Bempegaldesleukin (DB15140): A Comprehensive Post-Mortem Analysis of a Next-Generation IL-2 Agonist from Bench to Clinical Failure

Executive Summary

Bempegaldesleukin (development code NKTR-214) was an investigational anti-cancer agent that represented a highly rational, molecularly engineered approach to overcoming the profound limitations of high-dose interleukin-2 (IL-2) therapy. Designed as a CD122-preferential IL-2 pathway agonist, it aimed to selectively stimulate anti-tumor CD8+ T cells and Natural Killer (NK) cells while avoiding the activation of immunosuppressive regulatory T cells (Tregs), a primary drawback of conventional IL-2. Early Phase 1/2 clinical data, particularly from the PIVOT-02 trial in first-line metastatic melanoma, were exceptionally promising, demonstrating high objective and complete response rates that led to an FDA Breakthrough Therapy Designation and a multi-billion dollar strategic collaboration between its developer, Nektar Therapeutics, and Bristol Myers Squibb.

This initial promise, however, collapsed spectacularly in late-stage development. A series of large, randomized Phase 3 trials—PIVOT IO-001 in melanoma, PIVOT-09 in renal cell carcinoma, and the Phase 2 PIVOT-10 study in urothelial cancer—conclusively failed to meet their primary endpoints. In the pivotal melanoma trial, the combination of bempegaldesleukin and the PD-1 inhibitor nivolumab not only failed to improve outcomes over nivolumab monotherapy but resulted in a numerically lower response rate and increased toxicity. This definitive lack of clinical benefit, observed consistently across multiple tumor types, led to the complete termination of the global clinical development program in March and April of 2022.