Daily Respiratory Research Analysis

BACKGROUND: Sacituzumab tirumotecan (sac-TMT), a trophoblast cell-surface antigen 2-targeting antibody-drug conjugate, combined with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, has shown promising antitumour activity as first-line therapy for non-small-cell lung cancer (NSCLC) in early-phase studies. Our aim was to evaluate the efficacy and safety of sac-TMT plus pembrolizumab as first-line treatment for patients with PD-L1-positive advanced NSCLC without targetable genomic alterations. METHODS: In this randomised, open-label, phase 3 trial (OptiTROP-Lung05) conducted across 68 hospitals in China, eligible patients had locally advanced or metastatic NSCLC without targetable genomic alterations and a PD-L1 tumour proportion score (TPS) of 1% or greater. Patients were randomly assigned (1:1) to receive sac-TMT (4 mg/kg on days 1, 15, and 29) plus pembrolizumab (400 mg fixed dose on day 1), or pembrolizumab alone, administered intravenously every 6 weeks. The primary endpoint was progression-free survival, as assessed by blinded independent central review in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT06448312). Recruitment is complete, with the trial ongoing and the final analysis to be reported later. FINDINGS: Between June 7, 2024, and March 27, 2025, 741 patients were screened and 413 eligible patients were randomly assigned to receive sac-TMT plus pembrolizumab (n=208) or pembrolizumab alone (n=205). At the prespecified interim analysis, conducted after a median follow-up of 10·5 months (IQR 8·7-12·5), median progression-free survival was significantly longer with sac-TMT plus pembrolizumab than with pembrolizumab alone (not reached vs 5·7 months; stratified hazard ratio [HR] 0·35 [95% CI 0·26-0·47]; p<0·0001). The progression-free survival benefit was broadly consistent across subgroups, including patients with PD-L1 TPS of 1-49% (HR 0·28 [95% CI 0·19-0·41]) and those with PD-L1 TPS of 50% or greater (HR 0·47 [0·29-0·77]). Grade 3 or higher treatment-emergent adverse events occurred in 115 (55%) of 208 patients in the sac-TMT plus pembrolizumab group and 64 (31%) of 204 patients in the pembrolizumab group. INTERPRETATION: Among patients with PD-L1-positive advanced NSCLC without targetable genomic alterations, first-line treatment with sac-TMT plus pembrolizumab significantly prolonged progression-free survival compared with pembrolizumab alone. Therefore, sac-TMT plus pembrolizumab has the potential to redefine first-line treatment for patients with PD-L1-positive advanced NSCLC without targetable genomic alterations. FUNDING: Sichuan Kelun-Biotech Biopharmaceutical.

BACKGROUND: Combined therapy with delamanid, bedaquiline, and quabodepistat (DBQ) showed potent early bactericidal activity and was well tolerated in a phase 2a, 14-day early bactericidal activity trial in participants with drug-susceptible pulmonary tuberculosis. This subsequent proof-of-concept trial evaluated the efficacy and safety of a 4-month, three-dose level regimen of DBQ in participants with drug-susceptible pulmonary tuberculosis compared with 6 months of the standard of care. METHODS: This open-label, randomised, proof-of-concept, non-inferiority, phase 2b/c trial was conducted at six clinical research sites in South Africa. Adults aged 18-65 years with newly diagnosed, drug-susceptible pulmonary tuberculosis were recruited by research sites from community tuberculosis clinics. Participants were randomly assigned (1:2:2:1) by balanced block randomisation (block size six) to receive oral delamanid (300 mg once a day) and bedaquiline (400 mg once a day for 2 weeks then 200 mg three times a week) plus quabodepistat at once-daily doses of 10 mg (DBQ10 group), 30 mg (DBQ30 group), or 90 mg (DBQ90 group) for 4 months; or 6 months of RHEZ (rifampicin, isoniazid, ethambutol, and pyrazinamide for 8 weeks followed by 18 weeks of rifampin and isoniazid). All drugs were administered orally. Masking procedures were not used, although microbiology laboratory staff were masked to treatment assignment. The primary endpoints were the proportion of participants reaching sputum culture conversion by the end of the treatment period in the modified intention-to-treat (mITT) analysis set and safety in the safety analysis set. Non-inferiority, with a margin of 12%, was assessed for the primary endpoint in the mITT analysis set, comparing the pooled DBQ group and the RHEZ group using a two-sided 80% CI. This study was registered at ClinicalTrials.gov, NCT05221502, and is complete. FINDINGS: Between April 12, 2022, and May 19, 2024, 306 individuals were screened, of whom 122 were enrolled and randomly assigned: 20 to the DBQ10 group, 42 to the DBQ30 group, 39 to the DBQ90 group, and 21 to the RHEZ group. 121 participants received at least one dose of study drug and comprised the mITT analysis set. At the end of the treatment period, the proportion of participants with sputum culture conversion was 100·0% (95% CI 83·2-100·0, all 20 participants) in the DBQ10 group, 92·9% (80·5-98·5, 39 of 42 participants) in the DBQ30 group, 97·4% (86·2-99·9, 37 of 38 participants) in the DBQ90 group, 96·0% (90·1-98·9, 96 of 100 participants) in the pooled DBQ group, and 100·0% (83·9-100·0, all 21 participants) in the RHEZ group. The comparison between the pooled DBQ group and the RHEZ group met non-inferiority for the primary endpoint (difference -4·0% [80% CI -7·4 to 3·4]). Adverse events were mostly mild to moderate, with no serious adverse events or discontinuations attributed to trial medications. Rates of adverse events of grade 3 or higher were 20% (four of 20 participants) in the DBQ10 group, 14% (six of 42 participants) in the DBQ30 group, 11% (four of 38 participants) in the DBQ90 group, and 5% (one of 21 participants) in the RHEZ group. One participant (in the DBQ90 group) died after worsening pulmonary tuberculosis with pneumonia, which was assessed as not related to study treatment. 105 (87%) of 121 participants had at least one treatment-emergent adverse event: 17 (85%) of 20 in the DBQ10 group, 37 (88%) of 42 in the DBQ30 group, 30 (79%) of 38 in the DBQ90 group, and all 21 (100%) participants in the RHEZ group. The most common treatment-emergent adverse events in the total population of 121 participants were upper respiratory tract infection (n=36, 30%), headache (n=24, 20%), and diarrhoea (n=12, 10%). INTERPRETATION: In this proof-of-concept study, 4 months of DBQ showed a promising end-of-treatment non-inferiority signal versus 6 months of RHEZ and was generally well tolerated. Our results support further studies of quabodepistat as a potential component of new treatment-shortening regimens for tuberculosis. FUNDING: Otsuka Pharmaceutical Development & Commercialization, with partial funding from the Gates Foundation.

BACKGROUND: Benralizumab, an interleukin-5 receptor α antagonist, depletes blood eosinophils, reducing exacerbations of severe asthma by approximately 50% versus placebo. In this study, we aimed to characterise mechanisms underlying exacerbations occurring on benralizumab. METHODS: BenRex, a multicentre, prospective cohort study, recruited participants meeting national licensing criteria for benralizumab for asthma. The study was conducted in 15 UK severe asthma centres. After collecting baseline data, open-label benralizumab was administered for 12-18 months. At exacerbation, participants attended for medical review before initiating treatment, fractional exhaled nitric oxide (FeNO), spirometry, asthma control questionnaire, and blood and sputum sampling. FINDINGS: Between Sept 30, 2019, and April 23, 2024, 121 exacerbation events were assessed in 156 individuals. 90 participants (58%) were female and 66 (42%) were male; 147 (94%) of participants identified as White. Median blood eosinophil counts at exacerbation were 0 (IQR 0-0) cells per μL. Airway neutrophilia was present in 55% of exacerbations where sputum was available (27/49). Median C-reactive protein (CRP) increased from 3·00 mg/L (1·00-6·00) at baseline to 9·00 mg/L (3·00-17·00) at exacerbation (p=0·0067). Clinically relevant viral pathogens were seen in eight (20·5%) of 39 sputum samples; although viruses were detected in 22 (56·4%) of 39 samples. Influenza A, metapneumovirus, and rhinovirus were the most common viral pathogens (each found in 2 [5·1%] of 39 samples). New acquisition of Moraxella catarrhalis (3 [13·6%] of 22), Haemophilus influenzae (4 [18·2%] of 22), and Streptococcus pneumoniae (2 [9·1%] of 22) occurred. DNA-neutrophil elastase complexes (p=0·0080) and azurocidin-1 (p=0·012) concentrations rose from baseline to exacerbation. FeNO was ≥50 parts per billion in 56 (50·5%) of 111 assessed exacerbations and was associated with reduced odds of bacterial detection. FeNO did not correlate with CRP or sputum neutrophils. INTERPRETATION: Our findings suggested that eosinophilic inflammation is not involved in exacerbations when a patient is being treated with benralizumab. Airway neutrophilia, viral pathogens, and alteration of the sputum microbiome point to infection as the most prominent causes of exacerbations. This observation should improve precision management of asthma exacerbations occurring despite treatment with benralizumab. FUNDING: AstraZeneca.