alterations, allowing the development of targeted therapies. Here we provide a review of infigratinib, which is an oral small-molecule tyrosine kinase inhibitor targeting fibroblast growth factor receptor (FGFR). On the basis of positive phase II efficacy data, infigratinib received accelerated approval from the U.S. Food and Drug Administration (FDA) for adults with previously treated, unresectable locally advanced or metastatic CCA with an FGFR2 fusion or other rearrangement.

Role of ErbB1 in the Underlying Mechanism of Lapatinib-Induced Diarrhoea: A Review.

Lapatinib, an orally administered small-molecule tyrosine kinase inhibitor (SM-TKI), is an effective treatment for ErbB2-positive breast cancer. However, its efficacy as one of the targeted cancer therapies has been hampered by several adverse effects, especially gastrointestinal toxicity, commonly manifested as diarrhoea. Although it can be generally tolerated, diarrhoea is reported as the most common and most impactful on a patient's quality of life and associated with treatment interruption. Severe diarrhoea can result in malabsorption, leading to dehydration, fatigue, and even death. ErbB1 is an epidermal growth factor profoundly expressed in normal gut epithelium while lapatinib is a dual ErbB1/ErbB2 tyrosine kinase inhibitor. Thus, ErbB1 inhibition by lapatinib may affect gut homeostasis leading to diarrhoea. Nevertheless, the underlying mechanisms remain unclear. This review article provides evidence of the possible mechanisms of lapatinib-induced diarrhoea that may be related to/or modulated by ErbB1. Insight regarding the involvement of ErbB1 in the pathophysiological changes such as inflammation and intestinal permeability as the underlying cause of diarrhoea is covered in this article.

P710: CLINICAL STUDY ON THE RELATIONSHIP BETWEEN NON-ABL1 KINASE REGION MUTATION AND TKI DRUG RESISTANCE AND DISEASE PROGRESSION IN CHRONIC MYELOID LEUKEMIA

Background: The emergence of small molecule tyrosine kinase inhibitors (The Tyrosine Kinase Inhibitors, TKI) has gradually transformed chronic myelocytic leukemia (CML) from a fatal malignant disease into a chronic disease, while ABL1 kinase Kinase Domain (KD) mutation is the main reason for poor efficacy or resistance to TKIs. In recent years, with the clinical application of Next Generation Sequencing (NGS) technology, it has been found that CML patients are often accompanied by non-ABL1 kinase region gene mutations, but whether these accompanying mutations are related to the efficacy of TKIs and disease progression in CML? still uncertain. This study retrospectively analyzed the correlation between CML with non-ABL1 KD mutation and TKI efficacy and disease progression, in order to provide basis and scientific guidance for further accurate diagnosis and treatment of CML patients. Aims: To investigate the relationship between CML associated with non ABL1 Kinase Domain (KD) mutation and TKI efficacy and disease progression. Methods: 108 blood tumor related genes in 120 patients with CML were detected by Next-generation sequencing (NGS). The non ABL1 KD mutations and their relationship with relevant clinical information and ABL1 KD mutation were analyzed. Results: Non ABL1KD mutations were detected in 58 patients (48%), and the mutation proportion of patients with additional chromosome abnormalities (63%) was significantly higher than that of patients without additional chromosome abnormalities (34%) (P=0.003). In the analysis of mutation proportion in patients with different stages of CML, the mutation proportion in blastic phase(73%), accelerated phase (67%) and chronic phase (42%) decreased gradually (P=0.031). The proportion of WT1 mutation and transcriptional regulation related mutations in patients with AP CML (WT1+: 17%, P=0.027; Transcriptional regulatory mutations 42%, P=0.001) were higher than those in CP. In the analysis of TKI treatment response, the proportion of mutations detected in the best response group (30%), warning group (52%) and drug resistance group (61%) increased gradually (P=0.018). The proportion of RUNX1 mutation in TKI treatment failure group (17%) was higher than that in warning group (2%) (P=0.029). The proportion of ABL1 KD mutation in CML patients with non ABL1 KD mutation (60%) was significantly higher than that in patients without non ABL1 KD mutation (36%) (P=0.022). Summary/Conclusion: Non ABL1 KD mutations are closely related to TKI efficacy and disease progression, while WT1 and RUNX1 mutations may be new molecular targets for accurate diagnosis of CML.

Abstract LB077: Reengineering ponatinib to minimize cardiovascular toxicity

Abstract Introduction and Purpose of the Study: The advent of small molecule Tyrosine Kinase Inhibitors (TKIs) has revolutionized cancer treatment and greatly improved patient survival. However, the life-threatening cardiovascular toxicity of many TKIs present major concerns. Ponatinib is the most effective treatment for patients harboring the common T315I mutation of BCR-ABL that drives Chronic Myeloid Leukemia (CML) yet is one of the most cardiotoxic of TKIs. Ponatinib-induced events include myocardial infarction, heart failure, stroke, peripheral vascular disease and venous thrombosis. The aim of this study is to reengineer the chemical structure of ponatinib to minimize its adverse cardiovascular effects by using in vitro and in vivo models of cardiovascular toxicity. Experimental Procedures: We developed in vitro cardiovascular toxicity assays using human iPSC-cardiomyocytes (hiPSC-CMs) and human microvascular endothelial cells (HMVECs), and assessed anti-tumor efficacy in T315I mutated K562 CML cells. The cardiotoxicity was determined by impairment of cardiomyocyte contractility function, the vascular toxicity was defined by inability to form capillary-like networks in vasculogenesis assays. In vitro screening of ponatinib analogues probed chemical moieties responsible for its cardiovascular toxicity that were confirmed using mice xenograft mice models with human T315I mutant K562 cells. Summary of Unpublished Data: Compared to ponatinib, refined analogues showed markedly decreased adverse effects on HMVECs vasculogenesis and hiPSC-CMs contractility in vitro. The therapeutic window was increased in vivo, leading to regression of human T315I mutant CML xenografts comparable to ponatinib but without increasing serum levels of cardiac troponin. The kinase inhibition profiles of the “safe” analogues compared to ponatinib identified candidate mediators of ponatinib-induced toxicity. Validation by selective knockdown revealed likely mediators of cardiotoxicity, including FGFR. Conclusions: We succeeded in engineering a cardiovascular safe TKI that retained effective therapeutic properties against BCR-ABL T351 mutated form of CML, but with substantially decreased cardiovascular toxicity. Citation Format: Anna Pavlovna Hnatiuk, Arne A. Bruyneel, Dhanir Taylor, Mallesh Pandrala, Arpit Dheeraj, Wendy Li, Ricardo Serrano Fernandez, Dries A. Feyen, Michelle M. Wu, Prashila Amatya, Isabel Morgado, Volker Wiebking, Matthew H. Porteus, Sanjay Malhotra, Mark Mercola. Reengineering ponatinib to minimize cardiovascular toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB077.

Abstract LB515A: A MET targeting biparatopic antibody-drug conjugates (ADC), REGN5093-M114, has an antitumor efficacy in NSCLC harboring MET gene alterations

Abstract Introduction: Aberrations in MET occurs frequently in non-small cell lung cancer (NSCLC), via MET amplification or MET exon 14 skipping (METex14) mutation. Small-molecule tyrosine kinase inhibitors (TKIs) targeting MET have been developed, but durable response is invariably limited by the emergence of acquired resistance. In this study, we examined the preclinical activity of a MET x MET biparatopic antibody to a novel maytansinoid payload, REGN5093-M114, in MET-driven patient-derived models. Experimental Design: We had previously established patient-derived models from EGFR-TKIs resistant patients with MET-amplified or -overexpressed EGFR-mutant NSCLC. Patient-derived organoids (PDOs), patient-derived cells (PDCs), or ATCC cell lines were used for cell viability, apoptosis assay and western blots to investigate the activity of REGN5093-M114. In order to explore the predictive biomarker correlates of REGN5093-M114 and MET status, we investigated whole MET expression, surface MET expression by flow cytometry, MET amplification by copy number analysis. We evaluated the antitumor activity of REGN5093-M114 in patient-derived tumor xenograft (PDX) models from EGFR-mutant NSCLC patients with acquired resistance to osimertinib plus savolitinib, including acquired MET p.Y1230C mutation. Finally, we determined whether REGN5093-M114 is able to overcome acquired resistance to the MET-TKI, tepotinib, using PDC from METex14 mutant NSCLC patients. Result: In acquired MET-amplified EGFR-TKI resistant PDCs, PDOs, ATCC cell lines and PDX models, REGN5093-M114 alone exhibited a significant antitumor efficacy compared to MET-TKI or the MET x MET biparatopic antibody (REGN5093), but had no effect on some models with same MET copy number as the sensitive models. On the other hand, regardless of MET CNV, MET-overexpressed TKI-naïve EGFR mutant NSCLC cells showed a sensitive response to REGN5093-M114. Thus, we calculated the area under the curve plot for REGN5093-M114 by quantifying whole MET expression, surface MET expression, and MET CNV values for each cell line. As a result, the surface MET expression had the most predictive power on determining the efficacy of the REGN5093-M114. Notably, REGN5093-M114 potently reduced tumor growth of EGFR mutant NSCLC with PTEN loss or MET Y1230C mutation after progression on prior TATTON study. Furthermore, we demonstrated that the combined treatment of MET-TKI and REGN5093-M114 shows synergistic antitumor efficacy with a marked reduction of MET downstream signals and increased apoptotic proteins in the METex14 mutant NSCLC. Altogether, REGN5093-M114 is a potent candidate to overcome the current challenges faced in targeting MET pathway. Conclusion: REGN5093-M114 has the potential to be a novel therapeutic option in NSCLC harboring MET genetic alterations, and further clinical application is highly warranted. Citation Format: Seung Yeon Oh, Sun Min Lim, You Won Lee, Eun Ji Lee, Jae Hwan Kim, Seong Gu Heo, Mi Ra Yu, Min Hee Hong, Hye Ryun Kim, John DaSilva, Christopher Daly, Mi Ran Yun, Byoung Chul Cho. A MET targeting biparatopic antibody-drug conjugates (ADC), REGN5093-M114, has an antitumor efficacy in NSCLC harboring MET gene alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB515A.

BMS to buy Turning Point for $4.1 billion

Bristol Myers Squibb has agreed to buy Turning Point Therapeutics in a deal valued at $4.1 billion. Turning Point’s lead drug candidate, repotrectinib, is a small-molecule tyrosine kinase inhibitor (TKI) for patients with ROS1 -positive advanced non-small-cell lung cancer (NSCLC) and other cancers. The drug would compete with Pfizer’s Xalkori and Roche’s Rozlytrek, both approved by the US Food and Drug administration to treat metastatic ROS1 -positive NSCLC. Receptor tyrosine kinases are proteins that are part of cellular signaling cascades, and their dysfunction is known to be behind many types of cancer. TKIs treat tumors by targeting these malfunctioning proteins. In the case of ROS1-positive NSCLC, the receptor tyrosine kinase–encoding gene ROS1 fuses with another gene, and the resulting kinase becomes a driver of cancer cell growth. Repotrectinib was designed to nestle into the ATP binding pocket of that kinase, preventing ATP binding and blocking the signal cascade that allows

Aumolertinib plus apatinib versus aumolertinib as first-line treatment in patients with EGFR mutation–positive locally advanced or metastatic non–small cell lung cancer (NSCLC).

TPS9151 Background: Currently, EGFR-TKIs are widely accepted as the standard treatment for EGFR-mutant advanced NSCLC; however, acquired resistance is inevitable. Preclinical and clinical evidence has demonstrated that dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutant advanced NSCLC population to overcome the resistance to EGFR-TKIs. Aumolertinib (HS-10296) is a novel, third-generation EGFR-TKI approved in China to treat EGFR mutation positive non-small cell lung cancer. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for NSCLC. Here, we aimed to evaluate the safety and anticancer activity of aumolertinib alone/with apatinib for advanced/metastatic NSCLC patients with EGFR mutation. Methods: The phase III, multicenter, randomized, open-label, controlled study is evaluating the efficacy and safety of aumolertinib plus apatinib versus aumolertinib alone as first line therapy in adult patients with EGFR+ NSCLC. Adult patients with histologically confirmed stage IIIB/IV NSCLC harboring EGFR mutations without prior EGFR TKI treatment are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 300 patients, which will be randomized (1:1) to receive oral aumolertinib once daily 110 mg or adding apatinib 250 mg a day until assessed progressive disease(PD)，stratified by EGFR mutation (Ex19del /L858R/others) and distant metastases sites (brain/liver/others). The primary endpoint is progression free survival assessed by investigators using Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints are disease control rate, duration of response, overall survival and safety. Adverse effects were graded per CTCAE v.4.03. This trial is registered as ChiCTR2100047453. Results: Recruiting. Conclusions: Recruiting. Clinical trial information: ChiCTR2100047453.

Pilot study to evaluate safety and efficacy of cabozantinib in aged fragile patients with metastatic renal cell carcinoma. Preliminary results of CABOMAYOR-SOGUG study.

e16524 Background: Survival of patients with metastatic renal cell carcinoma (mRCC) has improved with targeted therapies, but they are rarely curative and often result in therapeutic resistance. Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, known to influence tumor growth, metastasis, and angiogenesis. Aged fragile patients are not usually included in clinical trials and efficacy and tolerability of available treatments in this population are unknown. The aim of this trial is to evaluate safety and efficacy of cabozantinib in aged patients with mRCC. Methods: Pilot open-label, multicenter study that includes previously untreated fragile (G8 scale < 14 points and one or two reversible deficiencies in ADL-activities in daily life- or CISR-G grade 2 comorbidities or weight loss of 5-10% during the last 3 months) patients > 70 years old with histological or cytological diagnosis of mRCC, ECOG 0-2 and adequate organ function. Patients received cabozantinib 40 mg p.o. once daily until unacceptable toxicity or other reasons for treatment discontinuation. Dose can be escalated to 60 mg if 40 mg is considered tolerated and can be reduced to 20 mg if 40 mg is considered not tolerated. Results: Twenty patients are included in this interim analysis, 9 of them are still under treatment. Median age was 78 years, 70% were men and 68% had ECOG 0 and metastatic disease at diagnosis. None of them received radiotherapy. 55% of pts were vulnerable according to G8 score, 5% had grade 3 comorbidities according to CIRS-G scale, 20% had a score < 3 in mini-COG test, 100% had score < 10 in Gijon's social-familial evaluation scale, 25% were vulnerable according to Vulnerable Elders Survey 13 (score ≥3) and 45% were frail and at risk of disability according to Short Physical Performance Battery (score < 10). Median duration of treatment was 3.3 months (max. 20.4). In none of the patients was the dose escalated to 60 mg/d and in 7 patients was the dose reduced to 20 mg/d. Of the 12 patients evaluable for response, 2 achieved partial response and 7 stable disease, with a clinical benefit rate of 75%. Most frequent toxicities (all grades) were: asthenia (30%), diarrhea (25%), mucosal inflammation (15%), dysgeusia (15%) and hypothyroidism (15%). Reported grade 3 toxicities were thrombocytopenia, pyrexia and hypertension (5%). Two patients stopped study treatment due to toxicity: perforated ischemic colitis and skin toxicity. Conclusions: Safety profile in aged people is similar of that observed in previous studies. The frequency of toxicities is slightly lower than expected in this aged fragile population, probably because the patients received treatment at a dose of 40 mg/d, lower than the approved dose. Clinical trial information: NCT04134390.

P-16 PROOF 301: A multicenter, open-label, randomized, phase 3 trial of infigratinib vs gemcitabine + cisplatin in patients with advanced cholangiocarcinoma with an FGFR2 gene fusion/rearrangement

First-line treatment options are limited for patients with advanced cholangiocarcinoma (CCA). Genetic alterations in the fibroblast growth factor receptor (FGFR) gene play an important role in CCA. FGFR gene fusions/rearrangements are present in 10–16% of intrahepatic CCA and may predict tumor sensitivity to FGFR inhibitors. Infigratinib (BGJ398) is a potent, orally bioavailable, selective, ATP-competitive, small-molecule tyrosine kinase inhibitor of FGFRs that showed promising clinical activity and a manageable adverse event profile in a phase 2 study in patients with previously treated, unresectable locally advanced/metastatic CCA with an FGFR2 gene fusion/rearrangement.

Phase 2 trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ locally advanced or metastatic breast cancer with and without brain metastases (HER2CLIMB-04, trial in progress).

TPS1111 Background: Tucatinib is an oral reversible small-molecule tyrosine kinase inhibitor highly selective for human epidermal growth factor receptor 2 (HER2). Tucatinib is approved in the US for use in combination with trastuzumab and capecitabine in adult patients with HER2+ metastatic breast cancer (MBC), with and without brain metastases, who have received ≥1 prior anti–HER2-based regimens in the metastatic setting. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) comprising a HER2-directed monoclonal antibody conjugated to a topoisomerase I inhibitor payload, is also approved in the US for patients with HER2+ MBC. In HER2+ breast cancer (BC) xenograft models, tucatinib increased the antitumor activity of a HER2-directed ADC comprising a HER2-directed monoclonal antibody conjugated with 8 exatecan moieties (T-Ex) when compared to T-Ex alone (Kulukian et al 2019). While significant advances have been made in the treatment of patients with HER2+ BC, treatment of metastatic disease remains a clinical challenge due to limited treatment options. Methods: HER2CLIMB-04 (NCT04539938) is a single-arm, open-label, multicenter, phase 2 study evaluating the efficacy and safety of tucatinib plus T-DXd in previously treated patients aged ≥18 years with unresectable, locally advanced, or metastatic (LA/M) HER2+ BC. Patients must have prior treatment with a taxane and trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without pertuzumab). Patients with brain metastases, including active brain metastases, may be enrolled. A safety lead-in portion of the study with 10 patients who were followed for at least 1 cycle has been completed. This portion of the study demonstrated a manageable safety profile so the trial will enroll approximately 60 response-evaluable patients (including the 10 patients from the safety lead-in), evenly distributed between patients with and without brain metastases. The primary endpoint is confirmed objective response rate (cORR) by investigator assessment per RECIST 1.1. Secondary endpoints are progression-free survival (PFS), duration of response (DOR), disease control rate (DCR) by investigator assessment per RECIST 1.1, overall survival, and safety. Exploratory endpoints will include cORR, PFS, DCR, and DOR by independent central review per RECIST 1.1, pharmacokinetic analyses, biomarker analyses, and changes in patient-reported outcomes. Efficacy and safety will be summarized with descriptive statistics. Enrollment in the US began in late 2020. Clinical trial information: NCT04539938.

PROOF 301: A multicenter, open-label, randomized, phase 3 trial of infigratinib versus gemcitabine plus cisplatin in patients with advanced cholangiocarcinoma with an FGFR2 gene fusion/rearrangement.

TPS4171 Background: First-line treatment options are limited for patients with advanced cholangiocarcinoma (CCA). Genetic alterations in the fibroblast growth factor receptor ( FGFR) gene play an important role in CCA. FGFR gene fusions/rearrangements are present in 10–16% of intrahepatic CCA and may predict tumor sensitivity to FGFR inhibitors. Infigratinib (BGJ398) is a potent, orally bioavailable, selective, ATP-competitive, small-molecule tyrosine kinase inhibitor of FGFRs that showed promising clinical activity and a manageable adverse event profile in a phase 2 study in patients with previously treated, unresectable locally advanced/metastatic CCA with an FGFR2 gene fusion/rearrangement. The multicenter, open-label, randomized, controlled phase 3 PROOF 301 trial is evaluating infigratinib vs standard-of-care gemcitabine + cisplatin as first-line treatment for patients with advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/rearrangement. Methods: Approximately 300 patients ≥18 years of age with histologically or cytologically confirmed, advanced/metastatic or inoperable CCA with an FGFR2 gene fusion/rearrangement (confirmed by central laboratory) are randomized 2:1 to oral infigratinib 125 mg once daily for the first 21 days of a 28-day treatment cycle vs intravenous standard gemcitabine (1000 mg/m2) + cisplatin (25 mg/m2) on days 1 and 8 of a 21-day cycle. Randomization will be stratified by unresectable locally advanced vs metastatic disease, geographic region, prior neoadjuvant/adjuvant treatment vs none, and receipt of up to 1 cycle of gemcitabine-based chemotherapy for unresectable locally advanced/metastatic disease prior to randomization vs none. Treatment will continue until confirmed progressive disease by blinded independent central review (BICR), intolerance, withdrawal of informed consent, or death. Patients on the gemcitabine + cisplatin arm who develop disease progression, confirmed by BICR, can cross-over to receive infigratinib. The primary endpoint is progression-free survival (PFS, RECIST v1.1), confirmed by BICR. Secondary endpoints include overall survival, PFS (investigator determined), overall response rate, best overall response, disease control rate, duration of response (BICR and investigator determined), and the type, frequency, and severity of adverse events (AEs) and serious AEs. PFS after subsequent therapy (PFS2), quality of life, pharmacokinetics and other exploratory genetic alterations/biomarkers will also be evaluated. Trial enrollment is ongoing in the US, EU, and APAC (including Australia). The Data Monitoring Committee last reviewed the trial in December 2021. Clinical trial information: NCT03773302.

The efficacy and safety of apatinib in patients with recurrent or metastatic nasopharyngeal carcinoma: a systematic review and meta-analysis.

BackgroundApatinib is a small-molecule tyrosine kinase inhibitor targeting VEGFR-2, which was recently used in a phase II clinical trial for the treatment of recurrent or metastatic nasopharyngeal carcinoma (rmNPC). However, there is no consistent conclusion on its efficacy and safety on rmNPC. This study conducted a meta-analysis of clinical research on the efficacy and safety of apatinib in the treatment of rmNPC.MethodsIn April 2022, the PubMed, Web of Science, Scopus, Chinese National Knowledge Infrastructure (CNKI), CMB, and Wanfang databases were systematically searched, and relevant research literature were screened and analyzed. The clinical trial literatures using apatinib as the main single or combined treatment for rmNPC patients were selected and combined with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and other efficacy and safety indicators.ResultsThe meta-analysis included 12 studies, including 408 patients with rmNPC. The methodological index for nonrandomized studies scale was used to evaluate the bias of the included literatures and found that the bias was low. A total of 408 rmNPC patients were included in the included literature, with 11 studies being a phase II single-arm trial and one being a phase II non-randomized controlled trial. The ORR of patients with rmNPC treated with apatinib was 41.5% (95% CI: 34.8%, 48.2%), and the DCR was 80.2% (95% CI: 70.9%, 89.6%). The median PFS was 6.4 months (95% CI: 5.3, 7.4), and the median OS was 14.8 months (95% CI: 10.7, 18.9). The incidence of hypertension, hand-foot skin reaction, and proteinuria was 31% (95% CI: 19–43%), 29% (95% CI: 20–39%), and 13% (95% CI: 6–20%), respectively.DiscussionThe efficacy of apatinib in the treatment of rmNPC patients is similar to that of the previous second-line chemotherapy drugs, but since most studies are phase II single-arm studies, the advantages and disadvantages of the existing second-line chemotherapy regimens cannot be determined.

Apatinib Induces Ferroptosis of Glioma Cells through Modulation of the VEGFR2/Nrf2 Pathway.

Background Glioma is a common tumor that originated from the brain, and molecular targeted therapy is one of the important treatment modalities of glioma. Apatinib is a small-molecule tyrosine kinase inhibitor, which is widely used for the treatment of glioma. However, the underlying molecular mechanism has remained elusive. Recently, emerging evidence has proved the remarkable anticancer effects of ferroptosis. In this study, a new ferroptosis-related mechanism of apatinib inhibiting proliferation of glioma cells was investigated, which facilitated further study on inhibitory effects of apatinib on cancer cells. Methods Human glioma U251 and U87 cell lines and normal astrocytes were treated with apatinib. Ferroptosis, cell cycle, apoptosis, and proliferation were determined. A nude mouse xenograft model was constructed, and tumor growth rate was detected. Tumor tissues were collected to estimate ferroptosis levels and to identify the relevant pathways after treatment with apatinib. Results Treatment with apatinib could induce loss of cell viability of glioma cells, but not of normal astrocytes, through eliciting ferroptosis in vitro and in vivo. It was also revealed that apatinib triggered ferroptosis of glioma cells via inhibiting the activation of nuclear factor erythroid 2-related factor 2/vascular endothelial growth factor receptor 2 (Nrf2/VEFGR2) pathway. The overexpression of Nrf2 rescued the therapeutic effects of apatinib. Conclusion Our study proved that treatment with apatinib could restrain proliferation of glioma cells through induction of ferroptosis via inhibiting the activation of VEGFR2/Nrf2/Keap1 pathway. Overexpression of Nrf2 could counteract the induction of ferroptosis by apatinib.

Recent Advances of Autophagy in Non-Small Cell Lung Cancer: From Basic Mechanisms to Clinical Application

Lung cancer is characterized by the most common oncological disease and leading cause of cancer death worldwide, of which a group of subtypes known as non-small cell lung cancer (NSCLC) accounts for approximately 85%. In the past few decades, important progression in the therapies of NSCLC has enhanced our understanding of the biology and progression mechanisms of tumor. The application of immunotherapy and small molecule tyrosine kinase inhibitors has brought significant clinical benefits in certain patients. However, early metastasis and the emergence of resistance to antitumor therapy have resulted in the relatively low overall cure and survival rates for NSCLC. Autophagy is a conserved process that allows cells to recycle unused or damaged organelles and cellular components. It has been reported to be related to the progression of NSCLC and resistance to targeted therapy and cytotoxic chemotherapy. Therefore, autophagy is considered as a potential therapeutic target for NSCLC. Mounting results have been reported about the combination of tyrosine kinase inhibitors and inhibitors of autophagy in models of NSCLC. This review aims to provide a comprehensive review on the roles of autophagy in NSCLC, focusing on related clinical data of agents that regulate autophagy in NSCLC. Furthermore, this study will provide a theoretical basis for further improvement of autophagy-based cancer therapy.

Antibiotic use reduces efficacy of tyrosine kinase inhibitors in patients with advanced melanoma and non-small-cell lung cancer

BackgroundAntibiotic (ABX) use can reduce the efficacy of immune checkpoint inhibitors and chemotherapeutics. The effect for patients treated with targeted therapies, namely, small-molecule tyrosine kinase inhibitors (TKIs), is less known.Patients and methodsRetrospective data were analysed for TKI-treated patients with advanced melanoma and non-small-cell lung cancer (NSCLC) between January 2015 and April 2017 at The Christie NHS Foundation Trust. Data on demographics, disease burden, lactate dehydrogenase (LDH) level, presence of brain metastases, ECOG performance status (PS) and ABX use were collected. Progression-free survival (PFS) and overall survival (OS) were compared between the ABX+ group (ABX within 2 weeks of TKI initiation-6 weeks after) and the ABX– group (no ABX during the same period).ResultsA total of 168 patients were included; 89 (53%) with NSCLC and 79 (47%) with melanoma. 55- (33%) patients received ABX. On univariable analysis, ABX+ patients demonstrated shorter PFS (208 versus 357 days; P = 0.008) and OS (294 versus 438 days; P = 0.024). Increased age, poorer PS and higher LDH were associated with shorter PFS and OS. On multivariable analysis, ABX use was independently associated with shorter PFS [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.05-2.34, P = 0.028] and OS (HR 2.19, 95% CI 1.44-3.32, P = 0.0002). The negative impact of ABX on OS was particularly pronounced for patients with PS of ≥2 (HR 3.82, 95% CI 1.18-12.36, P = 0.025).ConclusionFor patients treated with TKIs, ABX use is independently associated with reduced PFS and OS and judicious use is warranted, particularly in patients with poorer PS.

Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet?

Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety.

Tyrosine kinase inhibitors in sarcoma treatment (Review)

Sarcomas are a group of rare mesenchymal malignant tumors that arise from transformed cells of the mesenchymal connective tissue, which are challenging to treat. The majority of sarcomas are soft tissue sarcomas (STSs; 75%) and this heterogeneous group of tumors is further comprised of gastrointestinal stromal tumors (~15%) and bone sarcomas (10%). Although surgery remains the current primary therapeutic approach for localized disease, recurrent, metastatic and refractory sarcomas require cytotoxic chemotherapy, which usually yields poor results. Therefore the efficiency of sarcoma treatment imposes a difficult problem. Furthermore, even though progress has been made towards understanding the underlying molecular signaling pathways of sarcoma, there are limited treatment options. The aim of the present study was therefore to perform a systematic literature review of the available clinical evidence regarding the role of tyrosine kinase inhibitors (TKIs) in patients with recurrent or refractory STSs and bone sarcomas over the last two decades. Tyrosine kinases are principal elements of several intracellular molecular signaling pathways. Deregulation of these proteins has been implicated in driving oncogenesis via the crosstalk of pivotal cellular signaling pathways and cascades, including cell proliferation, migration, angiogenesis and apoptosis. Subsequently, small molecule TKIs that target these proteins provide a novel potential therapeutic approach for several types of tumor by offering significant clinical benefits. Among the eligible articles, there were 45 prospective clinical trials, primarily multicentric, single arm, phase II and non-randomized. Numerous studies have reported promising results regarding the use of TKIs, mainly resulting in disease control in patients with STSs. The lack of randomized clinical trials demonstrates the ambiguous efficiency of various studied treatment options, which therefore currently limits the approved drugs used in clinical practice. Research both in clinical and preclinical settings is needed to shed light on the underlying molecular drivers of sarcomagenesis and will identify novel therapeutic approaches for pretreated patients.

Pyrotinib-Containing Neoadjuvant Therapy in Patients With HER2-Positive Breast Cancer: A Multicenter Retrospective Analysis.

BackgroundPyrotinib, a small-molecule tyrosine kinase inhibitor, has been investigated as a component of neoadjuvant therapy in phase 2 trials of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This study aimed to evaluate the effectiveness and safety of pyrotinib-containing neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer in the real-world setting.MethodsData of 97 patients with HER2-positive breast cancer from 21 centers across China treated with pyrotinib-containing neoadjuvant therapy were reviewed. Neoadjuvant therapy consisted of taxane/carboplatin/trastuzumab plus pyrotinib (TCbH+Py, 30 [30.9%]), anthracycline/cyclophosphamide followed by taxane/trastuzumab plus pyrotinib (AC-TH+Py) or taxane followed by anthracycline/cyclophosphamide/trastuzumab plus pyrotinib (T-ACH+Py, 29 [29.9%]), taxane/trastuzumab plus pyrotinib (TH+Py, 23 [23.7%]), and other pyrotinib-containing neoadjuvant treatment (15 [15.5%]). The primary outcome was breast pathological complete response (bpCR, ypT0/is) rate. Secondary outcomes included total pathological complete response (tpCR, ypT0/is ypN0) rate, objective response rate (ORR), and the incidence of preoperative adverse events.ResultsThe ORR of pyrotinib-containing neoadjuvant therapy was 87.6% (85/97). The bpCR and tpCR rates were 54.6% (95% confidence interval [CI], 44.2%-64.7%) and 48.5% [95% CI, 38.2%-58.8%], respectively. The most common grade 3 or 4 treatment-related adverse events included diarrhea (15 [15.5%]), decreased hemoglobin (nine [9.3%]), and decreased neutrophil count (eight [8.2%]). No treatment-related deaths occurred.ConclusionPyrotinib-containing neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer shows favorable effectiveness with manageable toxicity in the real-world setting. Trastuzumab plus pyrotinib may be a novel option of dual HER2-targeted blockade.