1596TiP - DUBLIN-3, a stage IIIb/IV NSCLC phase (Ph)3 trial comparing the plinabulin (P)/Docetaxel(D) combination with D Alone

Abstract

BackgroundThe PD-L1 inhibitors Avelumab (AV) and Atezolizumab (AT) have proven clinical anticancer efficacy, however in NSCLC trials, Javelin Lung 200 (JAV for AV) failed, whereas OAK (for AT) met primary endpoint showing better survival vs 75mg/m2 D as comparator. The authors suggested JAV trial design factors may have played a role (Barlesi, Lancet Oncology 2018). Firstly, its open-label study design lead to more D patients (pts) dropping out prior to receiving first D dose (8% vs 1% for D vs AV). Secondly, JAV did not stratify for region, resulting in 29% vs 25% Asian pts with D vs AV; Asian pts tend to respond better to D then non-Asians. However, tumor stage also might be another factor, since advanced primary and metastatic lesions likely harbor antigens (Ags) for which immune tolerance has already been developed. Mutation burden of advanced primary and metastatic lesions show high concordance (Sherwood, J Exp & Clin Canc Res 2015). In contrast, early or novel subclonal lesions located in the lung are more likely to harbor (novel) immunogenic Ags (De Bruin, Science 2014). More pts in JAV (close to 100% (6%M0) vs OAK (70.6%) were at stage IIIb/IV (Rittmeyer, Lancet 2016; OAK Team, 2019). P is a novel Dendritic Cell (DC) modulator that is combined with D. D induces Ags that DC cells can present to CD4 and CD8 T-Cells after P stimulation (Lloyd, AACR 2016). P has favorable safety/tolerability in>500 pts and prevents D-induced-Neutropenia (N) and -Thrombocytopenia (Blayney, ASCO 2018; IASLC 2018; ESMO 2018). DUBLIN-3 may have avoided some of the JAV design limitations. Trial designDUBLIN-3 (NCT02504489), is a global, single-blinded (for pts) Ph3 study in EGFR wild-type, stage IIIb/IV NSCLC pts (target n=554) stratified for region (Asia/non-Asia), and receiving 2nd- or 3rd-line systemic therapy with D+P or D in a 1:1 ratio. Key inclusion criteria are, pts must have at least one measurable lesion located in the lung, and have failed a prior platinum-based regimen. Prior PD1/PD-L1 use is allowed. Primary endpoint is OS. Key secondary endpoints are incidence of Gr 4 N, D dose modification due to N, QoL, ORR, PFS, and DoR. The first pre-specified Interim Analysis (IA) occurred at ∼150 events and a second IA at ∼ 300 events is projected for Q4 2019. Clinical trial identificationBPI-2358-103 NCT02504489. Legal entity responsible for the studyBeyondSpring Pharmaceuticals, Inc. FundingBeyondSpring Pharmaceuticals, Inc. DisclosureR. Mohanlal: Leadership role, Travel / Accommodation / Expenses, Full / Part-time employment, Officer / Board of Directors: BeyondSpring Pharmaceuticals, Inc; Shareholder / Stockholder / Stock options: BeyondSpring, Inc. L. Huang: Leadership role, Travel / Accommodation / Expenses, Full / Part-time employment, Officer / Board of Directors: BeyondSpring Pharmaceuticals, Inc; Shareholder / Stockholder / Stock options: BeyondSpring, Inc.