Plinabulin/docetaxel versus docetaxel in survival benefits of 2L/3L EGFR wild-type NSCLC after platinum regimens (DUBLIN-3): A randomized phase III trial

BackgroundSecond/third line (2L/3L) advanced or metastatic NSCLC remains an unmet need. Recent phase 3 studies, including PD-1/L1 inhibitors combined with TKI or anti-TIGIT, and novel ADC agents failed to show overall survival (OS) benefit vs. docetaxel, standard-of-care in this population.MethodsDUBLIN-3 (NCT02504489) was a single blinded (patient), randomized phase 3 trial in 58 centers (US/China/Australia). EGFR wild-type NSCLC patients who progressed after platinum therapy, were randomized (1:1) to receive docetaxel 75 mg/m2 on Day 1 and either plinabulin (DP, 30 mg/m2) or placebo (D) on Days 1 and 8 in 21-day cycles until progression, unacceptable toxicity, withdrawal, or death. The primary endpoint was OS in the intent-to-treat (ITT) population (NCT02504489).ResultsBetween 30-Nov-2015 and 06-Jan-2021, 559 patients received either DP (n=278 [M/F: 199/79]) or D (n=281 [M/F: 207/74]). Plinabulin significantly improved median OS (DP: 10.5 months or M vs. D: 9.4 M; HR=0·82 (95% CI: 0·68, 0·99; p=0·0399) in the final ITT analysis. In all subgroup analyses, including histology, age, prior use of PD-1/L1, all HR for OS is < 1, in favor of DP group. With additional exploratory 24-month follow-up after database lock, OS benefit sustains in the ITT population with median OS favoring DP (10.8 vs. 9.3 M, HR 0.81, p=0.027), and more pronounced in non-squamous subgroup (11.4 vs. 8.8 M, HR 0.72, p=0.0078). Treatment emergent adverse events occurred in DP: 273/274 (99.6%) vs. D: 276/278 (99.3%). Plinabulin significantly reduced Grade 4 neutropenia from 27.8% to 5.3% (p<0·0001). Higher Grade 3/4 GI disorders (16.8% vs. 2.9%) and transient Grade 3 hypertension (18.2% vs. 2.9%) occurred in DP vs. D group. Treatment emergent death was 12 (4.4%) in DP vs. 10 (3.6%) in D group.ConclusionsPlinabulin is a novel immune-chemotherapeutic agent that enhances dendritic cell maturation and T cell proliferation. Plinabulin and docetaxel significantly improved OS, ORR, PFS, 2- and 3- year OS rates, and significantly decreased the incidence of Grade 4 neutropenia. Additional 2-year survival follow-up showed sustained survival benefit.Clinical trial identificationNCT02504489.Legal entity responsible for the studyBeyondSpring, Inc.FundingBeyondSpring, Inc.DisclosureT.M. Feinstein: Financial Interests, Institutional, Speaker, Consultant, Advisor, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sanofi, Sobi; Financial Interests, Institutional, Invited Speaker: Speaker's bureau. B. Han, G. Chen, J. Shi, Z. Jie, F. Ye, Z. Liu: Financial Interests, Personal and Institutional, Speaker’s Bureau, manuscript writing and educational events: MSD, BeiGene, Roche, AstraZeneca. C. Hu: Financial Interests, Institutional, Local PI: BeyondSpring Pharmaceuticals. L. Bazhenova: Financial Interests, Personal, Advisory Board: Pfizer, AnHeart, Sanofi, Gilead, Teligene, Neuvogen, Bayer, BioAtla, Summit therapeutics; Financial Interests, Institutional, Advisory Board: Takeda, Daiichi Sankyo; Financial Interests, Institutional, Local PI: AnHeart, AstraZeneca, Janssen, Dizal, Bio Atla, Daiichi Sankyo. Y. Wu, L. Huang: Financial Interests, Personal, Full or part-time Employment: BeyondSpring Pharmaceuticals, Inc. All other authors have declared no conflicts of interest.