A phase 2 study of plinabulin (Plin)/docetaxel (Doc) plus pembrolizumab (Pemb) in metastatic NSCLC (mNSCLC) after acquired resistance (AR) to anti–PD-1/L1 alone or in chemotherapy combination: Efficacy and immunophenotyping.

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8567 Background: PD-1/L1 inhibitors have become a part of 1L treatment for EGFR/ALK wild-type NSCLC. However, >60% patients (pts) develop AR associated with T cell exhaustion and defective antigen presentation. Doc remains a mainstay for pts who relapse after anti-PD-1/L1 therapy, while multiple late-stage clinical trials have failed in comparison. Plin is a first-in-class, brain-penetrating dendritic cell maturation agent with clinically validated potential to restore antigen presentation/T cell function after AR to PD-1/L1 inhibitors. Plin also reduces severe neutropenia and thereby increases Doc tolerability. In a global phase 3 study (Dublin-3, n=559), Plin/Doc outperformed Doc with significant OS/PFS/ORR benefits, doubling of 2-/3-year OS rates, and 80% reduction in G4 neutropenia (p<0.0001). The aim of this study was to assess the efficacy/safety of Plin/Doc plus Pemb in mNSCLC after anti-PD-1/L1 based therapy. Methods: This single-arm phase 2 trial (NCT05599789; Study 303) enrolled 47 pts after immediate progression on anti-PD-1/L1 alone or combined with platinum doublets. Pts received Plin 30mg/m2, Doc 75mg/m2 and Pemb 200mg, on Day 1 in 21-day cycles. The primary/secondary endpoints at the median follow-up of 20.6 months (mo) are tabulated. For immunophenotyping, whole blood from baseline and post treatment were analyzed by flow cytometry. Results: At the data cutoff date of 31-Dec-2025, cORR was 18.2% with 79.5% DCR. mPFS was 7.0 mo, and mDoR at 9.3 mo. While mOS was 34 mo, the 24-mo OS rates were 64.3% (ITT), 71.1% (NSQ), and 52.0% (SQ). In all endpoints assessed, prior Pemb exposure did not reduce the efficacy of this regimen. Whole blood analysis indicated that activated CD4+/CD8+ T cells and proliferating Ki67+CD8 T cells were significantly increased post two cycles of treatment. Also observed were concurrent elevations of Ki67+B cells and CD38+NK cells. Conclusions: Plin/doc plus Pemb shows promising efficacy in mNSCLC with AR to anti-PD-1/L1 confirmed by immune activation post-treatment. TRAEs were manageable. These findings along with DUBLIN-3 support a global confirmatory study in EGFR/ALK wild-type NSQ NSCLC following progression on anti-PD1/L1 based therapy. Clinical trial information: NCT05599789 . Efficacy endpoints. Endpoint* ITT(N=47) NSQ(N=30) SQ(N=17) Primary endpoint cORR (RECIST 1.1) 18.2% 13.8% 26.7% Secondary endpoints mPFS (RECIST 1.1) 7.0 mo 7.7 mo 5.5 mo mOS 34 mo (not reached) 34 mo mDoR (RECIST 1.1) 9.3 mo (not reached) 9.1 mo DCR (PR+SD > 4 mo) 79.5% 82.8% 73.3% 12-mo OS rate 78.2% 80.0% 74.8% 24-mo OS rate 64.3% 71.1% 52.0% *cORR/DoR/DCR: 44 evaluable pts; PFS/OS & follow-up duration: ITT.

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