Han B, Feinstein T, Shi Y, Chen G, Yao Y, Hu C, Shi J, Feng J, Wu H, Cheng Y, Guo QS, Jie Z, Ye F, Zhang Y, Liu Z, Mao W, Zhang L, Lu J, Zhao J, Bazhenova L, Ruiz J, Kloecker GH, Sujith KR, Oliff IA, Wong M, Liu B, Wu Y, Huang L, and Sun Y
Background: There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations., Methods: In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m 2 on day 1 and either plinabulin (30 mg/m 2 ) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed., Findings: Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group., Interpretation: Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population., Funding: BeyondSpring Pharmaceuticals., Competing Interests: Declaration of interests TF received research funding from BeyondSpring Pharmaceuticals to conduct this trial and is a speaker for Sanofi and Sobi. CH received research funding from BeyondSpring Pharmaceuticals to conduct this trial. GHK is President of Kentucky Society of Oncology and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from BMS, Genentech, AstraZeneca, Regeneron, Guardant, EMD Serono, and Novartis; consulting fees from BMS, Genentech, AstraZeneca, Regeneron, and Guardant; and payment for participation on a data safety monitoring board or advisory board from BMS, Genentech, AstraZeneca, and Regeneron. LB has received research support from Beyondspring and consulting fees from Sanofi, Gilead, Pfizer, Boehringer Ingelheim, Neuvogen, Bayer, BioAtla, Daichi, Summit, Anheart, Merck, Abbvie, Regeneron, Janssen, Genentech, Novocure, InterVenn, Elevation Oncology, Turning Point, and Novartis; and has participated on data safety monitoring board or advisory boards for ORIC Pharmaceuticals. JZ, ZJ, BH, FY, ZL, YSu, and JS have received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, and educational events from MSD, BeiGene, Roche, and AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)