Ensartinib in the treatment of anaplastic lymphoma kinase-positive locally advanced or metastatic patients with lung squamous or adenosquamous carcinoma: A real-world, retrospective study.

AIM: To report the efficacy and safety of ensartinib, an anaplastic lymphoma kinase (ALK) inhibitor, in treating patients with ALK-positive advanced lung squamous cell carcinoma (LUSC) or lung adenosquamous carcinoma (LASC) in China. METHODS: This retrospective study analyzed data for 36 advanced-stage patients with ALK-positive LUSC (cohort A) and 13 patients with ALK-positive LASC (cohort B) between December 16, 2020 and December 16, 2021. All patients received once-daily ensartinib 225 mg. Outcome analysis included the demographic characteristics, tumor response, progression-free survival (PFS), and treatment-related adverse events (TRAE). RESULTS: Among the 49 patients, the majority were under 65 years old (73.5%), non-smokers (85.7%), had an Eastern Cooperative Oncology Group Performance Status of 0-1 (77.6%), and were at stage IV (71.4%). All patients were included in the efficacy and safety analysis. Seven PFS events were reported in cohort A while no patients experienced PFS events in cohort B. The median PFS was not estimable for both cohorts. In cohort A, the objective response rate (ORR) was 63.9%, and the disease control rate (DCR) was 83.3%. In the cohort B, the ORR was 76.9% and the DCR was 100.0%. Rash was the only TRAE reported in the cohort A (8.3%) and cohort B (23.1%). No patients had grade 3 or higher TRAE. CONCLUSION: Ensartinib has been tentatively proven favorable efficacy and tolerability in the treatment of patients with ALK-positive advanced LUSC or LASC in the real-world. However, confirmatory studies are still needed in larger sample sizes.

Application of the ESMO Magnitude of Clinical Benefit Scale to assess the clinical benefit of antibody drug conjugates in solid cancer: a systematic descriptive analysis of phase III and pivotal phase II trials.

OBJECTIVE: The aim of this study was to assess the clinical benefit value of approved antibody drug conjugates (ADCs) for solid tumours using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) V.1.1. DESIGN: Systematic descriptive analysis. DATA SOURCES: PubMed was searched for publications from 1 January 2000 to 18 October 2023. ELIGIBILITY CRITERIA: We included the phase III randomised controlled trials or phase II pivotal trials leading to approval of ADCs in solid tumours. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and discrepancies were resolved by consensus in the presence of a third investigator. RESULTS: ESMO-MCBS Scores were calculated for 16 positive clinical trials of eight ADCs, which were first approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China National Medical Products Administration and the Japanese Pharmaceuticals and Medical Devices Agency for solid cancers. Among 16 trials, 4 (25%) met the ESMO-MCBS benefit threshold grade, while 12 (75%) of the regimens did not meet the ESMO-MCBS benefit threshold grade. 5 (31%) of the 16 trials had no published scorecard on the ESMO website due to the approval by other jurisdictions but not by the FDA or EMA. Discrepancies between our results and the ESMO scorecard were observed in 4 (36%) of 11 trials, mostly owing to integration of more recent data. CONCLUSIONS: ESMO-MCBS is an important tool for assessing the clinical benefit of cancer drugs, but not all drugs met the meaningful benefit threshold.

Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study.

BACKGROUND: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. METHODS: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. RESULTS: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. CONCLUSION: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study.

BACKGROUND: Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress. FINDINGS: Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events. INTERPRETATION: Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall. FUNDING: Betta Pharmaceuticals (China). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Safety and tolerability of oral vorolanib for neovascular (wet) age-related macular degeneration: a phase I, open-label study.

OBJECTIVE: To evaluate the efficacy and safety of oral vorolanib for the treatment of neovascular (wet) age-related macular degeneration (nAMD). METHODS: In the dose escalation, participants received ascending doses of oral vorolanib (25-100 mg daily). In the dose expansion, participants received recommended doses (25 and 50 mg daily). RESULTS: Between March 15, 2015, and January 23, 2019, 41 participants were enrolled in 6 centres in China. At the data cut-off (November 14, 2019), two dose-limiting toxicities (DLTs) were observed during dose escalation (one in the 75 mg cohort and one in the 100 mg cohort). The maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 33 (80.5%) participants, and grade 3 or higher TRAEs occurred in 12 (29.3%) participants. No fatal TRAEs were observed. Increases in the mean best-corrected visual acuity (BCVA) from baseline to Day 360 of +7.7 letters (range, -5-29; n = 41) were observed in participants who were administered vorolanib. Corresponding reductions in mean central subfield thickness (CST) and choroidal neovascularization (CNV) area at Day 360 were observed in these three groups. CONCLUSIONS: Oral administration of vorolanib improved visual outcomes in participants with nAMD with manageable systemic safety profiles.

Safety, efficacy and pharmacokinetics of BPI-9016M in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer: a phase Ib study.

BACKGROUND: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS/DESIGN: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). RESULTS: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1-13.8%) and 42.1% (16/38, 95% CI 26.3-59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4-99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9-3.7) and 10.3 months (95% CI 7.3-not evaluable [NE]), respectively. CONCLUSION: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02929290 (11/10/2016).

Development of HPLC-MS/MS assay for quantitation of ensartinib in human plasma and its application to a pharmacokinetics study in Chinese patients.

Ensartinib is a novel anaplastic lymphoma kinase (ALK) inhibitor with potent activity against a broad range of known crizotinib-resistant ALK mutations and is developed to treat patients with non-small-cell lung cancer. This study was the first to develop and validate a rapid and sensitive HPLC-MS/MS method for the determination of ensartinib in human plasma. The plasma samples were extracted using liquid extraction, and chromatographic separation was performed using a Phenomenex, Luna phenyl-hexyl column (50 × 2.0 mm, 5 µm). Electrospray ionization in positive-ion mode and multiple reaction monitoring were used to monitor ion transitions at m/z 561.3 → 257.1 (ensartinib) and 565.2 → 261.2 (internal standard: X-396-d4), respectively. The method yielded excellent linearity in the range of 0.5-500 ng/ml with the lowest quantification of 0.5 ng/ml. Both intra- and inter-run precisions (relative standard deviation %) were less than 15%, with accuracy (relative error %) between ±15%. Extraction recovery, matrix effect, selectivity, and stability were also validated and found to be satisfactory. Finally, the validated method was successfully applied in a phase I clinical study of ensartinib in Chinese subjects with advanced ALK-positive non-small-cell lung cancer.

Adjuvant icotinib versus observation in patients with completely resected EGFR-mutated stage IB NSCLC (GASTO1003, CORIN): a randomised, open-label, phase 2 trial.

Background: This phase 2 trial aimed to compare adjuvant icotinib with observation in patients with epidermal growth factor receptor (EGFR) mutation-positive resected stage IB non-small cell lung cancer (NSCLC). Methods: We performed a randomised, open-label, phase 2 trial from May 1, 2015 to December 29, 2020 at Sun Yat-sen University Cancer Center in China. Patients with completely resected, EGFR-mutant, stage IB (the 7th edition of TNM staging) NSCLC without adjuvant chemotherapy were randomised (1:1) to receive adjuvant therapy with icotinib (125 mg, three times daily) for 12 months or to undergo observation until disease progression or intolerable toxicity occurred. The primary endpoint was 3-year disease-free survival (DFS). CORIN (GASTO1003) was registered with Clinicaltrials.gov, with the number NCT02264210. Findings: A total of 128 patients were randomised, with 63 patients in the icotinib group and 65 patients in the observation group. The median duration of follow-up was 39.9 months. The three-year DFS was significantly higher in the icotinib group (96.1%, 95% confidence interval [CI], 91.3-99.9) than in the observation group (84.0%, 95% CI, 75.1-92.9; P = 0.041). The DFS was significantly longer in the icotinib group than in the observation group, with a hazard ratio (HR) of 0.23 (95% CI, 0.07-0.81; P = 0.013). The OS data were immature, with three deaths in the observation arm. In the icotinib group, adverse events (AEs) of any grade were reported in 49 patients (77.8%), and grade 3 or greater AEs occurred in four patients (6.3%). No treatment-related deaths occurred. Interpretation: Our findings suggested that adjuvant icotinib improved the 3-year DFS in patients with completely resected EGFR-mutated stage IB NSCLC with a manageable safety profile. Funding: This study was sponsored by Betta Pharmaceutical Co., Ltd.

Radiomic-signature changes after early treatment improve the prediction of progression-free survival in patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer.

BACKGROUND: The prognosis of lung cancer varies widely, even in cases wherein the tumor stage, genetic mutation, and treatment regimens are the same. Thus, an effective means for risk stratification of patients with lung cancer is needed. PURPOSE: To develop and validate a combined model for predicting progression-free survival and risk stratification in patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) treated with ensartinib. MATERIAL AND METHODS: We analyzed 203 tumor lesions in 114 patients and evaluated average radiomic feature measures from all lesions at baseline and changes in these features after early treatment (Δradiomic features). Combined models were developed by integrating clinical with radiomic features. The prediction performance and clinical value of the proposed models were evaluated using receiver operating characteristic analysis, calibration curve, decision curve analysis (DCA), and Kaplan-Meier survival analysis. RESULTS: Both the baseline and delta combined models achieved predictive efficacy with a high area under the curve. The calibration curve and DCA indicated the high accuracy and clinical usefulness of the combined models for tumor progression prediction. In the Kaplan-Meier analysis, the delta and baseline combined models, Δradiomic signature, and two selected clinical features could distinguish patients with a higher progression risk within 42 weeks. The delta combined model had the best performance. CONCLUSION: The combination of clinical and radiomic features provided a prognostic value for survival and progression in patients with NSCLC receiving ensartinib. Radiomic-signature changes after early treatment could be more valuable than those at baseline alone.

Efficacy and safety of vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT).

BACKGROUND: Vorolanib is a highly potent tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor. This three-arm, randomised, registered study aimed to assess the combination of vorolanib and everolimus or vorolanib alone versus a control arm of everolimus as second-line treatment in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with advanced or metastatic RCC who had received one prior VEGFR-TKI were randomised (1:1:1) to receive the combination of vorolanib and everolimus or either monotherapy. Patients with brain metastases were excluded. The primary end-point was progression-free survival (PFS) assessed by the independent review committee per Response Evaluation Criteria in Solid Tumours v1.1. RESULTS: Between 10th March 2017 and 30th May 2019, 399 patients (133 in each group) were enrolled. By the cutoff date (30th April 2020), a significant improvement in PFS was detected in the combination group compared with the everolimus group (10.0 versus 6.4 months; hazard ratio, 0.70; P = 0.0171). PFS was similar between the vorolanib group and the everolimus group (median: 6.4 versus 6.4 months; hazard ratio, 0.94; P = 0.6856). A significantly higher objective response rate was observed in the combination group than in the everolimus group (24.8% versus 8.3%; P = 0.0003), whereas there was no significant difference between the vorolanib group and the everolimus group (10.5% versus 8.3%; P = 0.5278). The overall survival data were immature. A total of 96 (72.2%), 52 (39.1%) and 71 (53.4%) grade 3 or higher treatment-related adverse events occurred in the combination group, vorolanib group and everolimus group, respectively. CONCLUSIONS: The addition of vorolanib to everolimus as 2nd-line treatment for patients with advanced or metastatic RCC who have experienced cancer progression after VEGFR-TKI therapy provided a better objective response rate and PFS than everolimus alone with a manageable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03095040; Chinadrugtrials, CTR20160987.

Simultaneous quantitation of befotertinib (D-0316) and its metabolite D-0865 in human plasma by LC-MS/MS method.

A sensitive and reliable method was developed to determine befotertinib (D-0316) and its metabolite D-0865 from human plasma by LC-MS/MS. The samples were prepared by simple protein precipitation and 2 µL of the supernatant were chromatographed on a C18 analytical column (ACE Excel 2 Super C18, 50 × 2.1 mm). Elution was performed with mobile phase A (10 mM ammonium acetate in water containing 1 % formic acid) and mobile phase B (acetonitrile containing 1 % formic acid) under a gradient program in a total run time of 4 min. Triple Quadruple 5500 equipped with Turbo Ion Spray source and multiple reaction monitoring (MRM) were used for the analysis detection. The transitions were m/z 568.3 â†’ 72.1 m/z (befotertinib), m/z 554.2 â†’ 497.2 (D-0865), and m/z 455.2 â†’ 164.9 (verapamil, internal standard). According to the Chinese Pharmacopeia Commission and ICH Harmonised Guideline for Bioanalytical Method Validation, this method was validated within the spectrum of its accuracy, precision, selectivity, linearity, recovery, matrix effect, and stability. This LC-MS/MS method was successfully applied for the quantitation of befotertinib and its metabolite D-0865 in human plasma during the pharmacokinetics study of befotertinib in non-small cell lung cancer (NSCLC) patients.

A retrospective study of ensartinib-treated ALK-positive locally advanced or metastatic NSCLC patients in China.

Aim: This retrospective study aimed to assess the efficacy and safety of ensartinib in Chinese patients with ALK-positive advanced NSCLC in real-world clinical practice. Methods: Clinical data from ALK-positive NSCLC patients treated with ensartinib in China were collected and analyzed. Efficacy end points included objective response rate and progression-free survival. Safety profiles were also evaluated. Results: A total of 682 patients were included in this study. The study demonstrated promising efficacy with an objective response rate of 54.0%, and the median progression-free survival was not estimable. Ensartinib exhibited a manageable safety profile with treatment-related adverse events (TRAEs) consistent with prior clinical trials. The most common TRAE was rash (21.1%) and no TRAE led to death. Conclusion: Ensartinib is active and well tolerated for ALK-positive NSCLC patients in real-world clinical settings.

Targeted therapies have significantly improved outcomes for patients with ALK-positive NSCLC. Ensartinib, a drug which blocks an enzyme in the body called ALK tyrosine kinase, has shown to be efficient and well tolerated in clinical trials. However, real-world evidence is crucial to confirm its effectiveness and safety in diverse patient populations. We analyzed the real-world outcomes of ensartinib treatment in 682 ALK-positive NSCLC patients in China, by looking at past records. The results showed that ensartinib demonstrated positive effects in most patients, meaning it helped in controlling their cancer progression. Side effects affected approximately one quarter of patients and most reported side effects were mild. Rash was the most reported side effect, accounting for about 21%. This study provides valuable insights into the real-world clinical performance of ensartinib, confirming its effectiveness and safety as a treatment option for ALK-positive NSCLC patients.

Phase I Trial of a Third Generation EGFR Mutant-Selective Inhibitor (D-0316) in Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: D-0316 is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR T790M mutation that progressed after prior treatment with the first- or second-generation EGFR-TKI. METHODS: This phase I, open-label, multicenter clinical trial evaluated daily oral D-0316 administration in dose-escalation (25 to 150 mg; 17 patients) and dose-expansion (50, 100 mg; 67 patients) cohorts for safety, tolerability, anti-tumor activity, and pharmacokinetics. RESULTS: D-0316 was well tolerated at daily doses of 25 to 150 mg and the maximum tolerated dose (MTD) was not reached. The most common treatment-related adverse events (AEs) were platelet count decreased, electrocardiogram QT corrected interval prolonged, anemia, rash, low white blood cell count, hypertriglyceridemia, high cholesterol, headache, pruritus, cough, and aspartate transaminase (AST) or alanine transaminase (ALT) increased. Most of AEs were grade 1 or 2. In the 50 and 100 mg group, the overall response rate (ORR) was 33.3% and 45.5%, the disease control rate (DCR) was 86.7% and 93.9%, and the median PFS was 8.3 and 9.6 months, respectively. D-0316 exposure increased in proportion to dose from 25 to 150 mg. The recommended phase II dose (RP2D) was 100 mg. CONCLUSION: D-0316 is safe, tolerable, and effective for patients with locally advanced/metastatic NSCLC with the EGFR T790M mutation who previously received EGFR-TKI. CLINICALTRIALS.GOV IDENTIFIER: NCT03452150.

Vorolanib, a novel tyrosine receptor kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity.

Vorolanib (CM082) is a multi-targeted tyrosine kinase receptor inhibitor with a short half-life and limited tissue accumulation that has been shown to reduce choroidal neovascularization in rats. In this preclinical study, vorolanib demonstrated competitive binding and inhibitory activities with KDR, PDGFRß, FLT3, and C-Kit, and inhibited RET and AMPKα1 more weakly than sunitinib, indicating more stringent kinase selectivity. Vorolanib inhibited vascular endothelial growth factor (VEGF)-induced proliferation of human umbilical vein endothelial cells (HUVECs) and HUVEC tube formation in vitro. In mouse xenograft models, vorolanib inhibited tumor growth of MV-4-11, A549, 786-O, HT-29, BxPC-3, and A375 cells in a dose-dependent fashion. Complete tumor regression was achieved in the MV-4-11 xenograft model. No significant toxicities were observed in vorolanib groups, whereas a significant negative impact on body weights was observed in the sunitinib group at a dose of 40 mg/kg qd. Overall, vorolanib is a novel multi-kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity that is potentially less toxic than other similar kinase inhibitors.

Ensartinib in advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, two-staged, phase 1 trial.

Background: Ensartinib, a potent second-generation tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET and ROS1, was evaluated in a phase I clinical trial in patients with advanced, ALK-rearranged non-small cell lung cancer (NSCLC). Methods: Patients with advanced, ALK or ROS1-positive NSCLC were recruited from 2 centers in China. This study consisted of dose escalation and expansion stages. Patients were treated with oral ensartinib [dosage of escalation stage was from 150, 200, 225 to 250 mg per day, expansion stage was recommended phase II dose (RP2D)] in continuous 28-day cycles. The primary objectives were safety, dose limited toxicity (DLT), maximum tolerated dose (MTD), and RP2D based on tolerability. Key secondary objectives included pharmacokinetic (PK) and anti-tumor activity. Results: Forty-eight patients were enrolled, 37 (77.1%) were ALK TKI-naïve, 11 (22.9%) patients had previously received crizotinib, ceritinib or alectinib. Ensartinib was well tolerated and common treatment-related adverse events (TRAEs) included rash (87.5%), transaminase elevation (60.4%), pruritus (45.8%) and creatinine elevation (35.4%). The top 3 grade 3-5 TRAEs were rash (14.6%), elevated alanine aminotransferase (ALT) (12.5%) and aspartate transaminase (AST) (4.2%). Two DLTs were observed in 250 mg, so MTD and RP2D was 225 mg per day. Ensartinib was moderately absorbed (median Tmax: 3.00-4.00 h) and slowly eliminated (mean T1/2: 21.0-30.2 h). The area under the curve (AUC) of ensartinib reached saturation at 200 to 225 mg and no major accumulation after daily administration. For all patients, the objective response rate (ORR) and disease control rates (DCR) were 64.6 % and 81.3%, median progression-free survival (mPFS) was 16.79 months. In subgroup analysis, the ORR and mPFS was 81.3% and 45.5%, 25.73 and 4.14 months in TKI-naïve and -treated ALK+ patients, respectively. The intra-cranial ORR and mPFS for patients with measurable brain metastases were 66.7% and 22.90 months. ALK abundance may predict the efficacy of ensartinib. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed specific signaling pathways enrichment in long and short progression-free survival (PFS) groups. Conclusions: Ensartinib was well tolerated under 225 mg (MTD) and demonstrated promising anti-tumor activity in ALK+ NSCLC patients, including those with CNS metastases and those previously TKI-treated. Trial Registration: ClinicalTrials.gov NCT02959619.

Integrated Multiomics Analyses Revealing Different Molecular Profiles Between Early- and Late-Stage Lung Adenocarcinoma.

The molecular differences in genetic and epigenetic profiling between early-stage (ES) and late-stage (LS) lung adenocarcinoma (LUAD), which might help to understand cancer progression and biomarker guided precision treatment, need further be investigated. In this study, we performed comprehensive analysis using multi-omics next-generation sequencing (NGS) on tissue samples from 7 ES (stage I) and 10 LS (stage III/IV) LUAD patients to study molecular characteristics between the two groups. Characterization of the genomic and transcriptomic profiles showed stage-specific somatic mutations, copy number variations (CNVs) and differentially expressed genes (DEGs). LS samples tend to have more TP53, ERBB2 and CHD4 mutations. Gene copy number loss occurs in immune-related gene pathways in the late stage of LUAD. ATAC-seq analysis showed that LS samples harbored more open chromatin peaks around promoter regions and transcription start sites (TSS) than ES samples. We then identified the known transcription factor (TF) binding motifs for the differentially abundant ATAC-seq peaks between the ES and LS samples and found distinct regulatory mechanisms related to each stage. Furthermore, integrative analysis of ATAC-seq with WGS and RNA-seq data showed that the degree of chromatin accessibility is related to copy number changes, and the open chromatin regions could directly regulate the expression of some DEGs. In conclusion, we performed a comprehensive multi-omics analysis of the early and late stages of LUAD and highlighted some important molecular differences in regulatory mechanisms during cancer progression. Those findings help to further understand mechanism and biomarker related targeted therapy.

Efficacy of Icotinib, an EGFR Tyrosine Kinase Inhibitor in Non-Small Cell Lung Cancer Patients with Exon 19 Deletion and Exon 21 L858R: A Retrospective Analysis in China.

INTRODUCTION: The effect of icotinib on non-small cell lung cancer (NSCLC) patients with EGFR exon 19 deletions (19-Del) or L858R point mutation in exon 21 (21-L858R) remains inconsistent. This study aimed to evaluate the efficacy and safety of icotinib in patients with advanced NSCLC harboring these 2 EGFR mutations. METHODS: We retrospectively assessed the clinical effects of first-line icotinib on advanced NSCLC patients with 2 classic EGFR mutations. Kinase activity assays were used to reaffirm the preclinical efficacy. RESULTS: Among 2,757 patients, 2,365 (86%) harbored 19-Del (1,346/2,757, 49%) or 21-L858R (1,019/2,757, 37%) mutation. Patients with 19-Del had a higher response rate (ORR; 67.8 vs. 62.1%; p = 0.0039) and disease control rate (98.5 vs. 97.2%; p = 0.0223) than those with 21-L858R mutation. The median progression-free survival (PFS) in the 19-Del group (22.3 months, 95% confidence interval [CI]: 21.3-23.4) was significantly longer than that in the 21-L858R group (20.4 months, 95% CI: 19.5-21.7) (p = 0.004). In multivariate analysis, mutation types, clinical stage, and smoking history were significant factors for PFS. Additionally, an in vitro study indicated the 50% inhibitory concentrations (IC50) of icotinib was lower for EGFR 19-Del than 21-L858R. CONCLUSION: These results suggest that EGFR 19-Del confers superior PFS and response to the icotinib treatment compared to 21-L858R.

Transcriptomic and Mutational Analysis Discovering Distinct Molecular Characteristics Among Chinese Thymic Epithelial Tumor Patients.

INTRODUCTION: Thymic epithelial tumors (TETs) are malignancies arising from the epithelium of the thymic gland, rare but with relatively favorable prognosis. TETs have different pathological subtypes: thymomas and thymic carcinoma, and they show different clinical characteristics regarding prognosis, pathology, and molecular profiles, etc. Although some studies have investigated the pathogenesis of TETs, more molecular data is still needed to further understand the underlying mechanisms among different TETs subtypes and populations. METHODS: In this study, we performed targeted gene panel sequencing and whole transcriptome sequencing on the tumor tissues from 27 Chinese TET patients, including 24 thymomas (A, AB, and B subtypes) and 3 thymic squamous cell carcinomas. We analyzed the genetic variations and differentially expressed genes among multiple TET subtypes. Moreover, we compared our data with the published The Cancer Genome Atlas (TCGA) TET data on both the genetic and transcriptomic levels. RESULTS: Compared with the TCGA TET genomic data, we found that NF1 and ATM were the most frequently mutated genes (each with a frequency of 11%, 3/27). These mutations were not mutually exclusive, since one B1 thymoma showed mutations of both genes. The GTF2I mutation was mainly enriched in subtype A and AB thymomas, consistent with the previous reports. RNA-seq results unveiled that the genes related to thymus development (FGF7, FGF10 and CLDN4) were highly expressed in certain TET subtypes, implicating that the developmental process of thymus might be linked to the tumorigenesis of these subtypes. We found high expression of CD274 (PD-L1) in B2 and B3 thymoma samples, and validated its expression using immunohistochemistry (IHC). Based on the expression profiles, we further established a machine learning model to predict the myasthenia gravis status of TET patients and achieved 90% sensitivity and 70.6% specificity in the testing cohort. CONCLUSION: This study provides the first genomic and transcriptomic analysis of a Chinese TET cohort. The high expression of genes involved in thymus developmental processes suggests the potential association between tumorigenesis of TETs and dysregulation of developmental pathways. The high expression of PD-L1 in B2 and B3 thymomas support the potential application of immunotherapy on certain thymoma subtypes.

Safety but Limited Efficacy of Ensartinib in ROS1-Positive NSCLC: A Single-Arm, Multicenter Phase 2 Study.

INTRODUCTION: Some ALK inhibitors with good inhibition of ROS1 in preclinical studies have been reported to be possibly beneficial in ROS1-positive NSCLC. In this work, we studied the efficacy and safety of ensartinib in the treatment of patients with ROS1-positive NSCLC. METHODS: The exploratory study was a phase 2, single-arm, multicenter design (NCT03608007). Patients with ROS1-positive NSCLC with a previous chemotherapy line number of less than or equal to 1 who received ensartinib at the dose of 225 mg once daily were enrolled. The primary end point was objective response rate evaluated by an investigator per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: From June 2018 to July 2019, a total of 59 patients were enrolled at 23 centers in the People's Republic of China. At the time of data cutoff, the median follow-up was 19.8 months (range: 0.8-22.5). The median objective response rate was 27.0 % (95 % confidence interval [CI]: 13.8-44.1) with 10 partial responses. Median duration of response was 4.8 months (95 % CI: 1.8-10.8). The median progression-free survival was 4.6 months (95 % CI: 4.0-6.4). The median overall survival was not estimable (95 % CI: 14.9-not estimable). Of four patients with brain metastases, intracranial disease control was reported in three (75.0 %, 95 % CI: 19.4-99.4). The most common treatment-related adverse events (TRAEs) were rash and liver enzyme abnormalities, with good prognosis after adjustment for dosage and concomitant medication. Most of the TRAEs were of grades 1 to 2, and incidence of grade greater than or equal to 3 TRAEs was 25.4 %. CONCLUSIONS: Ensartinib had a modest efficacy in patients with ROS1-positive NSCLC with an acceptable safety profile.

Icotinib versus chemotherapy as adjuvant treatment for stage II-IIIA EGFR-mutant non-small-cell lung cancer (EVIDENCE): a randomised, open-label, phase 3 trial.

BACKGROUND: Icotinib has provided survival benefits for patients with advanced, epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). We aimed to compare icotinib with chemotherapy in patients with EGFR-mutant stage II-IIIA NSCLC after complete tumour resection. Here, we report the results from the preplanned interim analysis of the study. METHODS: In this multicentre, randomised, open-label, phase 3 trial done at 29 hospitals in China, eligible patients were aged 18-70 years, had histopathogically confirmed stage II-IIIA NSCLC, had complete resection up to 8 weeks before random assignment, were treatment-naive, and had confirmed activation mutation in exon 19 or exon 21 of the EGFR gene. Participants were randomly assigned (1:1) with an interactive web-based response system to receive either oral icotinib 125 mg thrice daily for 2 years or four 21-day cycles of intravenous chemotherapy (vinorelbine 25 mg/m2 on days 1 and 8 of each cycle plus cisplatin 75 mg/m2 on day 1 of each cycle for adenocarcinoma or squamous carcinoma; or pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 every 3 weeks for non-squamous carcinoma). The primary endpoint was disease-free survival assessed in the full analysis set. Secondary endpoints were overall survival assessed in the full analysis set and safety assessed in all participants who received study drug. This trial is registered with ClinicalTrials.gov, NCT02448797. FINDINGS: Between June 8, 2015, and August 2, 2019, 322 patients were randomly assigned to icotinib (n=161) or chemotherapy (n=161); the full analysis set included 151 patients in the icotinib group and 132 in the chemotherapy group. Median follow-up in the full analysis set was 24·9 months (IQR 16·6-36·4). 40 (26%) of 151 patients in the icotinib group and 58 (44%) of 132 patients in the chemotherapy group had disease relapse or death. Median disease-free survival was 47·0 months (95% CI 36·4-not reached) in the icotinib group and 22·1 months (16·8-30·4) in the chemotherapy group (stratified hazard ratio [HR] 0·36 [95% CI 0·24-0·55]; p<0·0001). 3-year disease-free survival was 63·9% (95% CI 51·8-73·7) in the icotinib group and 32·5% (21·3-44·2) in the chemotherapy group. Overall survival data are immature with 14 (9%) deaths in the icotinib group and 14 (11%) deaths in the chemotherapy. The HR for overall survival was 0·91 (95% CI 0·42-1·94) in the full analysis set. Treatment-related serious adverse events occurred in two (1%) of 156 patients in the icotinib group and 19 (14%) of 139 patients in the chemotherapy group. No interstitial pneumonia or treatment-related death was observed in either group. INTERPRETATION: Our results suggest that compared with chemotherapy, icotinib significantly improves disease-free survival and has a better tolerability profile in patients with EGFR-mutant stage II-IIIA NSCLC after complete tumour resection. FUNDING: Betta Pharmaceuticals TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.