Equivalent efficacy study of QL1101 and bevacizumab on untreated advanced non-squamous non-small cell lung cancer patients: a phase 3 randomized, double-blind clinical trial

Objective:This phase 3 study aimed to test equivalence in efficacy and safety for QL1101,a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer(NSCLC).Methods:Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab,15 mg/kg every 3-week for 6 cycles.This was followed by maintenance treatment with single agent QL1101 every 3-week.The primary end-point was objective response rate(ORR),with secondary end-points being progression-free survival(PFS),overall survival(OS),disease control rate(DCR),and adverse events(AEs).Results:Of 675 patients,535 eligible patients were randomized to the QL1101 group(n=269)and bevacizumab group(n=266).ORRs were 52.8%and 56.8%,respectively,for the QL1101 and bevacizumab groups,with an ORR hazard ratio 0.93(95%confidence interval:0.8-0131.1).The PFS,OS,DCR,and AEs were comparable between the 2 groups,which remained the same after stratification according to epidermal growth factor receptor mutation or smoking history.Conclusions:QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.

Identification of a male-specific region(MSR)in Spinacia oleracea

Dioecy,the presence of male and female individual,has evolved independently from hermaphroditism in multiple flowering plant lineages.Spinach,an important leafy vegetable crop worldwide,is a dioecious species with an XY sex-determination system.Although some markers that are fully linked to male-determination locus were identified,the male-specific region(MSR)remained unclear.In this research,five male individuals and five female lines were resequenced to identify the male-specific region.We identified a region(∼21 kb)on chromosome 4(putative sex chromosome)where the five females had a low reads coverage,while the five males had high coverage.A KASP marker,SponR,developed from a single nucleotide polymorphism(SNP)closely linked to the MSR was co-segregating with the sex determination gene in the population of 958 individuals,suggesting that the MSR might be specifically present in male spinach plants.

The Bone Microenvironmental Effect in the Dormancy of Cancer

Tumors have already threatened human life and health for centuries, especially the recurrent of bone metastases is difficult to cure. Relapse can occur years to decades after resection of primary tumor. This phenomenon is common in many clinical cases and animal experimental studies. The effect of traditional radiotherapy and chemotherapy on relapse is very limited, and the patients’ prognosis is poor. Because the delayed occurrence of metastases, researchers put forward a new concept “dormancy”, including a single dormant tumor cell (growth-arrest) and tumor mass dormancy (equivalence of the proliferation rate and apoptosis rate). It is probable that dormant tumor cells are the resource of relapse and the main reason of chemotherapy resistance. The mechanisms mediated tumor cell dormancy are complex and poorly understood, and bone marrow microenvironment plays an important role in this process. This review focuses on the bone marrow microenvironmental effect in inducing cancer cells to dormancy uncovered by the latest researches.

Toripalimab plus chemotherapy as second-line treatment in previously EGFR-TKI treated patients with EGFR-mutant-advanced NSCLC:a multicenter phase-II trial

This multicenter phase-II trial aimed to investigate the efficacy,safety,and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC.Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled.Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles,followed by the maintenance of toripalimab and pemetrexed.The primary endpoint was objective-response rate(ORR).Integrated biomarker analysis of PD-L1 expression,tumor mutational burden(TMB),CD8+tumor-infiltrating lymphocyte(TIL)density,whole-exome,and transcriptome sequencing on tumor biopsies were also conducted.Forty patients were enrolled with an overall ORR of 50.0%and disease-control rate(DCR)of 87.5%.The median progression free survival(PFS)and overall survival were 7.0 and 23.5 months,respectively.The most common treatment-related adverse effects were leukopenia,neutropenia,anemia,ALT/AST elevation,and nausea.Biomarker analysis showed that none of PD-L1 expression,TMB level,and CD8+TIL density could serve as a predictive biomarker.Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type.Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC.DSPP mutation might serve as a potential biomarker for this combination.A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing(NCT03924050).

Safety and activity of WX-0593(Iruplinalkib)in patients with ALK-or ROS1-rearranged advanced non-small cell lung cancer:a phase 1 dose-escalation and dose-expansion trial

WX-0593(Iruplinalkib)is a novel,highly selective oral ALK and ROS1 tyrosine kinase inhibitor(TKI).In this study,the safety,antitumor activity,and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer(NSCLC)patients with ALK or ROS1 rearrangement.In the dose-escalation phase and dose-expansion phase,patients were treated with WX-0593 until disease progression,unacceptable toxicity,or subject withdrawal.In the dose-escalation phase,the primary endpoints were maximum tolerated dose(MTD),dose-limiting toxicity(DLT),and safety assessed by investigators.In the dose-expansion phase,the primary endpoint was objective response rate(ORR)assessed by investigators.Between September 25,2017 and October 15,2018,a total of 153 patients received WX-0593 treatment.Two dose-limiting toxicities(DLTs)including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient.MTD was not reached.Overall,140 of the 152(92%)patients experienced treatment-related adverse events(TRAEs)and 35 of the 152(23%)patients had TRAEs≥grade 3.The overall ORR was 59.3%(32 of 54)for the dose-escalation phase and 56.6%(56 of 99)for the dose-expansion phase.For patients who were ALK-rearranged and ALK TKI naive,the ORR were 81.0%(17 of 21)in the dose-escalation phase and 76.3%(29 of 38)in the dose-expansion phase,and for patients who previously received crizotinib as the only ALK TKI,the ORR were 38.1%(8 of 21)and 45.7%(21 of 46)for the two phases,respectively.For patients who were ROS1-rearranged,the ORR were 30.0%(3 of 10)in the dose-escalation phase and 44.4%(4 of 9)in the dose-expansion phase.WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.