Small Molecule Tyrosine Kinase Inhibitors Research Articles

Efficacy and safety of erlotinib combined with bevacizumab in the treatment of non-small cell lung cancer: A systematic review and meta-analysis.

Background:Non-small cell lung cancer (NSCLC) has a poor prognosis despite conventional treatments of surgery, radiotherapy, and chemotherapy. Small-molecule tyrosine kinase inhibitors acting on epidermal growth factor receptor (EGFR) have shown high efficacy and low toxicity for NSCLC. In particular, combining erlotinib with the VEGF antibody bevacizumab has therapeutic value in NSCLC, but the drugs’ separate effects as monotherapy and any adverse outcomes of combination therapy remain unclear.Objectives:To determine the efficacy and safety of erlotinib and bevacizumab for NSCLC, we conducted a meta-analysis and systematic review of randomized controlled trials.Data sources:PubMed, Embase, Web of Science, and Cochrane databases were searched using keywords and manual review.Study eligibility criteria, participants, and interventions:We reviewed randomized controlled trials on the use of erlotinib combined with bevacizumab in adult patients with NSCLC, including data on outcome measures of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events.Study appraisal and synthesis methods:After quality assessment, datasets were evaluated for heterogeneity. In the event of significant heterogeneity, a random-effects model was used to assess the overall outcome measures as a result of treatments. Subgroup analysis was conducted to evaluate the source of heterogeneity on PFS.Results:Compared with erlotinib or bevacizumab alone, the combined treatment did not significantly prolong OS (95% confidence interval [CI] = 0.84–1.11; P = .62) or increase the ORR (95% CI = 0.91–1.20; P = .52), but significantly improved PFS (95% CI = 0.58–0.73; P < .001). This improvement was especially notable in patients with the following characteristics: Eastern Cooperative Oncology Group Performance Status score of 0 or 1, female, no smoking history, adenocarcinoma, and EGFR Exon19 deletion or Exon21 Leu858Arg mutation. Combination therapy significantly increased incidence of grade 1–2 hypertension (20.3% vs 6.3%, 95% CI 1.73–5.88; P < .01) and severe diarrhea (10% vs 3.2%, 95% CI 1.36–6.60; P = .01).Limitations:The low number of available randomized controlled trials could influence interpretation.Conclusions:Compared with erlotinib or bevacizumab monotherapy, their combination effectively prolongs PFS but increases incidence of adverse events in NSCLC patients.

Medullary Thyroid Cancer - Feature Review and Update on Systemic Treatment.

SUMMARYMedullary thyroid carcinoma (MTC) is a rare malignancy that originates from parafollicular (C cells) of the thyroid and accounts for 2-4% of all thyroid malignancies. MTC may be sporadic or inherited, the latter as part of the MEN 2 syndromes. Germline mutations in the RET proto-oncogene (REarranged during Transfection) are driver mutations in hereditary MTC, whereas somatic RET mutations and, less frequently, RAS mutations, have been described in tumor tissues of sporadic MTC. Genetic screening for germline mutations in RET proto-oncogene identifies gene carriers of germline mutations. That enables primary prevention (the avoidance of disease onset by total prophylactic thyroidectomy), or at least secondary prevention (early detection) of the disease. Radical surgery with complete tumor resection is still pivotal in attaining cure for MTC. Despite recent advances, the treatment of advanced, metastatic, and progressive MTC remains challenging. Metastatic MTC can have an indolent clinical course; therefore, it is necessary to assess which patient to cure and when to initiate the treatment. Multidisciplinary boards of various specialists involved in the diagnostics and therapy of the patients with MTC in highly specialized centers with a high volume of patients provide optimal patient management. Multikinase inhibitors (MKI) vandetanib and cabozantinib were approved for the treatment of progressive or symptomatic metastatic/unresectable MTC. Although these treatments have been shown to improve progression-free survival (PFS) with higher overall response rates (ORR) compared with placebo, no MKI has been shown to increase the overall survival (OS) yet, except in the subgroup of patients with RETM918T-mutations on cabozantinib therapy. As these drugs are nonselective, significant off-target toxicities may occur. Recently, next-generation small-molecule tyrosine kinase inhibitors (TKIs) have been developed. These highly selective RET-inhibitors are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. The selective RET-inhibitor selpercatinib has been very recently registered for the treatment of RET-mutated thyroid cancer.

Dynasore potentiates c-Met inhibitors against hepatocellular carcinoma through destabilizing c-Met

c-Met receptor is frequently overexpressed in hepatocellular carcinoma and thus considered as an attractive target for pharmacological intervention with small molecule tyrosine kinase inhibitors. Albeit with the development of multiple c-Met inhibitors, none reached clinical application in the treatment of hepatoma so far. To improve the efficacy of c-Met inhibitors towards hepatocellular carcinoma, we investigated the combined effects of the dynamin inhibitor dynasore with several c-Met inhibitors, including tivantinib, PHA-665752, and JNJ-38877605. We provide several lines of evidence that dynasore enhanced the inhibitory effects of these inhibitors on hepatoma cell proliferation and migration, accompanied with increased cell cycle arrest and apoptosis. Mechanically, the combinatorial treatments decreased c-Met levels and hence markedly disrupted downstream signaling, as revealed by the dramatically declined phosphorylation of AKT and MEK. Taken together, our findings demonstrate that the candidate agent dynasore potentiated the inhibitory effects of c-Met inhibitors against hepatoma cells and will shed light on the development of novel therapeutic strategies to target c-Met in the clinical management of hepatocellular carcinoma patients.

Synchronous inhibition of mTOR and VEGF/NRP1 axis impedes tumor growth and metastasis in renal cancer

Clear cell renal cell carcinoma (ccRCC) is known for its highly vascular phenotype which is associated with elevated expression of vascular endothelial growth factor A (VEGF), also known as vascular permeability factor (VPF). Accordingly, VEGF has been an attractive target for antiangiogenic therapies in ccRCC. Two major strategies have hitherto been utilized for VEGF-targeted antiangiogenic therapies: targeting VEGF by antibodies, ligand traps or aptamers, and targeting the VEGF receptor signaling via antibodies or small-molecule tyrosine-kinase inhibitors (TKIs). In the present article we utilized two entirely different approaches: targeting mammalian target of rapamycin (mTOR) pathway that is known to be involved in VEGF synthesis, and disruption of VEGF/Neuroplin-1 (NRP1) axis that is known to activate proangiogenic and pro-tumorigenic signaling in endothelial and tumor cells, respectively. Everolimus (E) and a small-molecule inhibitor EG00229 (G) were used for the inhibition of mTOR and the disruption of VEGF/NRP1 axis, respectively. We also exploited a liposomal formulation decorated with a proprietary tumor-targeting-peptide (TTP) to simultaneously deliver these two agents in a tumor-targeted manner. The TTP-liposomes encapsulating both Everolimus and EG00229 (EG-L) demonstrated higher in vitro and in vivo growth retardation than the single drug-loaded liposomes (E-L and G-L) in two different ccRCC models and led to a noticeable reduction in lung metastasis in vivo. In addition, EG-L displayed remarkable inhibition of tumor growth in a highly aggressive syngeneic immune-competent mouse model of ccRCC developed in Balb/c mice. Taken together, this study demonstrates an effective approach to achieve improved therapeutic outcome in ccRCC.

Elevation in serum uric acid levels predicts favourable response to erlotinib treatment in patients with metastatic non-small-cell lung cancer.

Erlotinib is a small molecule tyrosine kinase inhibitor which blocks the activation of epidermal growth factor receptor (EGFR), a transmembrane receptor that is upregulated in many cancer types. Inhibition of angiogenesis with consequent impairments in intratumoral microcirculation is one of the mechanisms through which EGFR inhibition halts the progression of cancer. A consequence of impaired microcirculation is intratumoral hypoxia, which results in increases in serum uric acid levels. The goal of this study was to investigate the relationship between serum uric acid levels and response to erlotinib in metastatic non-small-cell lung cancer (NSCLC). A total of 56 patients with metastatic non-small-cell lung cancer who received erlotinib for a duration of at least 3months were included in this retrospective cohort study. Demographic characteristics, progression status, baseline serum uric levels and 3-month serum uric acid levels were recorded and analysed. Of the study population, 21 (37.5%) were female and 35 (62.5%) were male patients. No significant difference in above demographic characteristics was observed among exitus, survivor with progression and survivor without progression groups. Patients who responded favourably to erlotinib with no progression of their disease had significantly increased uric acid levels at 3-month follow-up (P=.01). Such a correlation was not observed if the patient was exitus (P=.47) or had progressed on erlotinib therapy (P=.19). In conclusion, this study is the first to demonstrate significant increases in serum uric acid levels in patients with metastatic NSCLC who responded favourably to erlotinib and had no progression under erlotinib therapy. Further studies are required to confirm and characterize serum uric acid as a novel biomarker in predicting the outcome in those with metastatic NSCLC.

Current Approaches in NSCLC Targeting K-RAS and EGFR.

The research and treatment of non-small cell lung cancer (NSCLC) have achieved some important advances in recent years. Nonetheless, the overall survival rates for NSCLC remain low, indicating the importance to effectively develop new therapies and improve current approaches. The understanding of the function of different biomarkers involved in NSCLC progression, survival and response to therapy are important for the development of early detection tools and treatment options. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (K-RAS) are two of the main significant biomarkers for the management of NSCLC. Mutations in these genes were associated with development and response to therapies. For example, the use of small molecule tyrosine kinase (TK) inhibitors and immunotherapy has led to benefits in some, but not all patients with altered EGFR. In contrast, there is still no effective approved drug to act upon patients harbouring K-RAS mutations. In addition, K-RAS mutations have been associated with lack of activity of TK inhibitors. However, promising approaches aimed to inhibit mutant K-RAS are currently under study. Therefore, this review will discuss these approaches and also EGFR therapies, and hopefully, it will draw attention to the need of continued research in the field in order to improve the outcomes in NSCLC patients.

Tyrosine Kinase Inhibitors (TKIs) Targeting Syk and BTK Signaling Differentially Affect PI3K Signalosome Organization and Platelet Function

Small molecule tyrosine kinase inhibitors (TKIs) serve increasingly important roles in the treatment of hematologic malignancies and also have shown efficacy in a range of immunological and inflammatory conditions. However, many successful TKI therapies are associated with problematic effects - particularly on platelets - as bleeding complications have been reported for many TKIs, both on and off clinical trials. Bleeding risk is especially apparent for patients treated with ibrutinib and other irreversible inhibitors of Bruton's tyrosine kinase (BTK), several of which now effectively treat multiple B cell malignancies. Intriguingly, other therapeutic TKIs targeting mechanistic partners of BTK are not associated with platelet-related complications. For instance, inhibitors against the BTK-activating kinase Syk - both with selective (i.e., entospletinib) as well as promiscuous (i.e., fostamatinib) target profiles - are not associated with clinically increased bleeding, despite some reported antiplatelet effects. To gain insight into the multifaceted effects of Syk and BTK inhibitors on platelet function, we analyzed the effects of a panel of eight different clinically relevant Syk- and BTK-directed TKIs (i.e., fostamatinib/R406, entospletinib, ibrutinib, acalabrutinib, AVL-292 and others) on essential platelet responses. We first assessed the effects of TKI treatment on Syk and BTK-mediated signaling events downstream of the platelet immunoreceptor tyrosine-based activation motif (ITAM) receptor GPVI. All Syk and BTK TKIs tested inhibited the phosphorylation of phospholipase C (PLCγ2) Y1217, protein kinase Cδ (PKCδ) Y311 and Akt T308, as well as Akt substrate phosphorylation following platelet stimulation with the GPVI receptor agonist, crosslinked collagen-related peptide (CRP-XL). Independent of TKI target profile, Syk and BTK TKIs differentially inhibited the phosphorylation of DAPP1 Y132, phosphoinositide 3-kinase (PI3K) p85α Y458, Akt S473 and PKC substrates. Syk and BTK TKIs also inhibited platelet adhesion to immobilized CRP-XL in a manner matching the effects of each TKI on ITAM-mediated signaling events. However, platelet signaling and adhesion phenotypes did not match the effects of these same TKIs on GPVI-triggered dense granule secretion, which was inhibited by all TKIs tested with the exception of R406. In contrast, all Syk and BTK inhibitors tested inhibited platelet spreading on immobilized fibrinogen. Based on observations above, we hypothesized that TKIs that irreversibly bind to BTK may disrupt critical molecular interactions around BTK within the PI3K signalosome essential to the proper orchestration of platelet activation programs. To test the effects of Syk and BTK inhibitors on the organization of PI3K signaling in activating platelets, platelets were pretreated with TKIs prior to incubation on immobilized fibrinogen and processing for immunofluorescence microscopy. We found that under control conditions, PI3K p85α regulatory subunit localized to phospholipid PI(3,4)P2-rich regions in adherent platelets associated with active PKC signaling. While Syk and PI3K inhibitors abrogated platelet spreading on fibrinogen, PI3K p85α staining remained strong around undeveloped, nascent adhesions in platelets treated with Syk and PI3K inhibitors. In contrast, PI3K p85α staining was diffuse, diminished or absent in platelets adherent to fibrinogen in the presence of all irreversible BTK inhibitors tested. Our results show that clinically effective kinase inhibitors that target Syk-BTK-PI3K signaling systems have varying effects on platelet function that may offer insights to adverse effects of therapeutic TKIs in different contexts. Moreover, our findings suggest that in addition inhibiting protein kinase activities, the discrepant effects of some TKIs may be attributed to, in part, altered protein relations around BTK, PLCγ2 and other components of the PI3K signalosome in activating platelets. Ongoing studies aim to specify protein:protein interactions affected by reversible as well as irreversible TKIs; to examine patient samples for evidence of PI3K mislocalization - especially in cases of BTK inhibitor-associated bleeding; and, to determine if PI3K signalosome disorganization has roles in other physiological, therapeutic and toxic effects of TKIs. Disclosures Shatzel: Aronora, Inc.: Consultancy.

TMIC-48. MACROPHAGE DEPLETION COMBINED WITH RADIATION IN A PRECLINICAL MEDULLOBLASTOMA MODEL

Abstract BACKGROUND Radiation induces a measurable immune response, yet this anti-tumor immunity is often suboptimal at eliminating residual brain tumor cells. Medulloblastomas, along with other pediatric brain tumors, tend to recur in the primary resection bed following irradiation. Infiltrating macrophage within the tumor (TAM) are radioresistant immune cells that may limit the effectiveness of radiotherapy and promote tumor regrowth through their immunosuppressive and pro-tumorigenic functions. Therefore, we explored whether CSF-1 receptor (CSF1R) inhibition, and essentially TAM depletion, could augment radiation and/or reduce local recurrence. METHODS Selected CSF1R inhibitors were tested on both human and mouse macrophage in vitro. In vivo studies were performed on a patient-derived orthotopic xenograft (PDOX) model of Group 3 medulloblastoma, Med411-FH. Macrophage depletion was achieved using the anti-murine CSF1R antibody, AFS98, injected intra-peritoneally 10 days prior to, concurrently, and after radiation. RESULTS CSF1R antibodies and small molecule tyrosine kinase inhibitors were effective at stanching macrophage survival in culture. In a PDOX medulloblastoma model, both classes of CSF1R inhibitors were effective at reducing macrophage in the brain after approximately 10 days of administration, with maximal effect of 90% depletion achieved after 21 days. In a combinatorial study of AFS98 and irradiation, TAM depletion conferred a very modest effect on tumor growth (p=0.003) and had no effect on overall survival when combined with radiation (p=0.86). Interestingly, we did observe a trend toward reduction in metastatic spinal disease following radiation in the AFS98-treated cohort. CONCLUSION CSF1R antibody administration effectively eliminated macrophage and microglia in the brain and spine, suggesting adequate blood-brain barrier penetration in our xenograft model. While CSF1R inhibition combined with radiation was ineffective at prolonging survival, further studies are needed to investigate a modest effect on brain tumor growth and an observed (yet not statistically significant) difference in metastatic spinal recurrence in drug-treated animals.

478O - Phase II study of fruquintinib plus gefitinib in stage IIIb/IV NSCLC patients harboring EGFR activating mutations

BackgroundFruquintinib is a potent and highly selective oral small molecule tyrosine kinase inhibitor of VEGFR. Preclinical data showed that a combined blockade of VEGFR and EGFR had synergistic antitumor effects. In the JO25567 trial, bevacizumab plus erlotinib had significantly prolonged median progression-free survival (PFS) in EGFR mutant NSCLC patients. Approaching this combined blockade with two oral drugs may improve ease of use for patients and greater therapeutic flexibility for physicians, while the high selectivity and shorter half-life of fruquintinib vs. a VEGF antibody may provide a better safety profile. MethodsThis is a single arm, open-label, multi-center, 2-cohort study in first line EGFR mutant NSCLC patients (NCT02976116). All patients receive 250 mg QD gefitinib (Gefi) continuously. Fruquintinib (Fruq) is given at 4 mg QD for 3 weeks followed by 1 week off in the first 4-week cycle. In cohort 1 the fruquintinib dose is escalated to 5 mg under the same 4-week cycle if no ≥grade 3 adverse event (AE) or ≥grades 2 liver dysfunction occurs in the first cycle. In cohort 2 fruquintinib remains at 4 mg. The primary objective is to assess the efficacy (objective response rate, ORR) and tolerability of this combination. The secondary objective is to assess PFS. ResultsAs of July 5, 2019, 26 and 24 patients have been enrolled in cohort 1 and cohort 2, respectively, and received at least one dose of each drug. Among them 26 had L858R mutation, and 24 had exon 19 deletions. The efficacy and safety data are summarized in the table below.Table478OTableCohort 1 N = 26Cohort 2 N = 24All N = 50EFFICACYORR73.1%70.8%72.0%Median PFS (months)14.714.714.7SAFETYAny TEAE26 (100%)24 (100%)50 (100%)≥ grade 3 TEAE17 (65.4%)11 (45.8%)28 (56.0%)SAE6 (23.1%)3 (12.5%)9 (18.0%)TEAE leading to Fruq / Gefi discontinuation6 (23.1%) / 6 (23.1%)4 (16.7%) / 4 (16.7%)10 (20.0%) / 10 (20.0%)TEAE leading to Fruq / Gefi interruption9 (34.6%) / 14 (53.8%)8 (33.3%) / 15 (62.5%)17 (34.0%) / 29 (58.0%)TEAE leading to Fruq / Gefi reduction18 (69.2%) / 0 (0%)15 (62.5%) / 0 (0%)33 (66.0%) / 0 (0%) ConclusionsFruquintinib plus gefitinib showed an overall acceptable safety profile and promising efficacy. 4 mg of fruquintinib (in combination with 250 mg of gefitinib) was better tolerated than 5 mg, without compromising efficacy. Confirmatory studies at this recommended dose are required to further verify the full potential of this treatment. Clinical trial identificationNCT02976116. Legal entity responsible for the studyHutchison MediPharma. FundingHutchison MediPharma. DisclosureS. Lu: Advisory / Consultancy: Hutchison MediPharma. Y. Chen: Full / Part-time employment: Hutchison MediPharma. W. Su: Full / Part-time employment: Hutchison MediPharma. All other authors have declared no conflicts of interest.

Nanoformulations of small molecule protein tyrosine kinases inhibitors potentiate targeted cancer therapy.

Protein tyrosine kinases (PTKs) are closely related to tumor development and usually participate in apoptosis, DNA repair, and cell proliferation by activating signaling pathways. Therefore, PTKs have become the most promising targets for cancer therapy. In recent years, a large number of studies on the mechanism of tyrosine kinase activation have indicated that tyrosine kinase inhibitors (TKIs) have important clinical significance and application prospects as targeted anticancer drugs because they can effectively block certain cellular signaling pathways, inhibit tumor metastases and reduce tumor proliferation. Although the increasing emergence of anticancer drug resistance limits the clinical application of TKIs, emerging nanotechnology has made it possible to solve this problem. In this work, the state-of-art of small molecule protein tyrosine kinase inhibitors and the applications of drug delivery systems for TKIs are reviewed, and the potentials and challenges for future research of small molecule TKIs are addressed.

Apatinib-loaded nanoparticles inhibit tumor growth and angiogenesis in a model of melanoma

Anti-angiogenic drugs are an effective therapeutic method for the treatment of melanomas. Apatinib is a small-molecule tyrosine kinase inhibitor, which has potent inhibitory activity on tumor angiogenesis. Due to the low water solubility and stability of Apatinib, we aimed to design and develop poly (lactic-co-glycolic acid) (PLGA) and Poloxamer 407 nanoparticles to encapsulate Apatinib (Apa/p NPs) to improve the efficacy of application in melanoma treatment. The size and morphology of the nanoparticles were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro proliferation assays were used to assess the capacity of Apa/p NPs to suppress the growth of B16 cells. Furthermore, we constructed melanoma models using C57BL/6 mice, and preliminary evaluation of the effect and mechanism of Apa/p NPs on tumor inhibition was performed in vivo. The results showed that the size of Apa/p NPs averaged 136 ± 0.27 nm and the nanoparticles were evenly dispersed. Moreover, Apa/p NPs significantly inhibited the growth of B16 cells and melanoma tumors, compared with the naked drug treatment and control groups. The protein levels of VEGFR-2, phosphorylated (p)-VEGFR-2 and p-ERK1/2 in tumor tissues were inhibited by Apa/p NP treatment, as detected by Western blot. The results of this study suggested that Apa/p NPs could inhibit the growth of melanoma tumors by inhibiting the phosphorylation and expression of VEGFR-2 and downstream ERK1/2, providing a theoretical basis for the clinical application of Apatinib in the treatment of melanoma.

ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway

Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) and MET proto-oncogene, receptor tyrosine kinase (MET). Unfortunately, hepatotoxicity is a serious limitation in its clinical application, and the reason remains largely unknown. In this study, we tested the effect of crizotinib in human hepatocyte cell line HL-7702 and human primary hepatocytes, and the results showed that crizotinib treatment caused hepatocyte damage, suggesting that crizotinib induced liver injury by causing hepatocyte death, consistent with the clinical cases. Mechanistically, crizotinib induced hepatocyte death via the apoptotic pathway, and cleaved PARP (c-PARP) was observed as a signaling protein. Moreover, mitochondrial membrane potential (MMP) decrease contributed to crizotinib-induced hepatocyte apoptosis accompanied by hepatocyte DNA damage and reactive oxygen species (ROS) generation. Importantly, crizotinib induced hepatocyte apoptosis independent of its targets, ALK, ROS1 and MET. In conclusion, our data showed that crizotinib induced liver injury through hepatocyte death via the apoptotic pathway which was independent of ALK, ROS1 and MET. And we also found that MMP decrease, DNA damage and ROS generation were involved in the process.

Pexidartinib: First Approval.

Pexidartinib (TURALIO™) is an orally administered small molecule tyrosine kinase inhibitor with selective activity against the colony-stimulating factor 1 (CSF1) receptor, KIT proto-oncogene receptor tyrosine kinase (KIT) and FMS-like tyrosine kinase 3 harboring an internal tandem duplication mutation (FLT3-ITD). In August 2019, the US FDA approved pexidartinib capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. This approval was based on positive results from the phase III ENLIVEN trial. Pexidartinib is being investigated in various malignancies as monotherapy or combination therapy. This article summarizes the milestones in the development of pexidartinib leading to its first approval for TGCT.

Pulmonary Adverse Events of Small Molecule Tyrosine Kinase Inhibitors: Meta-Analysis and Systematic Review

Background Small molecule tyrosine kinase inhibitors (smTKI) are signalling molecules, which modulate the cytokine receptor-mediated intracellular signal cascade, and is an effective treatment for several autoimmune diseases and malignancies. As smTKI are novel, long-term safety is uncertain. Commonly reported side effects include infections, typically pulmonary and herpes zoster. As published data mainly examines tofacitinib trials, the class effect of smTKI is unknown. Methods We performed a meta-analysis of all published trial data on the pulmonary adverse effects of smTKIs. EMBASE, MEDLINE, and CENTRAL databases were searched up to September 2018 for randomized controlled trials, observational studies, case reports, and post marketing surveillance, comparing any smTKI with placebo or another therapy, or as monotherapy at different doses. Primary outcomes comprised of any respiratory complications including upper and lower respiratory tract infections, influenza, opportunistic respiratory infections, pneumonia, interstitial pneumonitis, pulmonary embolism, and lung neoplasm. Findings We identified 2253 citations for screening, and selected 150 for full text review. Seventy-five studies were analyzed, including 49 RCTs, 16 observational studies, three case reports, and seven post-marketing surveillance studies, comprising 153,942 participants. Median duration of RCTs was 24 weeks. The overall risk of any pulmonary adverse event with smTKI is low across RCTs and observational studies. There was significantly increased risk of developing upper respiratory tract infections (URTI) (RD 0·03, 95% CI 0·02 to 0·04, p<0·00001, 36 trials, 16419 participants), pneumonia (RD 0·0032; 95% CI 0·0003 to 0·0060, p=0·03, 31 trials, 15001 participants) and influenza (RD 0·0078; 95% CI 0·0031, 0·0126; p=0·001, 5 trials, 16395 participants) after smTKI exposure. No significantly increased risk was found for other respiratory complications. Interpretation SmTKI increases risk of URTI, pneumonia and influenza compared with placebo or conventional agents. The risk of any pulmonary adverse event with smTKI is low. Funding Nil

Signal detection of chemotherapy-related cardiac dysfunction on small molecule tyrosine kinase inhibitors

Abstract Background Treatment results of small molecule tyrosine kinase inhibitors (TKIs) have been improved, but cancer treatment-related cardiac dysfunction (CTRCD) has become a problem. However, the CTRCD risk of TKIs has not been fully clarified, and monitoring indicators have not been established. Therefore, in order to detect CTRCD early, we aimed to pinpoint the TKIs that needs attention. Method Data from the Japanese Adverse Drug Event Report database from April 2004 through January 2018 was used. In this study, a total of 25 TKIs in monotherapy were studied in principle to avoid the presence of concomitant medication. We examined the relationship between heart failure and TKIs with a reporting odds ratio (ROR) which is a signal detection by data mining Method. The 95% confidence interval lower limit value > 1 was taken as a signal. We also confirmed the target kinase and heart failure alert in the package insert of the TKIs. Result Signals of heart failure were detected in 10 (Alectinib, Axitinib, Bosutinib, Dasatinib, Imatinib, Osimertinib, Pazopanib, Ponatinib, Ruxolitinib and Sunitinib) of the 25 TKIs, and ABL-1, VEGFR and PDGFR were common in the target kinases. Signals were also detected in Alectinib, Bosutinib and Osimertinib, but their package inserts did not alert for heart failure. Death cases were also included in reported heart failure cases. Conclusion Knowledge of the ten TKIs or drugs having ABL-1, VEGFR, PDGFR as the target kinase that signal for a risk of heart failure may lead to the early detection of adverse events by monitoring. There are also serious cases for three drugs for which the risk of heart failure is unknown, so we suggest that it is necessary to conduct periodic monitoring.

1033P - Phase Ib/IIa study assessing the safety and efficacy of adding AL3818 (anlotinib) to standard platinum-based chemotherapy in subjects with recurrent or metastatic endometrial, ovarian or cervical carcinoma

BackgroundAL 3818 (Anlotinib, Catequentinib) is a novel small molecule tyrosine kinase inhibitor that is administered orally. The primary objective of this study is to evaluate the safety, tolerability, and efficacy of adding AL3818, to standard platinum-based plus/or paclitaxel chemotherapy in patients with recurrent or metastatic endometrial, ovarian or cervical carcinoma in Phase 1b/2a studies. MethodsPatients with a diagnosis of recurrent or metastatic endometrial, ovarian, or cervical carcinomas requiring ≥ 2nd line treatment with standard platinum-based chemotherapy were eligible for enrollment on a 21 days cycle. In the Phase 1b study, after chemotherapy at Day 1, patients were started on Day 8 with daily AL 3818 at an initial dose of 12mg for 14 days on a 21day cycle. A 3+3 dose de-escalation design to 10mg, 8mg, and 6mg to determine the recommended Phase II dose (RP2D) was utilized. In the Phase 2a study, patients were treated with the RP2D in combination with either combination platinum based therapy or single agent paclitaxel based on origin of disease. 1st line endometrial patients are allowed. Maintenance monotherapy with AL3818 was given after chemotherapy stopped. ResultsIn the Phase 1b study: (1) 9 subjects with recurrent or metastatic endometrial, ovarian or cervical carcinomas participated with RP2D determined; (2) common treatment emergent adverse event (TEAE) include abdominal pain), alopecia, anemia, arthralgia, asthenia, back pain, and constipation. Overall, most TEAEs were well tolerated by subjects. In Phase 1b and 2a studies: (1) the objective response rate (ORR) and disease control rate (DCR) were 58% and 79% for 19 evaluable endometrial subjects; (2) ORR and DCR were 50% and 93% for all 14 evaluable ovarian subjects; (3) 48 subjects with recurrent or metastatic endometrial, ovarian, and cervical carcinoma were enrolled in the Phase 2a study. ConclusionsAL3818 has demonstrated positive combined synergic efficacy with standard platinum-based plus/or paclitaxel chemotherapy in both endometrial and ovarian cancer patients. Clinical trial identificationNCT02584478. Legal entity responsible for the studyAdvenchen Laboratories, LLC. FundingAdvenchen Laboratories. DisclosureZ. Li: Full / Part-time employment: Advenchen laboratories. M. Chen: Full / Part-time employment: Advenchen laboratories. J. Chen: Full / Part-time employment: Advenchen laboratories. All other authors have declared no conflicts of interest.

EP1.01-23 SRC Inhibition with Bosutinib as a Potential Approach for Restoring Pemetrexed Responsiveness

One of the principle approaches in malignant mesothelioma andnon-squamousnon-smallcelllung cancer management is cellular folate-dependentpathways inhibition with pemetrexed(PEM) combined with platinum-basedchemotherapy. Despite the promising activity of PEM, drug resistance demands new approaches allowing for abolishing resistance and better outcomes. In lung cancer, there is an association betweenin vitroPEMresistance, SRC over-expression, and thymidylatesynthase(TS) overexpression. We treated lung cancer cell line (A549) and mesothelioma cell line (MSTO) with PEM and bosutinib (a small molecule tyrosine kinase inhibitor (TKI)) which is also an SCR inhibitor. Increasing dose regimen was adopted with these drugs. Then we conducted cellviability assays (MTT tetrazolium), detection of SRC andTS expression by western blot and apoptotic assays (AnnexinV) for drug effect evaluation. Data showed that sequential treatment with bosutinib then PEM lowered the IC50 of PEM of both cell lines as indicated by cellviability and apoptosis assays. There was a 9% increase in apoptosis with combination regimen compared to PEM only regimen. Nevertheless, a decrease in TS expression was found, with correlation to the decrease in SRC expression. Combining bosutinib’s SCR inhibition to PEM activity may improve the latter’s therapeutic response due to synergism. Further in vivo evaluation for these results are needed to better understand these effects on tumor response

Incidence of Bleeding Complications With Flexible Bronchoscopy in Cancer Patients With Thrombocytopenia.

Bronchoscopy is a safe procedure, but current guidelines recommend transfusion for platelets <20 K/μL. Studies of bronchoscopy in thrombocytopenia are limited. Our objective was to evaluate the incidence of bleeding with flexible bronchoscopy in those with thrombocytopenia especially those <20 K/μL. We performed a retrospective review of all flexible bronchoscopies between June 1, 2008 and December 31, 2010. Biopsies and therapeutic procedures were excluded. The χ, Fisher exact, and Rank-sum test were conducted to evaluate associations of clinically significant bleeding. There were 1711 patients who underwent 2053 flexible bronchoscopies. Cancer diagnosis included hematologic (61.3%) and solid organ malignancy (34.9%). Half of the bronchoscopies had moderate to severe thrombocytopenia (<100 K/μL) with the following ranges: 14.7% with 50 to <100 K/μL, 20.6% with 20 to <50 K/μL, 10.6% with 10 to <20 K/μL, 4.1% with <10 K/μL. Platelet transfusion was given in 90.6% of those with platelets <10 K/μL and 55.5% of those with platelets 10 to <20 K/μL. The nasal route for bronchoscopy was used in 92.4%. Bleeding complication rate however was 1.1% (0.2% major) and not affected by platelets. Bronchoscopy with lavage can be safely performed without platelet transfusion in those with platelets of ≥10 K/μL. In the absence of nasal bleeding, trauma, or deformity, the nasal route can be used for bronchoscopy.

Efficacy of Low-dose Apatinib in Advanced HER2-negative Breast Cancer

Abstract Background HER2-negative breast cancer patients have fewer treatments than HER2-positive patients, especially in patients with metastatic breast cancer, Apatinib is a small-molecule tyrosine kinase inhibitor that selectively targets VEGFR-2. Previous studies have shown that apatinib can increase the anti-tumor activity of paclitaxel on drug-resistant tumor cells, and the application prospect of apatinib in breast cancer is considerable. However, intolerable side effects have forced patients who are clinically effective to stop taking drugs, which is a problem that has long plagued clinicians and patients. In this study, we assessed the efficacy and adverse effects of low-dose apatinib in advanced breast cancer. Methods 47 patients with advanced breast cancer admitted to Jiangsu Province Hospital from March 2017 to May 2019 were involved. Apatinib was prescribed orally at a dose of 250mg once daily. After two cycles of treatment, efficacy was evaluated by CT and MRI. If the economic conditions permit, the patient will also be tested for NGS before treatment. Results 47 patients had a median PFS of 4·8 months. Among them, there was no patient with complete remission, 12 cases with partial remission, 26 cases with stable disease, 9 cases with disease progression. Objective response rate (ORR) was 25·5%, and disease control rate (DCR) was 80·9%. Patients with BRCA mutations achieved median PFS of 11·0 months, compared with 3·8 months in patients without a mutation(P = 0·016). Patients without liver metastasis, the PFS was 5·0 months, and the PFS was 3·8 months in patients who have had liver metastasis before treatment (P = 0·020). Most of the adverse effects (hypertension, anemia, and hand-foot syndrome) were grade 1 to 2. Conclusion Patients with advanced breast cancer can benefit from low-dose apatinib treatment, while the adverse effects are mild, which deserves further study. Meanwhile, BRCA mutations may be a strong predictor of apatinib in HER2-negative breast cancer. Patients without liver metastasis had significantly longer PFS than patients with liver metastases, suggesting the organ selectivity of apatinib treatment.

Apatinib in patients with extensive-stage small-cell lung cancer after second-line or third-line chemotherapy: a phase II, single-arm, multicentre, prospective study

BackgroundSmall-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies.MethodsEligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate.ResultsForty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand–foot syndrome, increased L-gamma-glutamyltransferase.ConclusionsApatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted.Trial registrationNCT02945852.