Dataset Information

First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer.

ABSTRACT: BACKGROUND:BPI-9016M is a novel small-molecule inhibitor that simultaneously targets both c-Met and AXL tyrosine kinases. This phase I study aimed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of BPI-9016M in Chinese patients with advanced non-small cell lung cancer (NSCLC). METHODS:Over the dose range of 100?mg to 800?mg, eligible patients were administered with a single dose of 9016M tablet and received 7?days of pharmacokinetics evaluation, followed by continuous dose administration (QD dosing, 28?days). Standard "3 + 3" dose escalations were performed. RESULTS:Twenty NSCLC patients were treated. All patients experienced at least one adverse event (AE), of which treatment-related adverse events (TRAEs) were reported in 17 (85.0%) patients. The most common TRAEs were alanine transaminase (ALT) elevation (60%), bilirubin increased (40%), dysgeusia (40%), constipation (30%), hypertension (25%), and palmar-plantar erythrodysesthesia syndrome (15%). The TRAEs of grade 3 or higher during treatment were hypertension (15%), pulmonary embolism (5%), and laryngeal pain (5%). No dose-limiting toxicity (DLT) was observed, and the MTD was not reached. The median time to Cmax ranged from 2.0 to 3.5?h, and the plasma concentration of BPI-9016M declined rapidly after Tmax fitting a single-compartment model. The mean AUC0-72?h of M1 and M2-2, main metabolites of BPI-9016M, were 4.8-6.6 folds and 4.1-9.8 folds higher than that of BPI-9016M, respectively. Exposure to BPI-9016M, M1, and M2-2 reached moderate saturation at 600?mg. Among 19 evaluable patients, 1 had a partial response and 10 patients had stable disease. CONCLUSION:BPI-9016M showed favorable safety and pharmacokinetic profiles, and no DLT was observed at doses up to 800?mg once daily. The promising antitumor activity in Chinese NSCLC patients supports further development of this tyrosine kinase inhibitor. TRIAL REGISTRATION:Clinical Trial ID: NCT02478866, registered May 21, 2015.

SUBMITTER: Hu X

PROVIDER: S-EPMC6966871 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer.

Hu Xingsheng X Zheng Xin X Yang Sheng S Wang Lin L Hao Xuezhi X Cui Xinge X Ding Lieming L Mao Li L Hu Pei P Shi Yuankai Y

Journal of hematology & oncology 20200116 1

<h4>Background</h4>BPI-9016M is a novel small-molecule inhibitor that simultaneously targets both c-Met and AXL tyrosine kinases. This phase I study aimed to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of BPI-9016M in Chinese patients with advanced non-small cell lung cancer (NSCLC).<h4>Methods</h4>Over the dose range of 100 mg to 800 mg, eligible patients were administered with a single dose of 9016M tablet and received 7 days of pharmacokinetics ...[more]

PMID: 31948451

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Project description:Activation of c-Met plays a critical role in tumorigenesis, migration and invasion in lung cancer. Here, we explored the therapeutic efficacy of a novel small-molecule c-Met inhibitor (BPI-9016M) in lung adenocarcinoma and investigated the underlying molecular mechanisms. Method: BPI-9016M, a c-Met tyrosine kinase receptor inhibitor, was used to treat patient-derived xenografts (PDX) from lung adenocarcinoma in NOD/SCID mice. Immunohistochemistry and Western blot analysis were used to determine the expression of c-Met and its downstream signaling molecules. CCK8, wound healing, and trans-well assays were used to analyze cell proliferation, spreading, migration and invasion. RNA sequencing and quantitative real-time PCR (qPCR) was used to screen and validate the expression of downstream genes in lung adenocarcinoma cells treated with BPI-9016M. Luciferase reporter assay was used to detect the interaction between miRNA and the targeted gene. Results: BPI-9016M significantly suppressed growth in three out of four lung adenocarcinoma PDX models, particularly in the tumors with high expression of c-Met. In lung adenocarcinoma cell lines, BPI-9016M treatment resulted in increased miR203, which reduced migration and invasion and also repressed Dickkopf-related protein 1 (DKK1) expression. Forced overexpression of DKK1 or down-regulation of miR203 reversed the inhibitory effect of BPI-9016M on migration and invasion. C-Met was verified to positively and negatively associate with DKK1 and miR203, respectively. High expression of c-Met/DKK1 or low expression of miR203 related to poor outcome of lung adenocarcinoma patients. Furthermore, we observed significantly enhanced tumor cell growth inhibition upon combining BPI-9016M treatment with miR203 mimics or DKK1 siRNA. Conclusion: Our data indicated that BPI-9016M is an effective agent against lung adenocarcinoma, particularly in tumors with c-Met activation, and likely functions through upregulation of miR203 leading to reduced DKK1 expression.

Project description:PURPOSE:Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non-small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first-line treatment for advanced NSCLC. MATERIALS AND METHODS:Published and presented literature was searched using the key search terms "non-small cell lung cancer" AND "checkpoint-inhibitors" (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first-line advanced NSCLC were identified. RESULTS:Four first-line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab-chemotherapy, atezolizumab-chemotherapy, and atezolizumab-bevacizumab-chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor-negative (EGFR-)/ anaplastic lymphoma kinase gene (ALK)- NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab-chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab-ipilimumab in all-comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab-chemotherapy administered based on PD-L1 status and histology is a preferred treatment option. Outcomes for atezolizumab-bevacizumab-chemotherapy in EGFR+/ALK+ patients are promising and require further exploration. CONCLUSION:First-line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR-/ALK- and squamous advanced NSCLC. IMPLICATIONS FOR PRACTICE:Single-agent immune checkpoint inhibitors are now standard of care for advanced non-small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE-189 and IMPower-130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE-407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first-line NSCLC. Programmed death ligand-1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy.

Project description:BackgroundThird-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance.MethodsFor Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at?-80°C.ResultsIn a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs.ConclusionAcquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.

Dataset Information

First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer.

Publications

First-in-human phase I study of BPI-9016M, a dual MET/Axl inhibitor, in patients with non-small cell lung cancer.

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