Background: Despite becoming a key therapeutic modality, ADCs face significant limitations on efficacy and safety. TOP1-ADCs including datopotamab deruxtecan (Dato-DXd) deliver payloads similar as irinotecan with severe neutropenia risk. To prevent or overcome resistance, ADCs are under investigation including moving into the first-line (±ICI, immune-checkpoint-inhibitors). In post-ICI settings, recent phase 3 studies of TOP1-ADC monotherapy did not surpass docetaxel in 2/3L NSCLC without actionable mutations (TROPION-Lung01; EVOKE-1).
Plinabulin is a late-stage Phase 3 asset with anti-cancer mechanism tied to its activation of GEF-H1 (guanine-nucleotide-exchange-factor-H1), a microtubule-associated, highly spatio-temporally regulated RhoA activator. As a GEF-H1 agonist, plinabulin promotes (i) DC maturation/M1 polarization and T-cell activation, (ii) HSPC proliferation and neutropenia prevention, and (iii) modulation of angiogenesis. Previously, plinabulin has shown improvements in Dato-DXd activity and tolerability (±pembrolizumab) (AACR2026). Besides significantly higher complete response (CR) rates and extended animal survival, we detected increased CD8+ T cells, central memory T cells (TCM) and CD8+T/Treg ratios in the blood. Here, we examined tumor-infiltrating leukocytes and further delineated plinabulin’s immune modulation profile within tumor-immune-microenvironment (TIME).
Methods: B-hPD-1 mice bearing hTROP2-MC38 tumors were randomly assigned into groups (n=6): vehicle control, Dato-DXd (5mg/kg/dose, day0), pembrolizumab (0.3mg/kg/dose, days1,4), plinabulin (7.5mg/kg/dose, days0,3,6), Dato-DXd±pembrolizumab, and Dato-DXd+pembrolizumab+plinabulin at matching dosing schedules. The tumor immunophenotyping was conducted on day 7 following an established protocol (STAR Protoc. 2024;5(3):103139).
Results: This early readout demonstrated that plinabulin addition improved Dato-DXd antitumor activity (doublet) and with pembrolizumab (triplet). Activation of DCs and M1 macrophages were associated with plinabulin (±Dato-DXd) and plinabulin/Dato-DXd (±pembrolizumab) respectively. Interestingly, plinabulin alone or in combination with Dato-DXd (±pembrolizumab), increased the number of tumor-infiltrating NK cells.
Conclusions: Our results suggest that plinabulin could modulate TIME and boost tumor sensitivity to TROP2-directed TOP1-ADC. Clinical investigations assessing plinabulin safety and efficacy combined with TOP1-ADC alone or plus PD-1/PD-L1 inhibitor are in the planning phase.