Late-phase strategies to overcome limitations of PD-1/PD-L1 therapy: a clinical development trajectory through 2030

Frontiers in Oncology. 2026. Vol. 16. Article 1875861.

Elena A. Andresyuk, Natalya O. Porozova, Londaridze G., Moiseev I., Kotselyabina P., Yuri B. Porozov

Inhibition of the PD-1/PD-L1 axis has become a clinical standard across multiple malignancies, yet durable benefit remains restricted to selected settings, and many biologically rational combinations fail to maintain clinical benefit in late-phase evaluation. This structured, registry-derived narrative review, supported by expert-guided interpretation, was designed to identify the most clinically meaningful development directions among strategies intended to overcome the limitations of PD-1/PD-L1 inhibitor therapy and most likely to generate practice-relevant late-phase readouts through 2030. We searched major international and regional clinical trial registries and applied harmonization, cross-registry deduplication, formal late-phase filtering, semi-automated prioritization, and manual documentation-based verification. The final analytic corpus was interpreted using a two-level framework: first, by the dominant clinicobiological barrier limiting PD-1/PD-L1 efficacy, and second, by three criteria of clinical promise - exposure and effect, manageable toxicity, and confirmable clinical benefit. This approach narrowed a registry-derived pool of more than 13, 000 PD-1/PD-L1 studies to 47 clinically relevant late-phase programs that define the most likely near-term development trajectory through 2030. Within this corpus, a narrower confirmatory subset emerged in which incremental clinical benefit is tested most directly in comparative designs. These programs represent the most plausible leading strategies of the next phase of PD-1/PD-L1-based clinical development and provide a clinically interpretable framework for prioritizing future translational and late-phase efforts.

Keywords: biomarkers, PD-1, PD-L1, Combination strategies, Immune checkpoint blockade, late-phase development, registry-based review, Resistance to immunotherapy

Publication based on the results of: Molecular evolution, protein motions and computational molecular modeling (2023)