Plinabulin plus docetaxel received fast track designation for pretreated nonsquamous NSCLC without actionable genomic alterations.
The FDA has granted fast track designation to plinabulin in combination with docetaxel for the treatment of patients with advanced or metastatic nonsquamous non–small cell lung cancer (NSCLC) without actionable genomic alterations whose disease has progressed after prior anti–PD-(L)1 antibody therapy and platinum-based chemotherapy.¹
Notably, plinabulin’s differentiated immune-modulating mechanism of action and previously reported data from the phase 3 DUBLIN-3 trial (NCT02504489) and the prospective phase 2 Study 303 (NCT05599789) have informed the design of the ongoing global phase 3 DUBLIN-4 trial in patients with post-immune checkpoint inhibitor (ICI) nonsquamous NSCLC.
“We believe the FDA fast track designation, an FDA-aligned global phase 3 strategy, and funding to support China-generated clinical data, would meaningfully strengthen our ability to advance plinabulin and DUBLIN-4 toward the trial’s next major clinical milestone—the prespecified interim analysis at 221 progression-free survival [PFS] events,” Min Qiu, chief executive officer of BeyondSpring, stated in a news release. “Fast track designation underscores the significant unmet medical need for the DUBLIN-4 patient population, [those with] NSCLC whose disease has progressed following ICI and without actionable genomic alterations, with limited options and docetaxel as the standard of care.”
Although approximately 60% of patients with NSCLC eventually develop resistance to anti–PD-(L)1 therapy, no new treatments have been recently approved in this setting. Additionally, multiple late-stage trials, including those investigating antibody-drug conjugate and anti–PD-(L)1 combination regimens, have failed to demonstrate an overall survival (OS) improvement over docetaxel.²
Plinabulin is a first-in-class, brain-penetrating, dendritic-cell maturation small molecule that has been administered to more than 700 patients with cancer across multiple clinical studies. It uses a reversible binder at a distinct tubulin pocket, and therefore does not alter tubulin dynamics or antagonize tubulin-stabilizing agents, including docetaxel. The agent is also designed to reduce chemotherapy-induced neutropenia, which may improve the tolerability of docetaxel. Overall, plinabulin’s mechanism of action may help restore T-cell function and antigen presentation following acquired resistance to ICIs.
Plinabulin Plus Docetaxel in Post-ICI Non-Squamous NSCLC: DUBLIN-3 Post Hoc Analysis
The DUBLIN-4 trial design is grounded in findings from a mechanism-driven, post hoc subset analysis of DUBLIN-3, which were presented at the 2025 IASLC World Conference on Lung Cancer and 2025 ASCO North America Conference on Lung Cancer. The multicenter, single-blind, randomized DUBLIN-3 study was conducted at 58 medical centers in the US, China, and Australia and enrolled 559 patients with EGFR wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned 1:1 to receive docetaxel at 75 mg/m² on day 1 plus either plinabulin at 30 mg/m² or placebo on days 1 and 8 of 21-day cycles. OS served as the primary end point.
In patients with EGFR wild-type nonsquamous NSCLC who progressed after anti–PD-(L)1 therapy with at least 3 months of prior clinical benefit, plinabulin plus docetaxel produced a median OS of 15.8 months vs 11.7 months with docetaxel alone (HR, 0.55).1,2 The median PFS values were 5.6 months vs 3.8 months, respectively (HR, 0.67), and the objective response rates were 18.2% vs 8.0%, respectively.2
In the DUBLIN-3 intention-to-treat EGFR wild-type population (n = 559), the combination was also associated with an improvement in metastasis-free survival (15.34 months vs 7.7 months; HR, 0.52; P = .0012) and a reduction in the incidence of new brain metastases (4.32% vs 7.83%). On the safety side, plinabulin significantly reduced docetaxel-induced grade 4 neutropenia (5.13% vs 33.58%; P < .0001) and was associated with significantly decreased exposure-adjusted grade 3/4 adverse effects (P = .0235).
BeyondSpring also reported that the DUBLIN-3 post-ICI findings were consistent with those from the prospective Study 303 in a similar patient population.
DUBLIN-4 is a randomized, global trial evaluating plinabulin plus docetaxel compared with docetaxel monotherapy in patients with advanced nonsquamous NSCLC who do not have actionable genomic alterations following progression on an ICI and chemotherapy.¹ This trial plans to enroll 442 patients. OS will serve as the primary end point; PFS and ORR will be key secondary end points.
DUBLIN-4 is intended to serve as the global confirmatory study that, together with DUBLIN-3, is expected to support a future new drug application for plinabulin in this patient population.²
