Setback for Selective IL-2 Agonist: BMS and Nektar Halt Global Development of Bempegaldesleukin Combination Therapy

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On April 14, Nektar and BMS jointly announced that based on the pre-planned analysis results of two late-stage clinical studies evaluating the biased IL-2 pathway agonist bempegaldesleukin (BEMPEG) in combination with the PD-1 inhibitor Opdivo (nivolumab) for the treatment of renal cell carcinoma (RCC) and bladder cancer. The two companies have jointly decided to terminate the global clinical development program for BEMPEG in combination with Opdivo. All ongoing studies related to these programs will be discontinued.

In the Phase III PIVOT-09 study of previously untreated patients with advanced or metastatic renal cell carcinoma, the final analysis of the objective response rate (ORR) assessed by the Blinded Independent Central Review Committee (BICR) showed that the combination of BEMPEG and Opdivo did not reach the prespecified boundary for statistical significance in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor-risk or all-risk populations compared to the tyrosine kinase inhibitor (TKI) control group. The interim analysis of overall survival (OS) in these populations also did not meet the prespecified boundary for statistical significance.

In the Phase II PIVOT-10 study conducted on patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin, the final ORR analysis assessed by BICR showed that the combination of BEMPEG and Opdivo did not meet the efficacy threshold to support continued treatment in urothelial carcinoma.

All other studies of BEMPEG in combination with Opdivo, including: a pivotal study in muscle-invasive bladder cancer (CA045-009), a Phase I1/II study of the two-drug combination with TKI (CA045-011) in 1L RCC (CA045-011), and a Phase I/II study in recurrent and/or refractory pediatric tumors (CA045-020), will be terminated.

On March 15, the two companies announced that the Phase III PIVOT IO-001 study of BEMPEG in combination with Opdivo vs. Opdivo monotherapy as first-line treatment for previously untreated unresectable or metastatic melanoma did not meet the primary endpoints of PFS and ORR. Based on these results, the two companies also decided to terminate the ongoing Phase III PIVOT-12 study of the two-drug combination as adjuvant therapy for melanoma (Recommended reading: Biased IL-2 agonist fails in Phase III study, company's stock price plunges 60%).

IL-2 stimulates immune cell proliferation and activation by binding to a receptor complex composed of IL-2Rα, IL-2Rβ, and IL-2Rγ, but its effects are bidirectional. High-dose IL-2 can bind to the IL-2Rβγ dimer, inducing T-cell proliferation and killing cancer cells. However, IL-2 can also bind to the IL-2Rαβγ trimer, expanding Treg cells with immunosuppressive effects.

BEMPEG is an immunostimulatory IL-2 cytokine prodrug. The prodrug design and receptor bias enable BEMPEG to selectively bind to IL-2Rβ, thereby eliminating overactivation of the IL-2 pathway. This allows BEMPEG to stimulate and expand specific anti-cancer T cells and natural killer cells (NK) without expanding intratumoral regulatory T cells that suppress immune responses.

Global companies developing biased IL-2Rβ agonists include Amgen, Synthekine, etc., and in China, Mabwell’s 8MW2311 has been submitted for clinical trials.