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.

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.

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.

Interferon-gamma and tumor necrosis factor-alpha synergistically enhance the immunosuppressive capacity of human umbilical-cord-derived mesenchymal stem cells by increasing PD-L1 expression.

BACKGROUND: The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several proinflammatory factors to express immunosuppressive factors such as programmed cell death 1 ligand 1 (PD-L1), which determines the clinical therapeutic efficacy of MSCs for inflammatory or immune diseases. In MSCs, interferon-gamma (IFN-γ) is a key inducer of PD-L1 expression, which is synergistically enhanced by tumor necrosis factor-alpha (TNF-α); however, the underlying mechanism is unclear. AIM: To reveal the mechanism of pretreated MSCs express high PD-L1 and explore the application of pretreated MSCs in ulcerative colitis. METHODS: We assessed PD-L1 expression in human umbilical-cord-derived MSCs (hUC-MSCs) induced by IFN-γ and TNF-α, alone or in combination. Additionally, we performed signal pathway inhibitor experiments as well as RNA interference experiments to elucidate the molecular mechanism by which IFN-γ alone or in combination with TNF-α induces PD-L1 expression. Moreover, we used luciferase reporter gene experiments to verify the binding sites of the transcription factors of each signal transduction pathway to the targeted gene promoters. Finally, we evaluated the immunosuppressive capacity of hUC-MSCs treated with IFN-γ and TNF-α in both an in vitro mixed lymphocyte culture assay, and in vivo in mice with dextran sulfate sodium-induced acute colitis. RESULTS: Our results suggest that IFN-γ induction alone upregulates PD-L1 expression in hUC-MSCs while TNF-α alone does not, and that the co-induction of IFN-γ and TNF-α promotes higher expression of PD-L1. IFN-γ induces hUC-MSCs to express PD-L1, in which IFN-γ activates the JAK/STAT1 signaling pathway, up-regulates the expression of the interferon regulatory factor 1 (IRF1) transcription factor, promotes the binding of IRF1 and the PD-L1 gene promoter, and finally promotes PD-L1 mRNA. Although TNF-α alone did not induce PD-L1 expression in hUC-MSCs, the addition of TNF-α significantly enhanced IFN-γ-induced JAK/STAT1/IRF1 activation. TNF-α up-regulated IFN-γ receptor expression through activation of the nuclear factor kappa-B signaling pathway, which significantly enhanced IFN-γ signaling. Finally, co-induced hUC-MSCs have a stronger inhibitory effect on lymphocyte proliferation, and significantly ameliorate weight loss, mucosal damage, inflammatory cell infiltration, and up-regulation of inflammatory factors in colitis mice. CONCLUSION: Overall, our results suggest that IFN-γ and TNF-α enhance both the immunosuppressive ability of hUC-MSCs and their efficacy in ulcerative colitis by synergistically inducing high expression of PD-L1.

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.

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.

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.

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.

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.

TNF-α augments CXCL10/CXCR3 axis activity to induce Epithelial-Mesenchymal Transition in colon cancer cell.

Chronic inflammation-induced metastases have long been regarded as one of the significant obstacles in treating cancer. Tumor necrosis factor-α (TNF-α), a main inflammation mediator within tumor microenvironment, affects tumor development by inducing multiple chemokines to establish a complex network. Recent reports have revealed that CXCL10/CXCR3 axis affects cancer cells invasiveness and metastases, and Epithelial-mesenchymal transition (EMT) is the main reason for frequent proliferation and distant organ metastases of colon cancer (CC) cells, However, it is unclear whether TNF-α- mediated chronic inflammation can synergically enhance EMT-mediated CC metastasis through promoting chemokine expression. According to this study, TNF-α activated the PI3K/Akt and p38 MAPK parallel signal transduction pathways, then stimulate downstream NF-κB pathway p65 into the nucleus to activate CXCL10 transcription. CXCL10 enhanced the metastases of CC-cells by triggering small GTPases such as RhoA and cdc42. Furthermore, overexpression of CXCL10 significantly enhanced tumorigenicity and mobility of CC cells in vivo. We further clarified that CXCL10 activated the PI3K/Akt pathway through CXCR3, resulting in suppression of GSK-3ß phosphorylation and leading to upregulation of Snail expression, thereby regulating EMT in CC cells. These outcomes lay the foundation for finding new targets to inhibit CC metastases.

Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing.

INTRODUCTION: By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC. METHODS: In a multicenter phase 2 trial, patients with ALK-positive NSCLC who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1, and progression disease (PD) and analyzed with a 212-gene panel. RESULTS: A total of 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior progression-free survival (4.2 mo versus 11.7 mo, p < 0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 versus 4.67 ± 0.39, p < 0.001). Although there was no significant difference in mutation load between these groups at cycle 3 day 1 (5.89 ± 2.25 versus 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 versus 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R, and E1210K increased markedly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, and epigenetic dysregulation. CONCLUSIONS: Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib.

Phylogenetic analysis of upland cotton MATE gene family reveals a conserved subfamily involved in transport of proanthocyanidins.

The multidrug and toxic compound extrusion (MATE) protein belongs to a secondary transporter family, which plays a role in transporting different kinds of substrates like phytohormones and secondary metabolites. In plant, MATE transporters related to the endogenous and exogenous mechanisms of detoxification for secondary metabolites such as alkaloids, flavonoids, anthocyanins and other secondary metabolites have been studied. However, a genome-wide analysis of the MATE family is rarely reported in upland cotton (Gossypium hirsutum L.). In the study, a total of 72 GhMATEs were identified from the genome of upland cotton, which were classified into four subfamilies with possible diverse functions such as transport of proanthocyanidins (PAs), accumulation of alkaloids, extrusion of xenobiotic compounds, regulation of disease resistance and response to abiotic stresses. Meanwhile, the gene structure, evolutionary relationship, physical location, conservative motifs, subcellular localization and gene expression pattern of GhMATEs have been further analysed. Three of these MATE genes (GhMATE12, GhMATE16 and GhMATE38) were identified as candidate genes due to their functions in transport of PA similar to GhTT12. These results provide a new perspective on upland cotton MATE gene family for their potential roles in transport of PA and a theoretical basis for further analyzing the function of MATE genes and improving the fiber quality of brown cotton.

A putative molybdate transporter LjMOT1 is required for molybdenum transport in Lotus japonicus.

Molybdenum (Mo) is an essential micronutrient that is required for plant growth and development, and it affects the formation of root nodules and nitrogen fixation in legumes. In this study, Lotus japonicus was grown on MS solid media containing 0 nmol l-1 (-Mo), 103 nmol l-1 (+Mo) and 1030 nmol l-1 (10 × Mo) of Mo. The phenotypes of plants growing on the three different media showed no obvious differences after 15 days, but the plants growing on -Mo for 45 days presented typical symptoms of Mo depletion, such as a short taproot, few lateral roots and yellowing leaves. A Mo transporter gene, LjMOT1, was isolated from L. japonicus. It encoded 468 amino acids, including two conserved motifs, and was predicted to locate to chromosome 3 of the L. japonicus genome. A homology comparison indicated that LjMOT1 had high similarities to other MOT1 proteins and was closely related to GmMOT1. Subcellular localization indicated that LjMOT1 is localized to the plasma membrane. qRT-PCR analyses showed that increasing Mo concentrations regulated the relative expression level of LjMOT1. Moreover, the Mo concentration in shoots was positively correlated to the expression of LjMOT1, but there was no such evident correlation in the roots. In addition, changes in the nitrate reductase activity were coincident with changes in the Mo concentration. These results suggest that LjMOT1 may be involved in the transport of Mo and provide a theoretical basis for further understanding of the mechanism of Mo transport in higher plants.

Molecular cloning, expression analysis and subcellular localization of a Transparent Testa 12 ortholog in brown cotton (Gossypium hirsutum L.).

Transparent Testa 12 (TT12) is a kind of transmembrane transporter of proanthocyanidins (PAs), which belongs to a membrane-localized multidrug and toxin efflux (MATE) family, but the molecular basis of PAs transport is still poorly understood. Here, we cloned a full-length TT12 cDNA from the fiber of brown cotton (Gossypium hirsutum), named GhTT12 (GenBank accession No. KF240564), which comprised 1733 bp with an open reading frame (ORF) of 1503 bp and encoded a putative protein containing 500 amino acid residues with a typical MATE conserved domain. The GhTT12 gene had 96.8% similarity to AA genome in Gossypium arboretum. Quantitative RT-PCR analysis denoted that the relative expression of GhTT12 in brown cotton was 1-5 folds higher than that in white cotton. The mRNA level was the highest at 5 days post anthesis (DPA) and reduced gradually during the fiber development. Expressing GhTT12-fused green fluorescent protein (GFP) in Nicotiana tabacum showed that GhTT12-GFP was localized in the vacuole membrane. The content of PAs increased firstly and decreased afterwards, and reached the maximum at 15 DPA in brown cotton. But for white cotton, the content of PAs remained at a low level during the fiber development. We speculate that GhTT12 may participate in the transportation of PAs from the cytoplasmic matrix to the vacuole. Taken together, our data revealed that GhTT12 was functional as a PAs transmembrane transporter.