Small Molecule Tyrosine Kinase Inhibitors Research Articles

Research progress on the role of bypass activation mechanisms in resistance to tyrosine kinase inhibitors in non-small cell lung cancer

The clinical application of small molecule tyrosine kinase inhibitors (TKIs) has significantly improved the quality of life and prognosis of patients with non-small cell lung cancer (NSCLC) carrying driver genes. However, resistance to TKI treatment is inevitable. Bypass signal activation is one of the important reasons for TKI resistance. Although TKI drugs inhibit downstream signaling pathways of driver genes, key signaling pathways within tumor cells can still be persistently activated through bypass routes such as MET gene amplification, EGFR gene amplification, and AXL activation. This continuous activation maintains tumor cell growth and proliferation, leading to TKI resistance. The fundamental strategy to treat TKI resistance mediated by bypass activation involves simultaneously inhibiting the activated bypass signals and the original driver gene signaling pathways. Some clinical trials based on this combined treatment approach have yielded promising preliminary results, offering more treatment options for NSCLC patients with TKI resistance. Additionally, early identification of resistance mechanisms through liquid biopsy, personalized targeted therapy against these mechanisms, and preemptive targeting of drug-tolerant persistent cells may provide NSCLC patients with more sustained and effective treatment.

Structure-Activity Relationship of Substituted Pyrazoline Derivatives as Small Molecule Tyrosine Kinase Inhibitors.

Tyrosine kinase inhibitors (TKIs) target certain cell signalling pathways, and have become a promising class of medications for the treatment of cancer in recent years. Because of their distinct structure and adaptable chemistry, pyrazolines have drawn a lot of interest from organic and medicinal chemists. Their exceptional TKI activity has prompted them to investigate chemotherapy for cancer. We aim to develop agents that inhibit tyrosine kinases highly effective with the least amount of harm possible, perhaps improving the course of cancer treatment. This review compiled current information from recent literature sources, includ-ing in vitro, in vivo, approved medications, active clinical trials, and the structure-activity relationships (SAR) linked to various pyrazoline analogues used as small-molecule Tyro-sine Kinase Inhibitors in cancer treatment. This study focuses on SAR inside the pyrazoline ring and its derivatives as TKIs, and it emphasizes current developments, including patents, authorized medications, and compounds in clinical trials. By enhancing our understanding of these compounds, our goal is to aid in making the roles of pharmacologists, scientists, and researchers who are designing and developing next-generation anticancer drugs with pyrazoline scaffolds easier. The future holds immense potential for the continued evolution of pyrazoline-based therapies, offer-ing renewed hope in the ongoing battle against cancer.

Ferroptosis - a potential feature underlying neratinib-induced colonic epithelial injury.

Neratinib, a small-molecule tyrosine kinase inhibitor (TKI) that irreversibly binds to human epidermal growth factor receptors 1, 2 and 4 (HER1/2/4), is an approved extended adjuvant therapy for patients with HER2-amplified or -overexpressed (HER2-positive) breast cancers. Patients receiving neratinib may experience mild-to-severe symptoms of gut toxicity including abdominal pain and diarrhoea. Despite being a highly prevalent complication in gut health, the biological processes underlying neratinib-induced gut injury, especially in the colon, remains unclear. Real-time quantitative polymerase chain reaction (RT-qPCR) and histology were integrated to study the effect of, and type of cell death induced by neratinib on colonic tissues collected from female Albino Wistar rats dosed with neratinib (50mg/kg) daily for 28 days. Additionally, previously published bulk RNA-sequencing and CRISPR-screening datasets on human glioblastoma SF268 cell line and glioblastoma T895 xenograft, and mouse TBCP1 breast cancer cell line were leveraged to elucidate potential mechanisms of neratinib-induced cell death. The severity of colonic epithelial injury, especially degeneration of surface lining colonocytes and infiltration of immune cells, was more pronounced in the distal colon than the proximal colon. Sequencing showed that apoptotic gene signature was enriched in neratinib-treated SF268 cells while ferroptotic gene signature was enriched in neratinib-treated TBCP1 cells and T895 xenograft. However, we found that ferroptosis, but less likely apoptosis, was a potential histopathological feature underlying colonic injury in rats treated with neratinib. Ferroptosis is a potential feature of neratinib-induced colonic injury and that targeting molecular machinery governing neratinib-induced ferroptosis may represent an attractive therapeutic approach to ameliorate symptoms of gut toxicity.

Targeting SARS-CoV-2-Induced Cardiovascular Injury: Exploring the Potential of Ponatinib in Mitigating Cardiovascular Necroptosis in COVID-19.

The incidence of Coronavirus Disease 2019 (COVID-19) has increased dramatically in recent years, affecting millions of people worldwide. The primary cause of morbidity and mortality in COVID-19 patients is respiratory illness. However, the disease can also significantly impact the cardiovascular system. SARS-CoV-2, the virus responsible for COVID-19, enters cells using the angiotensin-converting enzyme 2 (ACE-2) receptor. ACE-2 is a component of the renin-angiotensin system (RAS) and plays a crucial role in regulating various pathological processes. The interaction of the virus with ACE-2 in the myocardium can lead to direct heart damage. Several mechanisms may contribute to myocardial damage in COVID-19 patients, including systemic inflammation, myocardial interstitial fibrosis, interferon-mediated immune response, exaggerated cytokine response, T-cell-mediated damage, coronary plaque instability, and hypoxia. There has been concern that ACE inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) may increase vulnerability to SARS-CoV-2 by upregulating ACE-2 expression. However, it may be advisable to continue medications for patients with underlying cardiovascular disorders. The precise mechanisms of cardiomyocyte injury in COVID-19 are not fully understood, but necroptosis appears to play a significant role. Current treatments for cardiac damage in COVID-19 patients include IL-6 blockers and antiplatelet therapy. Ponatinib, a small molecule tyrosine kinase inhibitor designed using computational and structural approaches, has shown the potential to affect cell death through its impact on tyrosine kinase activity. By reviewing studies related to ponatinib's effects on necroptosis and cell death, we propose a novel approach to potentially reduce the cardiotoxic effects of COVID-19 on cardiomyocytes. Further research is needed to fully elucidate the mechanisms of cardiac injury in COVID-19 and to develop targeted therapies to protect the heart from the devastating effects of this disease.

Target and Gene-Based Therapeutic Strategies against Pancreatic Cancer: Current and Future Prospects.

Despite tremendous advancements in knowledge, diagnosis, and availability of both traditional and innovative treatments, pancreatic cancer remains a dangerous disease with a high death rate and dismal prognosis. The traditional strategy in adjuvant and palliative settings is still cytotoxic chemotherapy predicated on the purine derivative gemcitabine; nevertheless, there is an increasing need for new medicines that target the primary molecular pathways and pathophysiological abnormalities implicated. There is now just a tiny amount of evidence of therapeutic benefit when the targeted drug erlotinib is added to the conventional gemcitabine treatment. In preclinical and clinical trials, novel medications targeting mTOR, NF-κB, and proteasome, including the enzyme histone deacetylase, are currently being studied alongside the well-established monoclonal antibody treatments and small-molecule protein tyrosine kinase inhibitors. These novel medications may change the negative natural progression of this illness in conjunction with gene therapy and immunotherapy, both of which are undergoing clinical study. In this regard, leveraging miRNA manipulation to combat cancer is appealing due to its promise to deliver personalized treatment tailored to an individual's distinct gene or miRNA expression profile. Preclinical studies involving animals have showcased the effectiveness of miRNA-based therapies, with several of these treatments now progressing into human clinical trials for various malignancies and other medical conditions. This review describes the important developments of targeted therapeutics that are associated with pancreatic cancer and the discoveries which can help in dealing with this fatal malignancy in a more significant manner.

Soluplus-TPGS Mixed Micelles as a Delivery System for Brigatinib: Characterization and In Vitro Evaluation.

Lung cancer is a major public health concern, with a high incidence and fatality rate. Its treatment is very difficult, as it is mostly diagnosed in advanced stages. Non-small cell lung carcinoma (NSCLC) is the major form of lung carcinoma that persists. Brigatinib (BGT), a powerful small-molecule tyrosine kinase inhibitor, has demonstrated significant therapeutic potential in the treatment of NSCLC with anaplastic lymphoma kinase (ALK) mutations. However, the therapeutic applicability of BGT is hampered by its low solubility and bioavailability. In this study, we developed a mixed micelle system comprising Soluplus and TPGS loaded with BGT. BGT was encapsulated into the mixed micelles using various combinations of Soluplus and TPGS, with encapsulation efficiency (EE%) ranging from 52.43 ± 1.07 to 97.88 ± 2.25%. The dynamic light scattering data showed that the mixed micelles ranged in size from 75.7 ± 0.46 to 204.3 ± 5.40 nm. The selected mixed micelles (F6) showed approximately 38% BGT release in the first 2 h, and subsequently, within 72 h, the release was 94.50 ± 5.90%. The NMR experiment confirmed the formation of micelles. Additionally, the mixed micelles showed significantly higher cellular uptake (p < 0.05) and increased cytotoxicity (p < 0.05) as compared to the free BGT. Specifically, the obtained IC50 values for BGT-loaded Soluplus-TPGS mixed micelles and free BGT were 22.59 ± 6.07 and 61.45 ± 6.35 μg/mL, respectively. The results of the in vitro stability experiment showed that the selected mixed micelle (F6) was stable at both room temperature and 4 °C, with only minor changes in size and PDI. Our results indicate great potential for the developed Soluplus-TPGS mixed micelles as a delivery system for BGT.

Treatment-free remission as a new goal in the management of chronic myeloid leukemia: Clinical and biological aspects.

The therapeutic armamentarium of chronic myeloid leukemia (CML) has dramatically improved after small molecule tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 became available, with a life expectancy now close to that of the general population. Although highly effective, these drugs also have a toxicity profile that is often mild to moderate, but sometimes severe. Indeed, long-term treatment with TKIs can lead to chronic adverse events that can negatively affect patients' quality of life and can promote significant morbidity and mortality, particularly in the case of second- or third-generation TKIs. Treatment discontinuation has therefore become an emerging goal for CML patients and numerous studies have evaluated in off-TKI subjects what requirements are appropriate for an attempt at treatment-free remission (TFR). TFR eligibility is currently limited to a small population of subjects with both deep and sustained molecular responses to TKIs. For those attempting TFR, average success rates are promising, with 25%-30% of patients experiencing prolonged TFR. In case of failure to maintain sustained TFR, safety results to date are reassuring, with almost all patients responding successfully to resumption of TKIs, and advanced-phase disease progression representing a very rare event. The purpose of this review is to discuss guidelines for TKI discontinuation, clinical advances from clinical trials and real-life experiences, and describe areas of research, particularly regarding the biological factors capable of predicting the success of TFR.

Longitudinal multiomics analysis of aggressive pituitary neuroendocrine tumors: comparing primary and recurrent tumors from the same patient, reveals genomic stability and heterogeneous transcriptomic profiles with alterations in metabolic pathways

Pituitary neuroendocrine tumors (PitNET) represent the vast majority of sellar masses. Some behave aggressively, growing rapidly and invading surrounding tissues, with high rates of recurrence and resistance to therapy. Our aim was to establish patterns of genomic, transcriptomic and methylomic evolution throughout time in primary and recurrent tumors from the same patient. Therefore, we performed transcriptome- and exome-sequencing and methylome microarrays of aggressive, primary, and recurrent PitNET from the same patient. Primary and recurrent tumors showed a similar exome profile, potentially indicating a stable genome over time. In contrast, the transcriptome of primary and recurrent PitNET was dissimilar. Gonadotroph, silent corticotroph, as well as metastatic corticotroph and a somatotroph PitNET expressed genes related to fatty acid biosynthesis and metabolism, phosphatidylinositol signaling, glycerophospholipid and phospholipase D signaling, respectively. Diacylglycerol kinase gamma (DGKG), a key enzyme in glycerophospholipid metabolism and phosphatidylinositol signaling pathways, was differentially expressed between primary and recurrent PitNET. These alterations did not seem to be regulated by DNA methylation, but rather by several transcription factors. Molecular docking showed that dasatinib, a small molecule tyrosine kinase inhibitor used in the treatment of chronic lymphocytic and acute lymphoblastic leukemia, could target DGKG. Dasatinib induced apoptosis and decreased proliferation in GH3 cells. Our data indicate that pituitary tumorigenesis could be driven by transcriptomically heterogeneous clones, and we describe alternative pharmacological therapies for aggressive and recurrent PitNET.

The Fibrotic Phenotype of Human Precision-Cut Lung Slices Is Maintained after Cryopreservation.

Human precision-cut lung slices (hPCLS) prepared from fibrotic lungs recapitulate the pathophysiological hallmarks of fibrosis. These hallmark features can also be induced by treating non-fibrotic hPCLS with a fibrotic cocktail (FC). As a result, the fibrotic and fibrosis-induced hPCLS are rapidly emerging as preferred models for disease modeling and drug discovery. However, current hPCLS models are limited by tissue viability in culture, as they are usually only viable for one week after harvesting. Here, we demonstrate that the fibrotic hPCLS can be cryopreserved, stored for months, and then thawed on demand without loss of hPCLS viability or protein content for 14 days post-thawing. Cryopreservation also preserves the pro-fibrotic potential of non-fibrotic hPCLS. Specifically, when we treated the thawed non-fibrotic hPCLS with an FC, we observed significant pro-fibrotic cytokine secretion and elevated tissue stiffness. These pro-fibrotic changes were inhibited by the small-molecule tyrosine kinase inhibitor, Nintedanib. Taken together, our work indicates that a feasible solution to prolong the pre-clinical utility of fibrotic and fibrosis-induced hPCLS is cryopreservation. We anticipate that cryopreserved hPCLS will serve as an advantageous predictive model for the evaluation of pro-fibrotic pathways during acute and chronic toxicity testing.

Advances and future directions in ROS1 fusion-positive lung cancer.

ROS1 gene fusions are an established oncogenic driver comprising 1%-2% of non-small cell lung cancer (NSCLC). Successful targeting of ROS1 fusion oncoprotein with oral small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment landscape of metastatic ROS1 fusion-positive (ROS1+) NSCLC and transformed outcomes for patients. The preferred Food and Drug Administration-approved first-line therapies include crizotinib, entrectinib, and repotrectinib, and currently, selection amongst these options requires consideration of the systemic and CNS efficacy, tolerability, and access to therapy. Of note, resistance to ROS1 TKIs invariably develops, limiting the clinical benefit of these agents and leading to disease relapse. Progress in understanding the molecular mechanisms of resistance has enabled the development of numerous next-generation ROS1 TKIs, which achieve broader coverage of ROS1 resistance mutations and superior CNS penetration than first-generation TKIs, as well as other therapeutic strategies to address TKI resistance. The approach to subsequent therapy depends on the pace and pattern of progressive disease on the initial ROS1 TKI and, if known, the mechanisms of TKI resistance. Herein, we describe a practical approach for the selection of initial and subsequent therapies for metastatic ROS1+ NSCLC based on these clinical considerations. Additionally, we explore the evolving evidence for the optimal treatment of earlier-stage, non-metastatic ROS1+ NSCLC, while, in parallel, highlighting future research directions with the goal of continuing to build on the tremendous progress in the management of ROS1+ NSCLC and ultimately improving the longevity and well-being of people living with this disease.

Budget impact analysis of introducing fruquintinib for metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and biologics in the United States from the payer perspective

Aims Fruquintinib is a selective small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 recently approved in the United States (US) for the treatment of adult patients with metastatic colorectal cancer (CRC) who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, anti-epidermal growth factor receptor therapy. This study aimed to estimate the 5-year budget impact of fruquintinib from a US payer perspective (commercial and Medicare). Materials and methods A budget impact model was developed to compare two scenarios: a reference scenario in which patients received regorafenib, trifluridine/tipiracil, or trifluridine/tipiracil with bevacizumab and an alternative scenario in which patients received reference scenario treatments or fruquintinib. Market shares were evenly divided across available options. A 5-year time horizon and a hypothetical health plan of 1 million members was assumed. The model included epidemiological inputs to estimate the eligible population; clinical inputs for treatment duration, progression-free survival, overall survival, and adverse event (AE) frequency; and cost inputs for treatment, AEs, disease management, subsequent therapy, and terminal care costs. Budget impact was reported as total, per member per year (PMPY), and per member per month (PMPM). Results The model estimated an eligible population of 194 patients (39 per year) over 5 years. In the base case, the estimated 5-year budget impact of fruquintinib was $4,077,073 ($0.82 PMPY and 0.07 PMPM) for a commercial health plan. During the first year, the estimated budget impact was $627,570 ($0.63 PMPY and 0.05 PMPM). Results were robust across sensitivity analyses. PMPM costs from the Medicare perspective were greater than the base-case (commercial) ($0.17 vs. $0.07) due to higher incidence of CRC in that population. Conclusions Fruquintinib is associated with a low budget impact for payers based on proposed thresholds in the US.

Post-marketing safety surveillance of fostamatinib: an observational, pharmacovigilance study leveraging FAERS database

ABSTRACT Objective Fostamatinib, an FDA-approved oral small-molecule spleen tyrosine kinase (SYK) inhibitor, is used to treat thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have not responded to previous treatments. However, comprehensive safety data is lacking. This study uses the FDA Adverse Event Reporting System (FAERS) database to explore real-world adverse events (AEs) related to fostamatinib, aiming to inform its clinical use. Methods The FAERS database was retrospectively queried to extract reports associated with fostamatinib from 2019 to 2023. To identify and evaluate potential AEs in patients receiving fostamatinib, various disproportionality analyses such as the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed. Results A total of 23 AE signals were included in our analysis. Among them, hypertension, blood pressure increase, blood pressure abnormality, hepatic enzyme increase, and diarrhea were consistent with the common AEs described for fostamatinib in clinical trials. In addition, unexpected serious AEs were detected including cerebral thrombosis and necrotizing soft tissue infection. The median time to onset of fostamatinib-related AEs was 86 days. Conclusion Our investigation revealed several possibly emergent safety concerns associated with fostamatinib in real-world clinical practice, which might provide essential vigilance evidence for clinicians and pharmacists to manage the safety issues of fostamatinib.

Multifunctional Nanotherapeutics with Long-Acting Release against Macular Degeneration by Minimally Invasive Administration.

Neovascular age-related macular degeneration (AMD), a leading cause of blindness, requires frequent intravitreal injection of antivascular endothelial growth factor (anti-VEGF), which could generate a succession of complications with poor patient compliance. The current VEGF-targeting therapies often fail in half of patients due to the complex pathologic microenvironment of excessive reactive oxygen species (ROS) production, and increased levels of inflammation are accompanied by choroidal neovascularization (CNV). We herein reported multifunctional nanotherapeutics featuring superior antioxidant and anti-inflammation properties that aim to reverse the pathological condition, alongside its strong targeted antiangiogenesis to CNV and its ability to provide long-term sustained bioactive delivery via the minimally invasive subconjunctival injection, so as to achieve satisfactory wet AMD treatment effects. Concretely, the nanomedicine was designed by coencapsulation of astaxanthin (AST), a red pigmented carotenoid known for its antioxidative, anti-inflammatory and antiapoptotic properties, and axitinib (AXI), a small molecule tyrosine kinase inhibitor that selectively targets the vascular epidermal growth factor receptor for antiangiogenesis, into the Food and Drug Administration (FDA) approved poly(lactic-co-glycolic acid) (PLGA), which forms the nanodrug of PLGA@AST/AXI. Our results demonstrated that a single-dose subconjunctival administration of PLGA@AST/AXI showed a rational synergistic effect by targeting various prevailing risk factors associated with wet AMD, ensuring persistent drug release profiles, maintaining good ocular biocompatibility, and causing no obvious mechanical damage. Such attributes are vital and hold significant potential in treating ocular posterior segment diseases. Moreover, this nanotherapeutic strategy represents a versatile and broad-spectrum nanoplatform, offering a promising alternative for the complex pathological progression of other neovascular diseases.

Small molecule inhibitors of the VEGF and tyrosine kinase for the treatment of cervical cancer.

Cervical cancer accounts for most deaths due to cancer in women, majorly in developing nations. The culprit behind this disease is the human papillomavirus(HPV) which accounts for more than 90% of cervical cancer cases. The viral strains produce proteins that favor the knocking down of the apoptosis process and continuous growth of cells in the cervix leading to tumor growth. Proangiogenic growth factors, such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), angiopoietins, and other endothelial growth factors (EGF), are secreted by tumor cells and the surrounding microenvironment, which further advances the development of cancer. The extracellular domain of receptor tyrosine kinases is employed by ligands (like VEGF and EGF) to engage and activate them by inducing receptor dimerization, which facilitates the cascade impact of these factors. The tyrosine kinase domains of each receptor autophosphorylate each other, activating the receptor and initiating signaling cascades that promote angiogenesis, migration, proliferation, and survival of endothelial cells. Cancer cells benefit from its modified signaling pathways, which cause oncogenic activation. Upon early cervical cancer detection, the second-line therapy strategy involves blocking the signaling pathways with VEGF and small molecule tyrosine kinase inhibitors (TKIs). This review paper highlights the genesis of cervical cancer and combating it using VEGF and tyrosine kinase inhibitors by delving into the details of the currently available inhibitors. Further, we have discussed the inhibitor molecules that are currently in various phases of clinical trials. This paper will surely enhance the understanding of cervical cancer and its treatment approaches and what further interventions can be done to alleviate the disease currently serving as a major health burden in the developing world.

Spotlight on the treatment of non-small cell lung cancer with rare genetic alterations and brain metastasis: Current status and future perspectives.

In patients with non-small cell lung cancer (NSCLC), oncogenic variants present in <5% of cases are considered rare, the predominant of which include human epidermal growth factor receptor 2 (HER2) mutations, mesenchymal-epithelial transition (MET) alterations, c-ros oncogene 1 (ROS1) rearrangements, rearrangement during transfection (RET) fusions, v-raf mouse sarcoma virus oncogene homolog B1 (BRAF) mutations, and neurotrophic troponin receptor kinase (NTRK) fusions. Brain metastases (BMs) occur in approximately 10%-50% of patients with NSCLC harboring rare genetic variants. The recent advent of small-molecule tyrosine kinase inhibitors and macromolecular antibody-drug conjugates (ADCs) has conferred marked survival benefits to patients with NSCLC harboring rare driver alterations. Despite effective brain lesion control for most targeted agents and promising reports of intracranial remission associated with novel ADCs, BM continues to be a major therapeutic challenge. This review discusses the recent advances in the treatment of NSCLC with rare genetic variants and BM, with a particular focus on intracranial efficacy, and explores future perspectives on how best to treat these patients.

A pilot study of nintedanib in molecularly selected patients with advanced non-small cell lung cancer.

Nintedanib is a small molecule tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). The purpose of the study was to evaluate the response rate for patients with advanced non-small cell lung cancer (NSCLC) with mutations in TP53, VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3 treated with nintedanib as part of an open-label, single-arm pilot study. Patients with advanced NSCLC previously treated with platinum-doublet chemotherapy with the above mutations were enrolled. Exclusion criteria included necrotic tumors with invasion of blood vessels, history of recent thromboembolic events, increased risk of bleeding or thrombosis, myocardial infarction, and weight loss >10% within past 6 months. Nintedanib was administered at a dose of 200 mg orally twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary endpoints included progression-free survival (PFS) and correlating outcomes with specific mutations. This study was registered with ClinicalTrials.gov, number NCT02299141. Between 2015 and 2019, 20 patients were enrolled with a median age was 66 years, 15 (75%) were females, 15 (75%) had adenocarcinoma, and 17 patients had a TP53 mutation (85%). Seventeen (85%) had received prior immunotherapy and 11 (55%) had received at least three prior lines of systemic therapy. The ORR was 15% with three partial responses (PR), while 12 patients had stable disease (SD), with disease control rate (DCR) consisting of a PR and SD greater than or equal to 16 weeks of 65% (n=13). Median PFS was 4.3 months [95% confidence interval (CI): 1.8-7.9] and median overall survival (OS) was 11.3 months (95% CI: 3.5-44.2). Three patients experienced prolonged clinical benefit from nintedanib, remaining on treatment for over 1 year and all three had a TP53 mutation and received prior immunotherapy. The most common adverse events of any grade included nausea (80%), fatigue (70%), diarrhea (60%), and anorexia (60%). In this pilot study in heavily pretreated and molecularly selected patients with metastatic NSCLC, nintedanib showed modest activity.

Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN-ALK Fusion In Vitro.

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)-ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN-ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN-ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN-ALK), particularly in those with STRN-ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer.

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance. Human epidermal growth factor receptor 2 (HER2) is one of the most important targets in targeted therapy for gastric cancer. Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer. The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified. However, monoclonal antibodies, due to their large molecular weight, inability to penetrate the blood-brain barrier, and drug resistance, lead to decreased therapeutic efficacy, so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer. Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Fruquintinib plus capecitabine versus capecitabine as first-line maintenance treatment of metastatic colorectal cancer (mCRC): Update results from the randomized, controlled, phase Ib/II study.

3567 Background: Capecitabine (Cap) is a standard first-line maintenance treatment option for colorectal cancer. Fuquinitinib (Fru) is a highly selective small molecule tyrosine kinase inhibitor that inhibits VEGFR1/2/3, which has been approved by the U.S. Food and Drug Administration (FDA) for adults with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and has recommended by NCCN guidelines as a standard treatment. Preliminary research results found that adding Fru to Cap as maintenance treatment was safe and improved progression-free survival (PFS, primary endpoint) for mCRC patients (pts). Methods: Eligible pts had been confirmed mCRC who achieved disease control (including CR/PR and SD) after at least six cycles of first-line standard chemotherapy. During phase Ib, pts received Fru (4 mg p.o. qd, 3 weeks on/1 week off, q4w]) plus Cap (850 mg/m2, p.o. bid, d1-7 and d15-21, q4w). In phase II, pts were randomized in a 1:1 ratio to receive either Fru (RP2D, 3mg, 3 weeks on/1 week off) plus Cap or Cap alone. The primary outcome was PFS 1 (defined as time from randomization to disease progression or death). Secondary were PFS 2 (defined as time from first time receiving 1L treatment to disease progression or death), ORR and DCR. Results: At data cutoff (Jan 23, 2024), 46 pts were enrolled and 38 pts who had at least one tumor assessment post treatment were randomly assigned in Fru plus Cap arm (n=20) and Cap arm (n=18). Of these pts, the median age was 59.5 (39-78) and 58.5 (32-75) years, 11 (55.0%) and 10 (55.6%) had left-sided tumors, respectively. Most pts had previously received bevacizumab therapy (65.0% /66.7%) or cetuximab (30% /22.2%). The median cycles of first-line treatment were 8 (5-12) and 8 (4-13), 8 (40.0%) and 8 (44.4%) achieved PR in the pts who had received first-line therapy, respectively. The median PFS 1 was 9.2 mo in Fru plus Cap arm and 3.1 mo in Cap arm (HR=0.385 [95% CI: 0.163 - 0.906], p=0.024). And PFS 2 was also significantly prolonged in Fru plus Cap vs Cap (16.8 vs 8.5 mo, HR=0.314 [95% CI: 0.125 - 0.788], p=0.0098). Consistently, ORR (15.0% vs 5.6%) and DCR (80% vs 55.6%) were improved in Fru plus Cap arm. The safety was similar to the previous results without new safety signals appearing. Conclusions: PFS was significantly prolonged and ORR was improved in mCRC pts treated with Fru plus Cap as first-line maintenance treatment. This trial is ongoing and updated data will be presented in the future. Clinical trial information: NCT05451719 .

A phase II trial of nivolumab plus axitinib in patients with anti-PD1 refractory advanced melanoma.

TPS9600 Background: A significant portion of patients (pts) with advanced melanoma (mel) either do not respond or become refractory to immune checkpoint inhibitor (ICI) therapy, with no established second line treatment regimen. A key ICI resistance mechanism includes formation of an immunosuppressive tumor microenvironment (TME). We have shown that high oxidative metabolism (OXPHOS) of mel tumor cells is associated with a hostile TME (1). Furthermore, this is associated with high intra-tumoral hypoxia (ITH). In mel tumor cells with high OXPHOS, CD8+ tumor infiltrating lymphocytes (TIL) display increased exhaustion and decreased functionality (decreased IFN-γ and TNF-α production). Pts with metastatic mel who progressed on ICI had tumor cells with high OXPHOS and ITH. Axitinib is a VEGFR small molecule tyrosine kinase inhibitor with high inhibitory activity for VEGFR 1-3. We previously showed that low dose axitinib reduces ITH in B16 murine mel, and our pre-clinical data show that axitinib synergizes with ICI to produce an improved tumor response (2). We hypothesize that axitinib will re-sensitize mel to ICI by modulating angiogenesis and reducing ITH and resultant T cell dysfunction. Methods: This is an investigator-initiated, single arm phase II trial of nivolumab plus axitinib for pts with unresectable stage III or IV cutaneous, acral, or mucosal mel who have progressed on prior anti-PD1 based therapy in the adjuvant or metastatic setting (NCT04493203). Pts previously treated with concomitant anti-CTLA4, anti-LAG3, BRAF/MEK inhibitors, and/or pts with brain metastases (asymptomatic or stable treated disease x 2 weeks) are eligible. Pts will receive nivolumab 480 mg IV every 4 wks with axitinib PO 5 mg twice daily for up to 2 years, or until progression or unacceptable toxicity. Pts will undergo biopsy at baseline and at 12 wks, with optional biopsy at progression. Pts will receive an oral dose of pimonidazole 0.5 mg/m2 prior to each biopsy to permit in-vivo evaluation of ITH. Staging scans (full body PET-CT or CT and MRI brain) will be obtained at baseline, with restaging scans at 12 week intervals. Primary endpoint: overall response rate (ORR) by RECIST 1.1. Responses are determined by Blinded Independent Central Review (BICR). Secondary endpoints: safety analysis, progression-free survival (PFS) and overall survival (OS). Extensive correlative translational analyses will focus on immunophenotypic changes in the TME, ITH, profiling of tumor cell metabolism, and TIL function. The null hypothesis that the true ORR is 10% will be tested versus a one-sided alternative hypothesis of ≥25%, using Simon’s minimax two-stage design. This design has a type I error rate 0.08 and power 0.81 when the true response rate is 0.25. PFS and OS will be estimated via Kaplan-Meier method. 31 of planned 31 pts have been enrolled in January 2024, with no data analysis yet available. 1. Najjar et al., JCI Insight 2019. 2. Scharping et al., Nat Immunol 2021. Clinical trial information: NCT04493203 .