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.

A post-mortem analysis of the program's failure, informed by comprehensive biomarker data from the Phase 3 trials, points to a critical mechanistic disconnect. While bempegaldesleukin successfully induced the proliferation of T cells in the peripheral circulation, this activity failed to translate into an increased infiltration of effector T cells into the tumor microenvironment. Furthermore, contrary to its core design hypothesis, the agent also induced the proliferation of Tregs and its stimulatory effect on effector T cells appeared to wane over time. The saga of bempegaldesleukin serves as a profound cautionary tale in immuno-oncology, highlighting the perils of over-interpreting uncontrolled early-phase data and revealing that the biological complexity of the IL-2 pathway cannot be overcome by simply biasing receptor affinity. Its failure has provided invaluable lessons that are now shaping the development of the next wave of cytokine-based immunotherapies.

The Scientific Rationale for Bempegaldesleukin: Engineering a Smarter Interleukin-2

The conception of bempegaldesleukin was a direct response to the complex and challenging history of its parent molecule, interleukin-2. As one of the earliest forms of cancer immunotherapy, high-dose IL-2 demonstrated the profound potential of harnessing the immune system to achieve durable, complete responses in a subset of patients with metastatic melanoma and renal cell carcinoma, but its utility was severely hampered by its biological and pharmacological properties.[1]

The Double-Edged Sword of Interleukin-2: The Need for a Next-Generation Approach

High-dose IL-2 therapy, marketed as aldesleukin, was a pioneering treatment that validated the IL-2 pathway as a legitimate target in oncology.[1] However, its clinical application has been historically constrained by two fundamental limitations.

First, its administration is associated with severe, dose-limiting toxicities, most notably vascular leak syndrome (VLS), profound hypotension, and other systemic inflammatory effects. These toxicities are a direct consequence of the cytokine's potent, widespread activity and necessitate inpatient administration in intensive care units at specialized centers, precluding its use in the vast majority of cancer patients.[1]

Second, the mechanism of IL-2 is pleiotropic and, in some respects, counterproductive to a sustained anti-tumor response. IL-2 signals through a receptor complex composed of up to three subunits: IL-2Rα (CD25), IL-2Rβ (CD122), and the common gamma chain (γc​, CD132).[2] The high-affinity heterotrimeric receptor (

IL−2Rαβγc​) is constitutively expressed at high levels on immunosuppressive regulatory T cells (Tregs). In contrast, anti-tumor effector T cells (Teff) and Natural Killer (NK) cells primarily express the intermediate-affinity heterodimeric receptor (IL−2Rβγc​).[2] Due to their high-affinity receptors and IL-2's short half-life, Tregs effectively act as an "IL-2 sink," outcompeting effector cells for the limited available cytokine. This leads to the potent expansion of Tregs, which can actively suppress the very anti-tumor immune response the therapy is intended to generate.[3] These twin challenges of extreme toxicity and Treg expansion created a clear unmet need for a next-generation IL-2 therapeutic that could retain the beneficial effector cell stimulation while mitigating the deleterious effects.

Molecular Design and Mechanism of Action: A CD122-Preferential Prodrug Strategy

Bempegaldesleukin was engineered with a sophisticated design intended to solve both of the primary problems of aldesleukin. It is a recombinant form of human IL-2 in which an average of six releasable polyethylene glycol (PEG) chains are covalently conjugated to lysine residues.[7] This molecular modification conferred two key properties central to its therapeutic hypothesis.

First, the PEGylation acts as a prodrug mechanism. When fully PEGylated, bempegaldesleukin is biologically inert. Following intravenous administration, the PEG chains are designed to slowly and sequentially hydrolyze in vivo, releasing active IL-2 conjugates.[7] This process was intended to provide a controlled, sustained release of the active cytokine, extending its pharmacokinetic half-life and allowing for a more manageable dosing schedule (e.g., every three weeks) in an outpatient setting, thereby addressing the pharmacological limitations of aldesleukin.[3]

Second, and more critically, the PEG chains were strategically positioned to sterically hinder the interaction of IL-2 with the IL-2Rα (CD25) subunit of the high-affinity receptor.[3] This structural modification was the core of the drug's innovative design. By physically blocking the CD25 binding site, the released active forms of bempegaldesleukin were engineered to preferentially signal through the intermediate-affinity

IL−2Rβγc​ (CD122/CD132) complex. Because this receptor is predominantly expressed on the desired anti-tumor immune cells—CD8+ effector T cells and NK cells—this "CD122-preferential" agonism was hypothesized to tip the balance of IL-2 signaling decisively in favor of a productive anti-cancer response.[1] The intended outcome was the robust proliferation, activation, and infiltration of cancer-killing lymphocytes into the tumor microenvironment, without the concomitant expansion of immunosuppressive Tregs that plagues conventional IL-2 therapy.[1]

Preclinical Evidence and Hypothesized Synergy with Checkpoint Inhibition

The therapeutic hypothesis behind bempegaldesleukin was supported by preclinical studies in murine models, which demonstrated that the agent could systemically expand anti-tumor CD8+ T cells and increase the ratio of effector T cells to regulatory T cells within tumors.[1] This preclinical evidence provided a strong rationale for advancing the molecule into human clinical trials.

Furthermore, a compelling scientific basis existed for combining bempegaldesleukin with immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis, such as nivolumab. Early studies showed that bempegaldesleukin treatment led to an upregulation of PD-1 on the surface of effector lymphocytes and an increase in PD-L1 expression on tumor cells.[1] PD-1 expression is a marker of T-cell activation, but its interaction with PD-L1 on tumor cells acts as a brake, suppressing T-cell function. The combination was therefore envisioned as a powerful synergistic regimen: bempegaldesleukin would act as the "gas pedal," generating and activating a large army of tumor-reactive T cells, while nivolumab would act as the "brake release," preventing these newly activated T cells from being shut down by the tumor. This dual-mechanism approach was expected to produce deeper and more durable responses than could be achieved with either agent alone.

Table 1: Key Properties and Identifiers of Bempegaldesleukin

Property	Value/Description
Generic Name	Bempegaldesleukin
Development Code	NKTR-214, BEMPEG
Drug Type	Biotech, Interleukin
DrugBank ID	DB15140
CAS Number	1939126-74-5
INN	10593
Molecular Class	PEGylated recombinant human interleukin-2; Peptide
Developer	Nektar Therapeutics
Target	Interleukin-2 Receptor (IL-2R)
Mechanism of Action	CD122-preferential IL-2 pathway agonist

Data compiled from sources.[7]

The Clinical Development Program: A Trajectory of Promise and Peril

The clinical journey of bempegaldesleukin was a dramatic narrative of meteoric rise followed by a swift and comprehensive collapse. Fueled by exceptionally encouraging early-phase results, Nektar Therapeutics and its partner Bristol Myers Squibb launched an ambitious and expansive global development program, known as the PIVOT series of trials. This program, however, would ultimately fail to replicate the initial promise in rigorous, randomized Phase 3 settings, leading to its complete discontinuation.

PIVOT-02: Early Phase Success and the Foundation for a Global Program (NCT02983045)

The foundation of the entire bempegaldesleukin program was built upon the results of the PIVOT-02 study, a Phase 1/2 "basket" trial that evaluated the combination of bempegaldesleukin and nivolumab across various advanced solid tumors.[1] The results from the cohort of 38 efficacy-evaluable, previously untreated patients with metastatic melanoma were particularly striking and generated immense excitement within the oncology community.

In this cohort, the combination achieved a confirmed objective response rate (ORR) of 53%, with an unprecedented 34% of patients achieving a complete response (CR).[1] The responses were not only frequent but also deep and durable; 47% of patients experienced a 100% reduction in their target lesions, and the median progression-free survival (PFS) reached an impressive 30.9 months.[1] The safety profile in this early trial was also considered manageable, with relatively low rates of high-grade adverse events.[1]

These compelling data, which far exceeded historical benchmarks for PD-1 monotherapy, were perceived as strong evidence of the combination's synergistic potential. This perception was solidified in August 2019 when the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to the combination for the treatment of previously untreated unresectable or metastatic melanoma.[7] The PIVOT-02 results served as the direct and compelling rationale for launching a massive, multi-trial Phase 3 program to confirm these findings and pursue regulatory approval across multiple cancer types.[1]

PIVOT IO-001: The Definitive Phase III Failure in First-Line Metastatic Melanoma (NCT03635983)

The flagship trial of the development program was PIVOT IO-001, a large, global, randomized, open-label Phase 3 study designed to confirm the PIVOT-02 findings. The trial enrolled 783 patients with previously untreated, unresectable or metastatic melanoma, randomizing them to receive either the bempegaldesleukin-nivolumab combination or nivolumab monotherapy.[26]

In a stunning reversal of fortune, Nektar and Bristol Myers Squibb announced in March 2022 that the trial had failed to meet its primary endpoints at a pre-planned analysis.[7] The results were not merely neutral; they were unequivocally negative. The combination arm demonstrated a numerically

lower ORR of 27.7% compared to 36.0% in the nivolumab monotherapy arm.[30] The combination also failed to improve PFS, with a median of 4.17 months versus 4.99 months for nivolumab alone (Hazard Ratio 1.09), and showed no benefit in overall survival (OS).[30] The failure was so definitive that the independent Data Monitoring Committee recommended unblinding the trial, and no further analyses for OS were performed.[27] This catastrophic result was the first major blow to the program and immediately triggered the discontinuation of the related adjuvant melanoma study, PIVOT-12.[27]

PIVOT-09: Failure to Demonstrate Superiority in Advanced Renal Cell Carcinoma (NCT03729245)

Following the melanoma data, the fate of the program rested on the PIVOT-09 trial, a Phase 3 study in 623 patients with previously untreated advanced or metastatic clear cell renal cell carcinoma (ccRCC). This trial compared the bempegaldesleukin-nivolumab combination against the investigator's choice of a standard-of-care tyrosine kinase inhibitor (TKI), either sunitinib or cabozantinib.[7]

In April 2022, the companies announced that this trial had also failed.[35] In the primary analysis population of patients with intermediate- and poor-risk disease, the combination did not meet its co-primary endpoints. The ORR was again lower in the experimental arm (23.0%) compared to the TKI control arm (30.6%).[33] Similarly, the combination failed to demonstrate a statistically significant improvement in OS.[33] While the combination regimen was associated with fewer Grade 3/4 treatment-related adverse events (TRAEs) than the TKI arm, this modest safety benefit was rendered irrelevant by the profound lack of efficacy.[33]

PIVOT-10 & PIVOT-12: Corroborating Failures and the End of the Program

The final nails in the coffin for the bempegaldesleukin program came from two other key studies. The PIVOT-10 trial (NCT03785925) was a Phase 2 study evaluating the combination in patients with cisplatin-ineligible, locally advanced or metastatic urothelial cancer.[39] The final analysis revealed an ORR of only 17.9% in the primary population of patients with low PD-L1 expression, a result that did not meet the pre-specified efficacy threshold to warrant further investigation.[35]

The PIVOT-12 trial (NCT04410445) was a Phase 3 study designed to evaluate the combination as an adjuvant (post-surgery) therapy for patients with completely resected, high-risk melanoma.[24] Following the disastrous results of the PIVOT IO-001 trial in the metastatic setting, the scientific rationale for this study evaporated. Consequently, the companies announced the discontinuation of enrollment and unblinding of the PIVOT-12 study in March 2022.[27] With failures across melanoma, RCC, and urothelial cancer, the entire global clinical development program for bempegaldesleukin was officially terminated.[35]

Table 2: Overview of the Bempegaldesleukin PIVOT Clinical Trial Program

Trial ID (NCT Number)	Phase	Cancer Type	Setting	Arms/Intervention	Primary Endpoints	Status/Outcome
PIVOT-02 (NCT02983045)	1/2	Solid Tumors (incl. Melanoma, RCC, UC)	First-Line Metastatic	BEMPEG + Nivolumab	Safety, ORR	Completed; Showed strong preliminary efficacy, leading to Phase 3 program
PIVOT IO-001 (NCT03635983)	3	Metastatic Melanoma	First-Line	BEMPEG + Nivolumab vs. Nivolumab	ORR, PFS, OS	Terminated; Failed to meet all primary endpoints
PIVOT-09 (NCT03729245)	3	Renal Cell Carcinoma	First-Line	BEMPEG + Nivolumab vs. TKI (Sunitinib/Cabozantinib)	ORR, OS	Terminated; Failed to meet all primary endpoints
PIVOT-10 (NCT03785925)	2	Urothelial Carcinoma	First-Line (Cisplatin-ineligible)	BEMPEG + Nivolumab	ORR	Terminated; Failed to meet efficacy threshold
PIVOT-12 (NCT04410445)	3	Melanoma	Adjuvant	BEMPEG + Nivolumab vs. Nivolumab	Recurrence-Free Survival (RFS)	Terminated; Discontinued based on PIVOT IO-001 results

Data compiled from sources.[7]

Deconstructing the Clinical Data: An In-Depth Efficacy and Safety Analysis

A granular examination of the data from the pivotal Phase 3 trials reveals a consistent and unambiguous pattern: the addition of bempegaldesleukin to standard-of-care immunotherapy not only failed to enhance efficacy but also increased the toxicity burden, resulting in a clinically untenable risk/benefit profile.

Comparative Efficacy Analysis Across the PIVOT Program

The failure of bempegaldesleukin was not marginal; in the most critical head-to-head comparison, the combination therapy underperformed against the control arm.

In the PIVOT IO-001 trial in melanoma, the combination of bempegaldesleukin plus nivolumab yielded an ORR of 27.7%, which was statistically significantly lower than the 36.0% ORR observed with nivolumab monotherapy (p=0.0311).[30] This finding was particularly damning, as it suggested that bempegaldesleukin may have actively interfered with or antagonized the efficacy of nivolumab. The lack of benefit extended to all key endpoints. Median PFS trended worse for the combination (4.17 months) compared to nivolumab alone (4.99 months), with a hazard ratio of 1.09, indicating a 9% increased risk of progression or death for patients receiving the combination.[30] There was no difference in median OS between the two arms (29.67 months vs. 28.88 months; HR 0.94).[30]

A similar pattern emerged in the PIVOT-09 trial in RCC. When compared against standard TKI therapy in patients with intermediate- or poor-risk disease, the bempegaldesleukin plus nivolumab combination produced a lower ORR (23.0% vs. 30.6% for TKIs; p=0.0489).[33] While the hazard ratio for OS favored the combination (HR 0.82), the result was not statistically significant (

p=0.192) and could not overcome the failure on the ORR endpoint.[33]

Finally, in the single-arm PIVOT-10 trial in urothelial cancer, the combination achieved an ORR of 19.7% in all treated patients and 17.9% in the primary analysis population with low PD-L1 expression.[42] These response rates failed to clear the pre-specified efficacy bar needed to justify further development, particularly in a landscape where other ICI-based therapies have demonstrated ORRs in the range of 23-29% in similar patient populations.[45]

Table 3: Summary of Primary Efficacy Endpoints for PIVOT IO-001 (Melanoma)

Endpoint	BEMPEG + Nivolumab (n=391)	Nivolumab Monotherapy (n=392)	Hazard Ratio / P-value
Objective Response Rate (ORR)	27.7%	36.0%	p=0.0311
Complete Response (CR) Rate	5.6%	9.7%	N/A
Median Progression-Free Survival (PFS)	4.17 months	4.99 months	HR 1.09; p=0.3988
Median Overall Survival (OS)	29.67 months	28.88 months	HR 0.94; p=0.6361

Data compiled from sources.[30]

Table 4: Summary of Primary Efficacy Endpoints for PIVOT-09 (Renal Cell Carcinoma)

Endpoint (IMDC int/poor risk)	BEMPEG + Nivolumab (n=257)	TKI (sunitinib/cabozantinib) (n=257)	Difference / P-value
Objective Response Rate (ORR)	23.0%	30.6%	Difference: -7.7%; p=0.0489
Median Overall Survival (OS)	29.0 months	Not Estimable	HR 0.82; p=0.192

Data compiled from sources.[33]

Comprehensive Safety and Tolerability Profile: Assessing the Burden of Combination Therapy

While failing to improve efficacy, the addition of bempegaldesleukin consistently increased the rate of adverse events compared to nivolumab monotherapy. In PIVOT IO-001, the rate of Grade 3-4 TRAEs was nearly double in the combination arm (21.7%) compared to the nivolumab arm (11.5%).[30] The rate of serious adverse events was also substantially higher (10.1% vs. 5.5%).[30]

The most common TRAEs associated with the combination were constitutional and flu-like symptoms, including pyrexia, pruritus (itching), rash, fatigue, and nausea.[3] In the PIVOT-09 trial, while the overall rate of Grade 3/4 TRAEs was lower for the bempegaldesleukin combination compared to the TKI arm (25.8% vs. 56.5%), this was largely driven by the known toxicities of TKIs like hypertension and palmar-plantar erythrodysesthesia. However, the bempegaldesleukin combination caused markedly higher rates of specific all-grade TRAEs such as pyrexia (32.6% vs. 2.0%) and pruritus (31.3% vs. 8.8%).[33] Events of particular concern, such as syncope (fainting), were also noted, with a Grade 3/4 incidence of 8.2% in the RCC cohort of the PIVOT-02 study.[22]

This safety profile demonstrates a clear negative synergy. The combination of bempegaldesleukin and nivolumab not only failed to produce an additive or synergistic efficacy benefit but created an additive toxicity burden, leading to a risk/benefit calculation that was unequivocally unfavorable compared to the standard of care.

Table 5: Consolidated Profile of Key Grade ≥3 Treatment-Related Adverse Events (TRAEs) in Pivotal Trials

Adverse Event	PIVOT IO-001 (Combo %)	PIVOT IO-001 (Control %)	PIVOT-09 (Combo %)	PIVOT-09 (Control %)
Any Grade 3/4 TRAE	21.7%	11.5%	25.8%	56.5%
Pyrexia	0.8%	0%	0.6%	0%
Pruritus	0.5%	0.3%	0%	0.3%
Syncope	N/A	N/A	1.3%	0%
Increased Lipase	N/A	N/A	1.6%	2.0%
Fatigue	0.8%	0.8%	1.3%	2.6%
Rash	1.0%	0.3%	0.6%	1.0%

Data compiled from sources.[22]

A Mechanistic Post-Mortem: Why Did Bempegaldesleukin Fail?

The comprehensive failure of the bempegaldesleukin clinical program necessitates a deep analysis of the underlying mechanism. The stark contrast between the promising preclinical hypothesis and the negative Phase 3 outcomes can be largely explained by biomarker data from the PIVOT IO-001 trial, which revealed a fatal disconnect between the drug's activity in the peripheral circulation and its effect within the tumor microenvironment.

The Peripheral vs. Intratumoral Disconnect: A Failure to Mobilize an Effective Antitumor Response

The central mechanistic failure of bempegaldesleukin lies in its inability to translate systemic immune activation into a localized anti-tumor effect. Comprehensive biomarker analysis from PIVOT IO-001 confirmed that the combination of bempegaldesleukin and nivolumab did, in fact, achieve one of its primary pharmacodynamic goals: it mediated statistically significant increases in the peripheral blood counts of CD8+ T cells, CD4+ T cells, and NK cells compared to nivolumab alone.[49] This demonstrates that the drug was biologically active and engaging its target receptor systemically.

However, this peripheral expansion of immune cells proved to be therapeutically irrelevant. The crucial subsequent step—the infiltration of these newly expanded effector cells into the tumor—did not occur. Analysis of longitudinal tumor biopsies revealed no substantive difference in the increase of CD8+ tumor-infiltrating lymphocytes (TILs) between the combination arm and the nivolumab monotherapy arm.[49] An effective T-cell mediated anti-tumor response is predicated on the ability of cytotoxic T cells to enter the tumor microenvironment, recognize, and kill cancer cells. By failing to increase the density of TILs above the level achieved by nivolumab alone, bempegaldesleukin offered no additive or synergistic mechanism for enhanced tumor killing. This disconnect between peripheral and intratumoral activity is the most likely explanation for the combination's lack of clinical benefit.[49]

Pharmacodynamic Insights: Treg Expansion and Attenuation of T-Cell Proliferation

Further biomarker data revealed two additional findings that undermined the drug's therapeutic hypothesis. First, in direct contradiction to its core design principle of avoiding Treg stimulation, the bempegaldesleukin-nivolumab combination led to significant increases in proliferating Tregs in the peripheral blood.[49] This suggests that the PEGylation strategy, while designed to sterically hinder binding to the CD25 subunit, was not sufficient to prevent signaling through the high-affinity IL-2 receptor complex. The expansion of these immunosuppressive cells may have counteracted any potential benefit derived from the expansion of effector T cells.

Second, the stimulatory effect on effector cells was not durable. While the proliferation of peripheral CD8+ and CD4+ T cells was significant during the first cycle of treatment, this effect was markedly attenuated by the fifth cycle. A similar attenuation over time was observed for systemic levels of interferon-gamma (IFNγ), a key cytokine associated with T-cell effector function.[49] This waning pharmacodynamic effect suggests that the sustained signaling provided by the long-acting prodrug may have ultimately driven the expanded T cells toward a state of exhaustion or terminal differentiation, rendering them less effective over time.

A Critical Re-evaluation of the CD122-Biased Agonist Hypothesis

The collective evidence from the PIVOT program forces a critical re-evaluation of the entire CD122-biased agonist strategy as embodied by bempegaldesleukin. The underlying assumption was that simplifying the complex biology of IL-2—by isolating the "good" CD122-mediated effector cell stimulation from the "bad" CD25-mediated Treg stimulation—would yield a superior therapeutic. The clinical results prove this assumption was flawed.

The failure suggests that a successful IL-2-based therapy requires more than just the quantitative expansion of T cells in the periphery. The quality of the T-cell response—including the phenotype, trafficking capacity, and differentiation state of the expanded cells—is paramount. The bempegaldesleukin experience raises several critical questions for the field. Did the drug generate T cells that lacked the appropriate chemokine receptors to traffic to the tumor? Did the sustained, non-pulsatile signal drive T cells toward a terminally exhausted state rather than a self-renewing, stem-like memory phenotype capable of long-term tumor control? It is even possible that some level of signaling through the CD25 subunit, which the drug was designed to avoid, is necessary to program T cells for optimal function and trafficking. The attempt to engineer a "cleaner" IL-2 may have inadvertently removed a crucial biological signal required for clinical efficacy.

Corporate and Strategic Fallout

The clinical failure of bempegaldesleukin had immediate and severe consequences for its developer, Nektar Therapeutics, and represented a major setback for its collaborator, Bristol Myers Squibb. The collapse of the program serves as a high-profile case study in the financial risks and strategic volatility inherent in biotechnology drug development.

The Nektar-BMS Alliance: Anatomy of a High-Profile Collaboration Failure

In February 2018, buoyed by the promising early data from PIVOT-02, Nektar Therapeutics entered into a landmark strategic development and commercialization collaboration with Bristol Myers Squibb (BMS) for bempegaldesleukin.[7] The deal was one of the largest in the industry's history, with BMS paying Nektar $1.85 billion upfront, consisting of a $1 billion cash payment and an $850 million equity investment. The agreement also included up to $1.78 billion in potential future milestone payments, bringing the total potential value of the deal to over $3.6 billion.[52] BMS also agreed to cover a significant portion of the global development costs.

This massive investment was predicated on the hypothesis that bempegaldesleukin would synergize with BMS's flagship PD-1 inhibitor, Opdivo (nivolumab), and become a cornerstone of future immuno-oncology combination therapy. The definitive failure of the Phase 3 trials in March and April 2022 triggered the complete unwinding of this alliance. The companies jointly announced the termination of the entire global clinical development program for the bempegaldesleukin-nivolumab combination, a decision that encompassed not only the pivotal trials in melanoma, RCC, and bladder cancer but also all other ongoing studies, including those in pediatric tumors and muscle-invasive bladder cancer.[35] Similar collaborations with other pharmaceutical partners, including Pfizer and Merck, were also discontinued.[7]

The Aftermath: Corporate Restructuring and Strategic Pivot

For Nektar Therapeutics, the failure of its lead asset was catastrophic. The company had invested substantial resources in building out the late-stage clinical trial infrastructure and preparing for a potential commercial launch.[55] In the wake of the trial failures, Nektar announced a sweeping corporate restructuring plan in April 2022 designed to conserve capital and refocus its efforts. The plan involved a 70% reduction in its workforce, resulting in the loss of over 500 jobs.[55] Key executives, including the Chief Medical Officer and Chief Commercial Officer, departed the company.[53]

Following the wind-down of the bempegaldesleukin program, Nektar pivoted its strategy to prioritize its remaining, earlier-stage pipeline assets. The company's research and development efforts are now focused on NKTR-358 (rezpegaldesleukin), an IL-2 based regulatory T-cell stimulator for autoimmune diseases partnered with Eli Lilly, and NKTR-255, an IL-15 receptor agonist being investigated for its potential to enhance cell therapies and treat hematological malignancies.[55] The dramatic fallout from the bempegaldesleukin failure underscores the high-risk, high-reward nature of pharmaceutical R&D and serves as a stark reminder of the financial consequences when a lead asset fails to deliver on its initial promise.

Conclusion: Lessons from Bempegaldesleukin and the Future of Cytokine Therapy

The story of bempegaldesleukin, from its elegant scientific rationale to its definitive clinical failure, offers critical lessons for the field of immuno-oncology and provides a crucial, albeit cautionary, data set that will inform the future development of cytokine-based therapies.

Key Scientific and Clinical Takeaways for Immuno-Oncology Drug Development

The bempegaldesleukin saga reinforces several fundamental principles of modern drug development. First, it serves as a powerful testament to the potential for single-arm, uncontrolled Phase 2 studies to generate misleading signals of efficacy. The impressive response rates seen in the PIVOT-02 melanoma cohort created a perception of benefit that was not only absent but was actually reversed in a randomized, controlled setting. This highlights the absolute necessity of randomized data to truly discern the contribution of an investigational agent in a combination regimen before committing to large, resource-intensive Phase 3 programs.

Second, the failure underscores the critical importance of demonstrating robust and relevant intratumoral pharmacodynamic effects. The disconnect between bempegaldesleukin's ability to expand T cells in the periphery and its inability to increase their infiltration into the tumor is the central mechanistic lesson. Future immunotherapies that aim to modulate systemic immune cell populations must be accompanied by rigorous biomarker plans that can confirm target engagement and the desired biological effect within the tumor microenvironment itself.

The Evolving Landscape of IL-2 Agonists and Next-Generation Immunotherapies

While the failure of bempegaldesleukin was a major setback for the field, it has not extinguished interest in harnessing the power of the IL-2 pathway. Instead, it has provided invaluable data that are helping to guide a more nuanced and sophisticated approach to cytokine engineering.[56] The pipeline of next-generation IL-2 agonists remains robust, with numerous companies pursuing strategies designed to avoid the pitfalls that doomed bempegaldesleukin.[2]

These next-generation approaches include:

• Tumor-Targeted Immunocytokines: These are fusion proteins that link an IL-2 molecule to an antibody that targets a tumor-associated antigen. This strategy aims to concentrate the IL-2 activity directly within the tumor microenvironment, thereby maximizing local immune stimulation while minimizing systemic toxicity.[12]
• Novel Receptor Biasing: Rather than simply blocking the CD25 interaction, some new IL-2 muteins are being engineered with more complex modifications to fine-tune signaling through all three receptor subunits, including strategies that may even favor CD25 to preserve T-cell stemness or selectively expand Tregs for use in autoimmune disease.[57]
• Alternative Cytokines: The challenges with IL-2 have also spurred greater interest in related cytokines like IL-15, which shares the IL−2Rβγc​ receptor but does not engage Tregs, as a potentially cleaner way to stimulate CD8+ T and NK cells.[2]

Ultimately, the development and failure of bempegaldesleukin is not an end point but a critical data point in the long and complex journey of cytokine immunotherapy. By revealing the flaws in a seemingly rational hypothesis, it has forced the scientific community to confront the deeper complexities of IL-2 biology. The lessons learned from its failure—both clinical and mechanistic—will undoubtedly contribute to the design of safer, more intelligent, and ultimately more effective immunotherapies for cancer patients.

Works cited

1. Bempegaldesleukin Plus Nivolumab in First-Line Metastatic ..., accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8425826/
2. Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy - ResearchGate, accessed September 26, 2025, https://www.researchgate.net/publication/388031170_Current_landscape_and_future_prospects_of_interleukin-2_receptor_IL-2R_agonists_in_cancer_immunotherapy
3. Bempegaldesleukin plus nivolumab in first-line renal cell carcinoma: results from the PIVOT-02 study - PMC, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9021810/
4. Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy - Taylor & Francis Online, accessed September 26, 2025, https://www.tandfonline.com/doi/full/10.1080/2162402X.2025.2452654
5. (PDF) TransCon IL-2 β/γ: a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer - ResearchGate, accessed September 26, 2025, https://www.researchgate.net/publication/361920059_TransCon_IL-2_bg_a_novel_long-acting_prodrug_with_sustained_release_of_an_IL-2Rbg-selective_IL-2_variant_with_improved_pharmacokinetics_and_potent_activation_of_cytotoxic_immune_cells_for_the_treatmen
6. IL-2 based cancer immunotherapies: an evolving paradigm - Frontiers, accessed September 26, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1433989/full
7. Bempegaldesleukin - Wikipedia, accessed September 26, 2025, https://en.wikipedia.org/wiki/Bempegaldesleukin
8. Combining bempegaldesleukin (CD122-preferential IL-2 pathway agonist) and NKTR-262 (TLR7/8 agonist) improves systemic antitumor CD8+ T cell cytotoxicity over BEMPEG+RT - PMC, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9021762/
9. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/32005826/
10. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy - PMC, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6994577/
11. bempegaldesleukin | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 26, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10659
12. Mechanism of action of bempegaldesleukin. BEMPEG is an investigational... - ResearchGate, accessed September 26, 2025, https://www.researchgate.net/figure/Mechanism-of-action-of-bempegaldesleukin-BEMPEG-is-an-investigational-CD122-preferential_fig1_344303064
13. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02) | Cancer Discovery - AACR Journals, accessed September 26, 2025, https://aacrjournals.org/cancerdiscovery/article/10/8/1158/2710/Bempegaldesleukin-NKTR-214-plus-Nivolumab-in
14. Nektar Therapeutics and Bristol-Myers Squibb Announce U.S. FDA Breakthrough Therapy Designation for Bempegaldesleukin (NKTR-214) in Combination with Opdivo® (nivolumab) for the Treatment of Patients with Untreated Advanced Melanoma, accessed September 26, 2025, https://ir.nektar.com/news-releases/news-release-details/nektar-therapeutics-and-bristol-myers-squibb-announce-us-fda
15. PIVOT-12: A Phase 3 randomized study of adjuvant bempegaldesleukin (BEMPEG) plus nivolumab (NIVO - Nektar Therapeutics, accessed September 26, 2025, https://www.nektar.com/wp-content/uploads/2023/11/Eggermont_et_al._WCM_PIVOT-12_TiP_Poster_APR6_FINAL_1.pdf
16. A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors | Cancer Discovery - AACR Journals, accessed September 26, 2025, https://aacrjournals.org/cancerdiscovery/article/9/6/711/42257/A-First-in-Human-Study-and-Biomarker-Analysis-of
17. Bempegaldesleukin (BEMPEG; NKTR‐214) efficacy as a single agent and in combination with checkpoint‐inhibitor therapy in mouse models of osteosarcoma - PubMed Central, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7984260/
18. Bempegaldesleukin/Nivolumab Combo Upholds Durable Benefit in Metastatic Melanoma, accessed September 26, 2025, https://www.onclive.com/view/bempegaldesleukin-nivolumab-combo-upholds-durable-benefit-in-metastatic-melanoma
19. Bempegaldesleukin Completed Phase 1 / 2 Trials for Unspecified Adult Solid Tumor, Protocol Specific Treatment - DrugBank, accessed September 26, 2025, https://go.drugbank.com/drugs/DB15140/clinical_trials?conditions=DBCOND0028453&phase=1%2C2&purpose=treatment&status=completed
20. Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma - ASCO Publications, accessed September 26, 2025, https://ascopubs.org/doi/10.1200/JCO.21.00675
21. Nektar Therapeutics Presents Biomarker and Clinical Data from PIVOT-02 Phase 2 Study of Bempegaldesleukin with Nivolumab at 2019 ASCO Annual Meeting - PR Newswire, accessed September 26, 2025, https://www.prnewswire.com/news-releases/nektar-therapeutics-presents-biomarker-and-clinical-data-from-pivot-02-phase-2-study-of-bempegaldesleukin-with-nivolumab-at-2019-asco-annual-meeting-300860219.html
22. Bempegaldesleukin plus nivolumab in first-line renal cell carcinoma ..., accessed September 26, 2025, https://jitc.bmj.com/content/10/4/e004419
23. Nektar Therapeutics and Bristol-Myers Squibb Announce U.S. FDA Breakthrough Therapy Designation for Bempegaldesleukin (NKTR-214) in Combination with Opdivo® (nivolumab) for the Treatment of Patients with Untreated Advanced Melanoma, accessed September 26, 2025, https://news.bms.com/news/partnering/2019/Nektar-Therapeutics-and-Bristol-Myers-Squibb-Announce-US-FDA-Breakthrough-Therapy-Designation-for-Bempegaldesleukin-NKTR-214-in-Combination-with-Opdivo-nivolumab-for-the-Treatment-of-Patients-with-Untreated-Advanced-Melanoma/default.aspx
24. PIVOT-12: a phase III study of adjuvant bempegaldesleukin plus nivolumab in resected stage III/IV melanoma at high risk for recurrence - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/35073733/
25. Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/32723187/
26. CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL). - ASCO, accessed September 26, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT264259
27. Bristol Myers Squibb and Nektar Announce Update on Phase 3 PIVOT IO-001 Trial Evaluating Bempegaldesleukin (BEMPEG) in Combination with Opdivo (nivolumab) in Previously Untreated Unresectable or Metastatic Melanoma, accessed September 26, 2025, https://news.bms.com/news/details/2022/Bristol-Myers-Squibb-and-Nektar-Announce-Update-on-Phase-3-PIVOT-IO-001-Trial-Evaluating-Bempegaldesleukin-BEMPEG-in-Combination-with-Opdivo-nivolumab-in-Previously-Untreated-Unresectable-or-Metastatic-Melanoma/default.aspx
28. Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results - ASCO Publications, accessed September 26, 2025, https://ascopubs.org/doi/10.1200/JCO.23.00172
29. Nektar announced that IL-2 cytokine Bempeg with Opdivo failed in Phase 3 melanoma trial, accessed September 26, 2025, https://www.ppf.eu/en/insights/biotech-market/march-2022-biotechnology-review-of-news-from-the-most-innovative-therapeutic-area/nektar-announced-that-il-2-cytokine-bempeg-with-opdivo-failed-in-phase-3-melanoma
30. Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results, accessed September 26, 2025, https://mdanderson.elsevierpure.com/en/publications/bempegaldesleukin-plus-nivolumab-in-untreated-advanced-melanoma-t
31. Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/37651676/
32. PIVOT IO 001: First disclosure of efficacy and safety of bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) vs NIVO monotherapy in advanced melanoma (MEL) - Providence, accessed September 26, 2025, https://providence.elsevierpure.com/en/publications/pivot-io-001-first-disclosure-of-efficacy-and-safety-of-bempegald
33. Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09) | Journal of Clinical Oncology - ASCO Publications, accessed September 26, 2025, https://ascopubs.org/doi/abs/10.1200/JCO.23.02082
34. PIVOT-09: A phase III randomized open-label study of bempegaldesleukin (NKTR-214) plus nivolumab versus sunitinib or cabozantinib (investigator's choice) in patients with previously untreated advanced renal cell carcinoma (RCC). - ASCO, accessed September 26, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT286655
35. Bempegaldesleukin/Nivolumab Combo Misses Mark in RCC and Urothelial Cancer, accessed September 26, 2025, https://www.onclive.com/view/bempegaldesleukin-nivolumab-combo-misses-mark-in-rcc-and-urothelial-cancer
36. Global Clinical Development Program for Bempegaldesleukin in Combination With Nivolumab Will Be Discontinued - Pharmacy Times, accessed September 26, 2025, https://www.pharmacytimes.com/view/global-clinical-development-program-for-bempegaldesleukin-in-combination-with-nivolumab-will-be-discontinued
37. Nektar and Bristol Myers Squibb Announce Update on Clinical Development Program for Bempegaldesleukin (BEMPEG) in Combination with Opdivo (nivolumab), accessed September 26, 2025, https://news.bms.com/news/details/2022/Nektar-and-Bristol-Myers-Squibb-Announce-Update-on-Clinical-Development-Program-for-Bempegaldesleukin-BEMPEG-in-Combination-with-Opdivo-nivolumab/default.aspx
38. Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09) - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/38838287/
39. Bempegaldesleukin Completed Phase 2 Trials for Metastatic Cancer / Urinary Bladder Neoplasms Treatment | DrugBank Online, accessed September 26, 2025, https://go.drugbank.com/drugs/DB15140/clinical_trials?conditions=DBCOND0028461%2CDBCOND0001226&phase=2&purpose=treatment&status=completed
40. NCT03785925 | A Single-Arm Study of Bempegaldesleukin (NKTR-214) Plus Nivolumab in Cisplatin Ineligible Patients Who Have Locally Advanced or Metastatic Urothelial Cancer | ClinicalTrials.gov, accessed September 26, 2025, https://clinicaltrials.gov/study/NCT03785925
41. PIVOT-10: A phase II study of bempegaldesleukin (NKTR-214) in combination with nivolumab (NIVO) in cisplatin (cis) ineligible patients with previously untreated locally advanced or metastatic urothelial cancer (mUC). - ASCO Publications, accessed September 26, 2025, https://ascopubs.org/doi/10.1200/JCO.2020.38.6_suppl.TPS589
42. Bempegaldesleukin plus nivolumab in first-line advanced/metastatic urothelial carcinoma: Results from a phase II single-arm study (PIVOT-10) - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/39477771/
43. NCT04410445 | Study to Compare Adjuvant Immunotherapy of Bempegaldesleukin Combined With Nivolumab Versus Nivolumab After Complete Resection of Melanoma in Patients at High Risk for Recurrence | ClinicalTrials.gov, accessed September 26, 2025, https://www.clinicaltrials.gov/study/NCT04410445
44. Trial Examining BEMPEG/ Nivolumab Combination Discontinues | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways, accessed September 26, 2025, https://www.targetedonc.com/view/trial-examining-bempeg-nivolumab-combination-discontinues
45. Full article: PIVOT-10: Phase II study of bempegaldesleukin plus nivolumab in cisplatin-ineligible advanced urothelial cancer - Taylor & Francis Online, accessed September 26, 2025, https://www.tandfonline.com/doi/full/10.2217/fon-2020-0795
46. Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results - PMC, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10602507/
47. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02) - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/32439653/
48. Nektar Therapeutics Presents Biomarker and Clinical Data from PIVOT-02 Phase 2 Study of Bempegaldesleukin with Nivolumab at 2019 ASCO Annual Meeting, accessed September 26, 2025, https://ir.nektar.com/news-releases/news-release-details/nektar-therapeutics-presents-biomarker-and-clinical-data-pivot
49. 1473 Mechanism of action of bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in patients with unresectable or metastatic melanoma from the phase 3 randomized open-label PIVOT IO-001 clinical trial | Journal for ImmunoTherapy of Cancer, accessed September 26, 2025, https://jitc.bmj.com/content/10/suppl_2/a1532
50. 1473 Mechanism of action of bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in patients with unresectable or metastatic melanoma from the phase 3 randomized open-label PIVOT IO-001 clinical trial - ResearchGate, accessed September 26, 2025, https://www.researchgate.net/publication/365214521_1473_Mechanism_of_action_of_bempegaldesleukin_BEMPEG_plus_nivolumab_NIVO_in_patients_with_unresectable_or_metastatic_melanoma_from_the_phase_3_randomized_open-label_PIVOT_IO-001_clinical_trial
51. 1473 Mechanism of action of bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in patients with unresectable or metastatic melan, accessed September 26, 2025, https://jitc.bmj.com/content/jitc/10/Suppl_2/A1532.full.pdf
52. Nektar Announces Collaboration with SFJ Pharmaceuticals® for Bempegaldesleukin in Head and Neck Cancer, accessed September 26, 2025, https://ir.nektar.com/news-releases/news-release-details/nektar-announces-collaboration-sfj-pharmaceuticalsr
53. After bempeg failure, Nektar wields the axe - pharmaphorum, accessed September 26, 2025, https://pharmaphorum.com/news/after-bempeg-failure-nektar-wields-the-axe
54. Nektar Announces Agreement for Phase 2/3 Study of IL-2 Pathway Agonist, Bempegaldesleukin, in Combination with Merck's KEYTRUDA® (pembrolizumab) in Patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) - BioSpace, accessed September 26, 2025, https://www.biospace.com/nektar-announces-agreement-for-phase-2-3-study-of-il-2-pathway-agonist-bempegaldesleukin-in-combination-with-merck-s-keytruda-pembrolizumab-in-patients-with-squamous-cell-carcinoma-of-the-head-and-neck-scchn
55. Nektar hits reset button after bempeg failure, cuts 70% of staff - FirstWord Pharma, accessed September 26, 2025, https://firstwordpharma.com/story/5556221
56. Bempeg Failure Unlikely to Affect Other IL2 Drugs - PubMed, accessed September 26, 2025, https://pubmed.ncbi.nlm.nih.gov/35553619/
57. Optimising IL-2 for Cancer Immunotherapy - PMC - PubMed Central, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10917570/
58. Bempeg Failure Unlikely to Affect Other IL2 Drugs - AACR Journals, accessed September 26, 2025, https://aacrjournals.org/cancerdiscovery/article-pdf/12/7/1604/3176605/1604.pdf
59. Interleukin-2–based therapies in cancer - Ovid, accessed September 26, 2025, https://www.ovid.com/journals/stmed/pdf/10.1126/scitranslmed.abo5409~interleukin-2based-therapies-in-cancer
60. Interleukin-2-targeting Therapies: Journey from Bench to Bedside - DelveInsight, accessed September 26, 2025, https://www.delveinsight.com/blog/interleukin-2-targeting-therapies
61. Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies - MDPI, accessed September 26, 2025, https://www.mdpi.com/2076-393X/13/1/69
62. Molecular engineering of interleukin-2 for enhanced therapeutic activity in autoimmune diseases - PubMed Central, accessed September 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10947368/
63. Engineered IL-2 molecule shows promise in treating autoimmune disease - Health e-News, accessed September 26, 2025, https://healthenews.mcgill.ca/engineered-il-2-molecule-shows-promise-in-treating-autoimmune-disease/
64. Bempegaldesleukin - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 26, 2025, https://synapse.patsnap.com/drug/45aa5528f55f4ecabd30eafd5ee29150
65. Bempegaldesleukin | MedPath, accessed September 26, 2025, https://trial.medpath.com/drug/c681f9c59c920653/bempegaldesleukin?page=2