P2.01-23 DUBLIN-3, a Phase (Ph) III Trial Comparing the Plinabulin (P)/Docetaxel(D) Combination with D Alone in Stage IIIb/IV NSCLC
JOURNAL OF THORACIC ONCOLOGY(2019)
Abstract
In 2018, practice patterns changed in untreated metastatic NSCLC, as platinum-based chemotherapy (Chemo) started to be combined with pembrolizumab. Prior to 2018, checkpoint inhibitors (C-I) were given sequentially with Chemo. In C-I refractory metastatic NSCLC, single agent D is standard of care. Although effective, D induces AEs (Neutropenia (N) that may require dose reduction to sub-therapeutic levels. The addition of Plinabulin (P) to D (D+P) reduced D-induced grade 4 (Gr4) N (frequency of 33% vs 5% for D vs D+P; p<0.0003) and thrombocytopenia (P<0.02) vs D alone (Blayney ASH 2018; IASLC 2018) in Ph 2. Importantly, P added to D improved median overall-survival (OS) with 4.6-month, and duration of response (DoR) with 1-year (p<0.05) vs D alone (Mohanlal ASCO-SITC 2017) in pts with a measurable lesion (per RECIST 1.1) located in the lung. P induces Dendritic Cell (DC) maturation and CD40 upregulation and facilitates DC-dependent T-cell proliferation in an antigen (Ag) specific manner (Lloyd AACR 2016). Therefore, P is predicted to be the most effective in a setting that harbors novel Ags, that can stimulate the immune system. Subclonal lung lesions can induce novel Ags (De Bruin Science 2014), but clonal lung lesions can also harbor Ags that can stimulate the immune system, as long as immune tolerance is not yet developed. There is a high concordance in mutation status (thus Ags) between clonal primary and metastatic lesions in NSCLC (Sherwood J Exp & Clin Canc Res 2015), but the distant lesions had more time to induce immune tolerance development. Hence, we required the presence of measurable lesion present in the lung in DUBLIN-3. We combined P with D since D can release Ags which in turn can be presented by P-modulated DCs to cytotoxic CD8 T-cells. DUBLIN-3 (NCT02504489), is an ongoing global PhIII study in EGFR wild-type advanced or metastatic NSCLC pts (target n=554) receiving 2nd- or 3rd-line systemic therapy with D+P or D in a 1:1 ratio. The primary endpoint is OS. Key secondary endpoints are incidence of Gr 4 N on day 8 of Cycle 1, D dose modification due to N, QoL (EORTC QLQ-C30), ORR, PFS, and DoR. The study is single-blinded (for pts) to more reliable allow for QoL assessments. Pts must have at least one measurable lesion located in the lung and must have failed a prior platinum-based regimen. Prior PD1/PD-L1 use is allowed. A pre-specified first Interim Analysis (IA) occurred at reaching ∼150 events and a second pre-specified IA is to occur at ∼300 events. ∼400 patients have been enrolled to date with more than 200 events achieved. Based on the data at the 1st IA, the study will continue, unmodified, to the 2nd IA. The D+P combination holds the promise of a novel 2nd or 3rd line treatment option with superior efficacy and safety over D alone. The 2nd IA of DUBLIN-3 is expected to occur later in 2019.
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Key words
PD1-Failures,NSCLC,Plinabulin/Docetaxel Combination
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