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Background Rilvegostomig is a monovalent, bispecific humanized IgG1 monoclonal antibody that binds human TIGIT and PD-1 with high affinity. Engineered with a triple-mutation in its Fc domain, rilvegostomig prevents NK/macrophage-mediated depletion of TIGIT-expressing effector cells. Rilvegostomig has demonstrated encouraging results in a Phase I/II trial of non-small cell lung cancer (NSCLC) ( NCT04995523), and is currently being evaluated in multiple Phase III trials across several tumor types.Methods We hypothesized that rilvegostomig would demonstrate anti-tumor activity across a broader range of baseline characteristics in NSCLC tumors, even those typically unresponsive to conventional anti-PD-(L)1 therapies. To test this, we investigated shared and unique baseline features associated with rilvegostomig and anti-PD(x) activity using a nonclinical 3D human tumor explant model. Resected NSCLC tumors from 82 patients were analyzed for drug activity based on IFNγ secretion, a surrogate for immune activation, defined by a p < 0.05 and a fold-change > 1.5 versus untreated controls. Baseline samples underwent comprehensive profiling, including scRNA-seq, bulk RNA-seq, whole exome sequencing, spatial proteomics, histology, and 28-color spectral flow cytometry.Results Our analyses identified key baseline correlates that distinguish rilvegostomig activity from conventional anti-PD-(L)1 therapy. Rilvegostomig was active in tumors with unique driver mutations, lower CD8+ T cell infiltration, high growth factor activity, evidence of epithelial-mesenchymal transition, histological features linked to local micrometastasis, and increased tumor cell abundance. Notably, enhanced activity was observed in tumors with aPD-L1 tumor proportion score (TPS) of 1-49, a patient group less likely to respond to standard anti-PD-(L)1 agents. Rilvegostomig also demonstrated efficacy in tumors with features associated with anti-PD-(L)1 response, such as PD-L1 TPS > 50, high immune infiltration, and in current or former smokers.Conclusions In summary, our systematic evaluation of NSCLC tumor explants reveals that rilvegostomig demonstrates anti-tumor activity across a wider range of baseline tumor characteristics compared to conventional anti-PD-(L)1 therapies. Rilvegostomig can elicit ex vivo activity in resected tumors with conventional biomarkers of anti-PD-(L)1 response, or lack thereof, suggesting it may benefit a broader and more diverse NSCLC patient population. These findings underscore rilvegostomig’s promise as a novel immuno-oncology agent with activity beyond that of existing immune checkpoint inhibitors.Ethics Approval All work included in this abstract was conducted in accordance with the AstraZeneca Human Biological Sample global standard and approved by the HBS regulatory board. All samples used for these work were collected from patients that have provided informed consent.