Bempegaldesleukin

Summary

Bempegaldesleukin (BEMPEG; NKTR-358 predecessor, properly NKTR-214) is a CD122-biased PEGylated IL-2 prodrug developed by Nektar Therapeutics for oncology indications. It was studied extensively in combination with checkpoint inhibitors (notably nivolumab) in trials such as PIVOT IO 001 for metastatic melanoma and urothelial carcinoma. Development was largely discontinued after Phase 3 trials failed to meet primary endpoints in 2022.

Mechanism of Action

CD122-preferential IL-2 pathway agonist; a PEGylated interleukin-2 conjugate that selectively activates CD8+ T cells and NK cells via the IL-2Rβγ (CD122/CD132) receptor complex, with reduced binding to CD25 (IL-2Rα) on regulatory T cells, thereby promoting anti-tumor immunity with an improved therapeutic window compared to high-dose IL-2.

Routes of Administration

Goals & Uses

• Metastatic melanoma treatmentOncologyModerate
• Regulatory T cell suppression reductionImmunologyModerate
• Renal cell carcinoma treatmentOncologyLow
• Anti-tumor immunity enhancementOncologyModerate
• Urothelial carcinoma treatmentOncologyModerate

Contraindications

• Poor performance status (ECOG ≥2)Clinical StatusModerate
• Severe autoimmune diseaseImmunologicalHigh
• Prior severe IL-2 toxicityPrior Adverse ReactionHigh
• Active severe infectionInfectiousHigh

Adverse Effects

• Edema/fluid retentionFluid BalanceUncommon
• Flu-like symptoms (fever, chills, fatigue)ConstitutionalCommon
• HypotensionCardiovascularUncommonLow blood pressure
• Rash/skin toxicityDermatologicalCommon
• Immune-mediated adverse eventsImmunologicalUncommon
• Infusion-related reactionsHypersensitivityCommon

Drug Interactions

• Nivolumab (anti-PD-1)Moderate
• Ipilimumab (anti-CTLA-4)Moderate
• Pembrolizumab (anti-PD-1)Moderate
• CorticosteroidsModerate

Population Constraints

• Pediatric patientsAgeRelative
• Pregnant womenReproductiveRelative
• Patients with hepatic or renal impairmentOrgan ImpairmentRelative
• Patients with organ transplantsImmunologicalRelative

Regulatory Status

• European UnionInvestigationalNo EMA approval or marketing authorization application filed; clinical trials conducted but program discontinued.
• United StatesInvestigationalFDA Breakthrough Therapy designation was granted for combination with nivolumab in first-line melanoma; however, Phase 3 failure led to program discontinuation in 2022. No NDA submitted.
• United KingdomInvestigationalNo MHRA approval; participated in international clinical trials only.

No regulatory approval granted in any jurisdiction. Phase 3 development halted in 2022 after PIVOT IO 001 failed to demonstrate superiority over nivolumab monotherapy in melanoma and urothelial carcinoma. Nektar Therapeutics discontinued its oncology pipeline including BEMPEG in 2022.

Evidence & Sources

No sources recorded yet.