Plinabulin在有或无免疫检查点抑制剂的情况下增强基于拓扑异构酶抑制剂的抗体药物偶联物的抗肿瘤疗效

Background: Antibody drug conjugates (ADC) with topoisomerase inhibitors (TOP1-ADC) hold significant promise in cancer treatment. FDA-approved TOP1-ADC includes TROP2- or HER2-directed datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), respectively. To boost ADC efficacy without overlapping toxicity, combination strategies including immune checkpoint inhibitors (ICI) are under active investigation. Plinabulin (Plin) is a first-in-class, differentiated tubulin binder that exerts anticancer activity primarily by activating GEF-H1-mediated pathways in dendritic cell (DC) maturation and T cell activation. In Dublin-3 phase 3 study, Plin/docetaxel outperformed docetaxel with significant OS/PFS/ORR benefits and doubling of 2- and 3-year survival rates, and reduced docetaxel induced neutropenia. In post-ICI settings given after radiation, Plin potentiates anti-PD-1 with significantly higher GEF-H1 immune activation in responders of mixed cancer types. Preclinically, Plin boosts irinotecan activity in human colon cancer models and reduces topotecan-induced neutropenia. Here we investigated Plin synergy with TOP1-ADC in-vitro, and with or without PD-1/L1 inhibitor pembrolizumab (Pembro) or atezolizumab (Atezo) in-vivo. Methods: For combinations in-vitro, HER2+ KPL-4 breast cancer cells were treated with Plin (1.46 - 46.8 nM), T-DXd (0.105 - 3.37 μM) or both. For combinations in-vivo, MC38 mouse colon adenocarcinoma cells overexpressing hTROP2 (hTROP2-MC38) or hHER2 (hHER2-MC38), were inoculated in B-hPD-1 or B-hPD-1/hPD-L1/hHER2 mice respectively, and antitumor activities of Plin (7.5 mg/kg) plus Dato-DXd (5 mg/kg) ± Pembro (0.3 mg/kg) or T-DXd (3 mg/kg) ± Atezo (8 mg/kg) were evaluated. Results: On HER2+ KPL-4 cells, Plin showed synergistic activity with T-DXd with median CI <1 at 1:1, 2:1 and 4:1 ratios (T-DXd:Plin). In hTROP2+ MC38 tumor model, Dato-DXd antitumor activity was significantly enhanced by Plin (doublet) and further boosted by Pembro (triplet) with complete response rates of 0%, 20% and 60% respectively. Compared to Dato-DXd plus Plin or Pembro groups, the triple combo most significantly delayed tumor growth (p=0.009 or 0.028) and improved animal overall survival, and was better tolerated than Dato-DXd+Pembro (10% vs. 40% mortality). In hHER2+ MC38 tumor model, only the triple combo group (T-DXd+Plin+Atezo) prolonged animal survival better than T-DXd alone (p=0.0256). Conclusions : Plinabulin is a Phase 3 novel agent clinically validated to promote DC maturation and T-cell activation, which provides a durable response by strengthening the cancer-immunity cycle when combined with ICI and neutropenia-limiting agents such as docetaxel and ADCs. Clinical investigations assessing plinabulin safety and efficacy combined with TOP1-ADC alone or plus ICI are highly encouraged.