A Comprehensive Clinical and Pharmacological Profile of Tengonermin (NGR-hTNF): A Vascular-Targeting Agent's Journey from Promise to Pivotal Failure

Executive Summary

Tengonermin, also known as NGR-hTNF, is an investigational biotechnology-derived therapeutic agent engineered as a novel vascular-targeting drug for the treatment of solid tumors. Its design represents a sophisticated approach to cytokine therapy, aiming to harness the potent anti-tumor effects of Tumor Necrosis Factor-alpha (TNF-α) while mitigating the severe systemic toxicities that plagued earlier, untargeted applications of this cytokine. The drug is a recombinant fusion protein, comprising human TNF-α chemically conjugated to a tumor-homing peptide, CNGRCG. This peptide selectively targets an isoform of the CD13 receptor that is specifically overexpressed on the endothelial cells of the tumor neovasculature. This targeted delivery mechanism is designed to concentrate the pharmacological activity of TNF-α within the tumor microenvironment, thereby increasing the permeability of tumor blood vessels to enhance the penetration of co-administered chemotherapies and immune cells, and directly inducing apoptosis in angiogenic endothelial cells.

The clinical development program for Tengonermin explored its use both as a monotherapy and in combination with standard-of-care chemotherapy across a range of malignancies. Early-phase Phase I and II clinical trials demonstrated a manageable safety profile, characterized primarily by mild-to-moderate, transient infusion-related reactions, and showed promising signals of anti-tumor activity. Particularly noteworthy was an exceptional 75% overall response rate observed in a Phase II trial for patients with relapsed or refractory Primary Central Nervous System Lymphoma (PCNSL), where the drug was hypothesized to overcome the blood-brain barrier. Encouraging results were also seen in a Phase II study in Malignant Pleural Mesothelioma (MPM), which provided the rationale for advancing the drug into late-stage development.

Despite this early promise, the trajectory of Tengonermin was decisively altered by the outcome of the pivotal Phase III NGR015 trial. This large, randomized, placebo-controlled study in patients with previously treated MPM failed to meet its primary endpoint of improving overall survival. This negative result led to the discontinuation of the drug's development program for this indication. The story of Tengonermin thus serves as a critical case study in modern oncology drug development. It illustrates the profound challenges of translating a compelling and validated mechanism of action from early-phase trials into late-stage clinical success, underscores the context-dependent nature of complex biological therapies, and highlights the paramount importance of biomarker-driven patient selection strategies in navigating the heterogeneity of cancer.

Introduction and Drug Profile

Initial Data Disambiguation and Report Focus

This report provides a comprehensive analysis of the investigational drug Tengonermin, identified by DrugBank Accession Number DB16689 and CAS Number 1960461-99-7.[1] A critical preliminary step in this analysis is the disambiguation of the provided research data. A significant portion of the source material pertains to an entirely separate and unrelated pharmaceutical product: Atenolol, a small-molecule beta-blocker marketed under the brand name Tenormin (DrugBank ID: DB00335).[3] Atenolol is used for the treatment of cardiovascular conditions such as hypertension and has a distinct chemical structure, mechanism of action, and therapeutic indication. All information related to Atenolol/Tenormin is fundamentally irrelevant to the subject of this report and has been rigorously excluded from the subsequent analysis. The exclusive focus of this document is the biotechnology-derived, peptide-targeted oncology drug, Tengonermin. This initial clarification is essential to ensure the accuracy and integrity of the report.

Molecular Identity and Formulation

Tengonermin is a complex biologic therapeutic agent, classified as a biotech drug, specifically a recombinant protein and a peptide-targeted therapy.[1] Its molecular architecture is central to its intended function. It is a fusion protein meticulously engineered by conjugating the full-length human Tumor Necrosis Factor-alpha (TNF-α) cytokine to the C-terminus of a tumor-homing peptide with the amino acid sequence CNGRCG.[1] This unique structure is designed to confer tumor-specificity to the potent but otherwise systemically toxic TNF-α payload.

Throughout its development and in scientific literature, Tengonermin is frequently referred to by several synonyms. The most common of these is NGR-hTNF, which explicitly describes its components (the NGR peptide motif and human TNF).[1] It has also been associated with the brand name ARENEGYR.[2] For precise identification, the following identifiers are used:

• DrugBank Accession Number: DB16689 [1]
• CAS Number: 1960461-99-7 [2]
• Unique Ingredient Identifier (UNII): 2YQ0811D7K [9]

Origin and Development History

The development of Tengonermin was pioneered by researchers at the San Raffaele Scientific Institute in Milan, Italy, with subsequent corporate development and manufacturing attributed to AGC Biologics SpA.[7] The drug's development trajectory was aimed at addressing high unmet needs in oncology, which was recognized by regulatory agencies. Specifically, Tengonermin was granted Orphan Drug designation for the treatment of relapsed Malignant Pleural Mesothelioma in both the United States and Europe.[6] This designation provides incentives for the development of treatments for rare diseases and underscored the critical need for new therapeutic options in this patient population.

However, despite a comprehensive clinical program that advanced into late-stage trials, the highest development phase for Tengonermin is officially listed as "Discontinued".[7] This status is the ultimate outcome of its clinical journey and provides a crucial lens through which its entire development history must be viewed. The subsequent sections of this report, therefore, constitute a retrospective analysis aimed at understanding the scientific rationale, clinical performance, and strategic decisions that led from a promising therapeutic concept to the eventual cessation of its development program.

Pharmacology and Mechanism of Action (MoA)

The Vascular-Targeting Paradigm: Selective Homing

The pharmacological concept underpinning Tengonermin is that of a "molecular smart bomb," a vascular-targeting agent designed to deliver a highly potent cytotoxic payload directly to the tumor while minimizing exposure and toxicity to healthy tissues.[1] This approach was conceived as a direct solution to the primary obstacle that thwarted the clinical development of recombinant human TNF-α in the late 20th century: its profound and often fatal systemic toxicity when administered at therapeutically effective doses.[15] The design of Tengonermin is, therefore, an elegant example of second-generation cytokine therapy, where molecular engineering is employed to create a viable therapeutic window for a historically unmanageable agent.

The key to this targeted approach lies in the NGR peptide ligand, a molecule with the sequence CNGRCG that functions as a tumor-homing motif.[1] Mechanistic studies have demonstrated that this peptide selectively binds with high affinity to a specific isoform of the cell surface enzyme aminopeptidase N, also known as CD13.[1] Crucially, the expression of this particular CD13 isoform is largely restricted to the surface of endothelial cells that constitute the angiogenic tumor neovasculature—the newly formed blood vessels that tumors induce to support their growth and metastasis. This receptor is barely detectable on the vasculature of healthy, quiescent tissues.[1] This differential expression provides a molecular address unique to the tumor microenvironment, allowing Tengonermin to accumulate preferentially at the site of disease and spare non-tumor tissues, thereby uncoupling the desired local anti-tumor effects from the deleterious systemic effects of TNF-α.[1]

Downstream Effector Functions of Localized TNF-α

Upon successful homing and binding to the CD13 receptor on tumor blood vessels, the TNF-α component of Tengonermin is positioned to exert its powerful biological effects directly within the tumor microenvironment (TME).[1] The localized release of this pleiotropic cytokine initiates a cascade of downstream events that collectively contribute to its anti-tumor activity. This mechanism is multifaceted, functioning through at least two distinct but complementary pathways.

First, Tengonermin acts as a potent sensitizing agent for other therapies. TNF-α is a well-known modulator of vascular integrity. By acting on the tumor endothelium, it rapidly alters cell-cell junctions and increases the permeability of the tumor blood vessels.[13] This effect serves to break down the physical and physiological barriers that often limit the effective delivery of systemic treatments into the dense, high-pressure environment of a solid tumor. This enhanced permeability facilitates greater intratumoral penetration of co-administered chemotherapeutic agents, such as doxorubicin and cisplatin, as well as the infiltration of endogenous immune effector cells, like T-lymphocytes, into the tumor mass.[1] This function explains the strong preclinical and clinical rationale for combining Tengonermin with conventional chemotherapy and forms the basis of its synergistic potential.

Second, Tengonermin possesses direct anti-vascular activity. In addition to modulating permeability, the localized high concentration of TNF-α directly induces apoptosis, or programmed cell death, in the angiogenic endothelial cells to which it is bound.[1] By destroying the tumor's blood supply from within, this action can lead to a reduction in blood flow, starvation of the tumor cells, and ultimately, control of tumor growth. The complexity of this dual mechanism—acting as both a direct anti-vascular agent and a facilitator for other therapies—may account for the variability in its clinical efficacy across different cancer types, as the relative importance of each function could differ depending on the specific tumor biology and its microenvironment.

Pharmacodynamic Effects and Biomarkers

The biological activity of Tengonermin in patients has been confirmed through pharmacodynamic assessments in clinical trials. A key method used to quantify its anti-vascular effects was Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI), a non-invasive imaging technique that measures blood flow and vessel permeability.[17] Phase I studies demonstrated that administration of Tengonermin led to statistically significant reductions in key DCE-MRI parameters, including the volume transfer coefficient (

Ktrans) and the initial area under the gadolinium concentration curve (IAUGC). These changes, observed as early as two hours after the first dose, provided direct clinical evidence that the drug was engaging its target and exerting its intended physiological effect on the tumor vasculature in humans.[17]

Another monitored pharmacodynamic marker was the shedding of soluble TNF receptors (sTNF-R1 and sTNF-R2) into the bloodstream following drug administration. This phenomenon is a known biological response to TNF-α activity. Interestingly, studies showed that while receptor shedding occurred, the magnitude of this effect reached a plateau and did not continue to increase across higher dose levels.[17] This suggests a potential saturation of the systemic response, further supporting the concept that the targeted delivery mechanism effectively localizes the primary activity of TNF-α, preventing runaway systemic effects even as the administered dose is increased.

Clinical Development Program: Efficacy and Outcomes

The clinical development of Tengonermin was extensive, spanning multiple Phase I, II, and III trials across a variety of solid tumors. The program was designed to first establish a safe and biologically active dose and then to explore the efficacy of this novel agent, both alone and in combination with standard chemotherapy regimens. The following table summarizes the key clinical trials that defined its development path.

Table 1: Summary of Key Clinical Trials for Tengonermin (NGR-hTNF)

Trial ID (NCT#)	Phase	Indication	Treatment Regimen	# of Patients	Primary Endpoint	Key Outcomes/Results
NGR002	I	Advanced Solid Tumors	NGR-hTNF monotherapy (0.2-1.6 µg/m² q3w)	16	Safety	Optimal safety profile; stable disease in 44% of patients.20
NCT00305084	Ib	Advanced Solid Tumors	NGR-hTNF (0.2-1.6 µg/m²) + Doxorubicin (60-75 mg/m²)	15	Safety	Combination was well-tolerated; DCR 73%; 0.8 µg/m² dose selected for Phase II.15
Not Specified	I	Refractory Solid Tumors	NGR-hTNF (0.2-1.6 µg/m²) + Cisplatin (80 mg/m²)	22	Safety	Favorable toxicity profile; promising activity in platinum-pretreated patients.19
Not Specified	II	Malignant Pleural Mesothelioma (MPM)	NGR-hTNF monotherapy (0.8 µg/m²)	57	Progression-Free Survival (PFS)	DCR 46%; Median OS 16.2 months in patients with DC vs 8.3 months in progressors.21
NCT03536039 (INGRID)	II	Relapsed/Refractory Primary CNS Lymphoma (PCNSL)	NGR-hTNF + R-CHOP	28	Overall Response Rate (ORR)	Exceptionally active; confirmed ORR of 75% (21/28), including 11 complete responses.13
Not Specified	II	Hepatocellular Carcinoma (HCC)	NGR-hTNF monotherapy (0.8 µg/m²)	27	Response Rate	DCR 30%; Median OS 8.9 months; one complete response in a sorafenib-refractory patient.23
NCT00484341	II	Soft Tissue Sarcoma	NGR-hTNF + Doxorubicin	N/A	N/A	Trial completed; specific results not available in source material.24
NCT00483509	II	Small Cell Lung Cancer (SCLC)	NGR-hTNF + Doxorubicin	N/A	N/A	Trial completed; specific results not available in source material.25
NCT00994097	II	Non-Small Cell Lung Cancer (NSCLC)	NGR-hTNF + Standard Chemotherapy	N/A	N/A	Trial completed; specific results not available in source material.26
NGR015	III	Malignant Pleural Mesothelioma (MPM)	NGR-hTNF (0.8 µg/m² weekly) + Best Investigator Choice vs. Placebo + Best Investigator Choice	400	Overall Survival (OS)	Trial failed to meet primary endpoint. No significant improvement in OS or PFS.27

Phase I Studies: Establishing Safety and Dose

The initial phase of clinical development focused on determining the safety, tolerability, and appropriate dosing of Tengonermin. In a dose-escalation study of NGR-hTNF as a single agent, the maximum tolerated dose (MTD) was established at 45 µg/m² administered as a one-hour infusion every three weeks (q3w).[15] The dose-limiting toxicities (DLTs) were Grade 3 acute infusion-related reactions, consistent with the biological activity of TNF-α.[17] Subsequent studies demonstrated that by extending the infusion duration to two hours and using premedication with paracetamol, the dose could be safely escalated to levels as high as 325 µg/m² without reaching an MTD, indicating a highly manageable safety profile.[17]

Crucially, Phase I trials also evaluated Tengonermin in combination with standard chemotherapeutic agents. A Phase Ib study combined escalating low doses of NGR-hTNF (from 0.2 to 1.6 µg/m²) with fixed doses of doxorubicin (60-75 mg/m²) in patients with advanced solid tumors.[14] A similar study design was used to test the combination with cisplatin (80 mg/m²).[19] Both combinations proved to be feasible and were well-tolerated, with no unexpected toxicities or evidence of adverse pharmacokinetic interactions between the drugs.[15] These studies also provided the first hints of clinical efficacy, with promising anti-tumor activity observed even in patients who were previously refractory to the chemotherapy agent when used alone.[19] Based on a favorable balance of safety and activity, the dose of

0.8 µg/m² of NGR-hTNF was consistently selected as the recommended Phase II dose (RP2D) for further investigation.[15]

Phase II Investigations: Exploring Efficacy Across Tumor Types

With a safe and biologically active dose established, the development program advanced into Phase II to assess the efficacy of Tengonermin across several cancer types, yielding a mixed but highly informative set of results.

In Malignant Pleural Mesothelioma (MPM), a Phase II trial involving 57 patients who had progressed after pemetrexed-based chemotherapy produced encouraging results. Treatment with single-agent NGR-hTNF at 0.8 µg/m² led to a disease control rate (DCR) of 46%. Importantly, there was a significant survival benefit for patients who achieved disease control, with a median overall survival (OS) of 16.2 months compared to just 8.3 months for those with early progressive disease. The study also suggested that a weekly dosing schedule was superior to an every-three-weeks schedule.[21] These positive findings were the direct impetus for launching the large-scale Phase III trial in this indication.

In stark contrast, the results in Primary CNS Lymphoma (PCNSL) were nothing short of spectacular. The Phase II INGRID trial combined NGR-hTNF with the R-CHOP chemotherapy regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) for patients with relapsed or refractory PCNSL.[13] R-CHOP is typically ineffective in PCNSL due to its inability to cross the blood-brain barrier (BBB). The trial was based on the hypothesis that NGR-hTNF could transiently increase the permeability of the BBB, allowing the potent R-CHOP regimen to access the tumor. The results strongly validated this hypothesis. The combination was found to be highly active, achieving a confirmed overall response rate (ORR) of

75% (21 out of 28 patients), which included 11 patients (39%) with a complete response.[13] This level of efficacy in a highly refractory patient population was remarkable, and the treatment was well-tolerated with no unexpected toxicities.

Investigations in other tumors showed more modest activity. In a Phase II trial for previously treated, advanced Hepatocellular Carcinoma (HCC), single-agent NGR-hTNF demonstrated a DCR of 30% and a median OS of 8.9 months. Notably, one patient who was refractory to sorafenib achieved a complete response, indicating meaningful single-agent activity in a subset of patients.[23] Additionally, Phase II trials were completed in Soft Tissue Sarcoma, Small Cell Lung Cancer, Ovarian Cancer, and Non-Small Cell Lung Cancer, typically in combination with doxorubicin or other standard chemotherapies.[24] However, detailed efficacy results from these specific studies are not available in the provided documentation.

The clinical development of Tengonermin presents a classic "tale of two tumors." The dramatic success in PCNSL and the ultimate failure in MPM underscore the highly context-dependent nature of its mechanism of action. In PCNSL, the primary therapeutic challenge is a physical one: the blood-brain barrier. Tengonermin's unique ability to increase vascular permeability provides a direct and powerful solution to this specific problem, enabling an effective chemotherapy regimen to reach its target. In MPM, the biological challenges are likely different, perhaps involving intrinsic cellular resistance to chemotherapy. In this context, merely increasing drug penetration may not be sufficient to overcome the tumor's resistance mechanisms. This dichotomy demonstrates that Tengonermin's therapeutic value is not uniform but is instead exquisitely tied to specific pathophysiological contexts where its unique mechanism can address a key rate-limiting step in treatment efficacy.

The Pivotal NGR015 Phase III Trial in Malignant Pleural Mesothelioma

Based on the promising Phase II data, Tengonermin advanced to a pivotal Phase III trial, NGR015, in MPM. This was a large, robustly designed, randomized, double-blind, placebo-controlled study that enrolled 400 patients across 12 countries. The study population consisted of patients with MPM whose disease had progressed on or after first-line pemetrexed-based chemotherapy.[27] Patients were randomized to receive either weekly intravenous NGR-hTNF at 0.8 μg/m² plus the best investigator's choice of second-line therapy, or a placebo plus the best investigator's choice. The investigator's choice, decided prior to randomization, could be single-agent chemotherapy (gemcitabine, vinorelbine, or doxorubicin) or best supportive care.[27]

The trial failed to meet its primary endpoint of improving overall survival. The median OS in the NGR-hTNF group was 8.5 months, compared to 8.0 months in the placebo group. This difference was not statistically significant, with a Hazard Ratio (HR) of 0.94 and a p-value of 0.58, indicating no survival benefit from the addition of Tengonermin.[27] Furthermore, the trial also failed to show a benefit in its key secondary endpoint, progression-free survival (PFS). The median PFS was 3.4 months in the treatment arm versus 3.0 months in the placebo arm (HR = 0.95, p = 0.65).[27]

The only glimmer of potential efficacy came from a pre-planned subgroup analysis. In the subset of patients with a shorter treatment-free interval (less than the median of 4.8 months)—a proxy for more aggressive and rapidly progressing disease—there was a signal of improved PFS. In this group, median PFS was 3.4 months with NGR-hTNF versus 1.9 months with placebo (HR = 0.67, p = 0.0065).[27] While statistically significant, this finding was hypothesis-generating and could not overcome the negative result in the overall trial population. The failure of this pivotal trial was the decisive event that led to the discontinuation of Tengonermin's development for MPM.

The negative outcome of the NGR015 trial, following positive Phase II results, serves as a cautionary tale in oncology development. It exemplifies the risk of proceeding to a large, expensive Phase III trial based on mid-stage data without a validated predictive biomarker. The "all-comers" design of the Phase III study likely enrolled a heterogeneous patient population, diluting any potential treatment effect that may have existed in a specific subset. The intriguing signal in the rapid progressor subgroup suggests that a subpopulation, perhaps with more highly angiogenic tumors, might have benefited. A development strategy that included the discovery and validation of a biomarker to prospectively identify these likely responders could have potentially led to a different outcome. The failure, therefore, is not just a reflection on the drug itself, but on the clinical development strategy employed.

Safety, Tolerability, and Pharmacokinetics

Integrated Safety Profile

Across its entire clinical development program, including Phase I, II, and III trials, Tengonermin demonstrated a remarkably consistent and manageable safety profile.[13] The successful translation of its targeted design into a favorable safety profile represents a significant achievement of its molecular engineering. The primary goal of avoiding the severe systemic toxicities of untargeted TNF-α was largely met.

The most commonly reported adverse events (AEs) related to Tengonermin were mild-to-moderate (Grade 1-2), transient, infusion-related reactions. These included chills and pyrexia (fever), which are classic symptoms associated with cytokine administration and confirm the biological activity of the TNF-α payload.[17] These events were generally short-lived, occurred primarily during or shortly after infusion, and were manageable with standard supportive care such as premedication.[17]

A key advantage of Tengonermin, particularly for its use in combination regimens, is its lack of significant overlapping toxicities with conventional cytotoxic chemotherapies. Unlike many chemotherapy agents, Tengonermin does not cause common and often dose-limiting side effects such as myelosuppression (e.g., neutropenia).[31] This favorable characteristic allows it to be combined with full doses of agents like doxorubicin and cisplatin without exacerbating their toxicity profiles. Even in the large Phase III NGR015 trial, the safety data was reassuring. While the rate of Grade ≥3 AEs was slightly higher in the Tengonermin arm (70%) compared to the placebo arm (61%), the primary driver of this difference was a higher incidence of Grade ≥3 chills (5% vs 0%). The rates of serious adverse events (26% vs 24%) and treatment-related deaths were comparable between the two groups, confirming the drug's overall good tolerability.[27]

Pharmacokinetic (PK) Profile

While a complete and detailed characterization of Tengonermin's absorption, distribution, metabolism, and excretion (ADME) is not available in the public documentation, Phase I clinical trials provided key pharmacokinetic insights. The data indicate that the drug behaves in a predictable manner in humans. Studies showed that systemic exposure to NGR-hTNF, as measured by its maximum plasma concentration (Cmax​) and the total area under the concentration-time curve (AUC), increased in a dose-proportional manner following intravenous infusion.[19]

A Phase I study of NGR-hTNF in combination with cisplatin provided specific PK parameter values at the low doses tested. The mean (±SD) values for Cmax​ and AUC were as follows [28]:

• At 0.2 µg/m²: Cmax​ of 6.0 (±2.5) pg/mL and AUC of 1,003.4 (±569.0) min*pg/mL
• At 0.4 µg/m²: Cmax​ of 13.9 (±1.8) pg/mL and AUC of 2,187.7 (±876.4) min*pg/mL
• At 0.8 µg/m²: Cmax​ of 33.5 (±43.1) pg/mL and AUC of 3,650.1 (±2,692.7) min*pg/mL
• At 1.6 µg/m²: Cmax​ of 51.1 (±19.2) pg/mL and AUC of 4,948.6 (±1,144.4) min*pg/mL

Importantly for its intended use, clinical studies that combined NGR-hTNF with either cisplatin or doxorubicin found no evidence of any significant pharmacokinetic interactions between the drugs.[15] This means that NGR-hTNF did not alter the systemic exposure of the chemotherapy agents, and vice versa, simplifying its use in combination regimens.

Known and Potential Drug Interactions

The pharmacological profile of Tengonermin is defined by its intended synergistic interaction with other anti-cancer agents. The drug was specifically designed to be combined with chemotherapeutics like doxorubicin, cisplatin, and the R-CHOP regimen, with its primary mechanism of action being the enhancement of their penetration into the tumor microenvironment.[11]

However, clinical investigation also uncovered a clinically significant negative drug interaction involving a common class of medications. A key finding from the successful Phase II trial in PCNSL was that high plasma levels of a protein called Chromogranin A (CgA) were associated with a lower remission rate.[13] Subsequent mechanistic work confirmed that CgA acts as a direct antagonist to NGR-hTNF's function by enhancing endothelial barrier integrity, thereby counteracting the drug's intended permeability-increasing effect.[33] The clinical relevance of this finding is magnified by the fact that circulating levels of CgA can be significantly increased by the use of proton pump inhibitors (PPIs), a class of drugs widely used to manage gastric acid-related conditions.[33] This establishes a clear and actionable causal pathway: the use of PPIs can lead to increased CgA levels, which in turn can inhibit the mechanism of action of NGR-hTNF and reduce its clinical efficacy. Based on this evidence, the concurrent use of PPIs during therapy with NGR-hTNF is not recommended, and this interaction represents a critical, modifiable factor that could influence patient outcomes.

Regulatory Status and Concluding Analysis

Global Regulatory Trajectory

Despite a comprehensive clinical development program that spanned more than a decade and advanced to Phase III, Tengonermin (NGR-hTNF) has not received marketing approval from any major global regulatory authority. There is no record of approval by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the Therapeutic Goods Administration (TGA) of Australia.[34] The drug remains an investigational agent.

Its regulatory journey was notable for the granting of Orphan Drug designation by both U.S. and European authorities for the treatment of malignant pleural mesothelioma.[6] This status acknowledged the high unmet medical need in this rare and aggressive cancer and provided developmental and commercial incentives. However, these incentives could not overcome the clinical trial outcome. The definitive failure of the pivotal NGR015 Phase III trial to demonstrate a survival benefit in MPM effectively halted its regulatory path for that indication. Consequently, the originator organization, AGC Biologics SpA, has listed the drug's overall development status as "Discontinued".[7]

Expert Synthesis and Future Outlook

The clinical and pharmacological story of Tengonermin is a study in contrasts. On one hand, it represents a triumph of rational drug design. The engineering of the NGR-hTNF fusion protein successfully solved the central problem of systemic TNF-α therapy, creating a well-tolerated agent with a validated, targeted mechanism of action and a favorable safety profile. On the other hand, its journey culminated in a decisive late-stage clinical failure, leading to the cessation of its development. The central paradox of Tengonermin is its production of both spectacular success in a niche indication and conclusive failure in its lead indication.

The failure of the NGR015 trial in MPM warrants a deeper analysis. While the top-line result was unequivocally negative, the reasons may be multifaceted. The choice of a second-line, "all-comers" MPM population may have been strategically flawed. This is a notoriously difficult-to-treat cancer, and the patient population is highly heterogeneous. The hypothesis-generating signal of benefit in the subgroup of rapid progressors suggests that the drug's anti-vascular and permeability-enhancing effects may be most relevant in tumors with a highly aggressive, angiogenic phenotype. The trial's failure to incorporate a predictive biomarker to select for these patients likely doomed it to a null result by diluting the treatment effect. It suggests that in the broader MPM population, simply enhancing chemotherapy access was insufficient to overcome the complex mechanisms of intrinsic tumor resistance.

In contrast, the 75% overall response rate in relapsed/refractory PCNSL remains one of the most compelling efficacy signals generated by the drug. This result is not just a statistical anomaly but a clear validation of the drug's mechanism in a specific context where it is uniquely suited to the challenge. The blood-brain barrier is a physical impediment that NGR-hTNF was shown to overcome, enabling a potent therapy to work where it otherwise could not.

In conclusion, while Tengonermin's path to becoming a broadly used anti-cancer agent has ended, its legacy is twofold. First, it provides invaluable lessons for the future development of vascular-targeting agents, chief among them the absolute necessity of biomarker-driven patient selection to navigate tumor heterogeneity. Second, it leaves behind a remarkable and tantalizing dataset in PCNSL. The unfulfilled potential in this ultra-orphan indication, where effective therapies are desperately needed, remains a compelling scientific and clinical question. Whether this specific application could be resurrected by an academic group or a specialized pharmaceutical partner is uncertain. Nonetheless, the story of Tengonermin stands as a powerful testament to both the ingenuity of molecular targeting and the formidable challenges of translating such innovations into definitive clinical benefit for patients with cancer.

Works cited

1. Tengonermin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 24, 2025, https://go.drugbank.com/drugs/DB16689
2. Tengonermin | TargetMol, accessed September 24, 2025, https://www.targetmol.com/compound/tengonermin
3. Atenolol (Tenormin): Uses & Side Effects - Cleveland Clinic, accessed September 24, 2025, https://my.clevelandclinic.org/health/drugs/18066-atenolol-tablets
4. Tenormin (atenolol): Side effects, dosage, uses, and more - Medical News Today, accessed September 24, 2025, https://www.medicalnewstoday.com/articles/tenormin
5. Atenolol: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 24, 2025, https://go.drugbank.com/drugs/DB00335
6. NGR-hTNF (antitumor recombinant protein) - Wikipedia, accessed September 24, 2025, https://en.wikipedia.org/wiki/NGR-hTNF_(antitumor_recombinant_protein)
7. Tengonermin - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 24, 2025, https://synapse.patsnap.com/drug/9ccbd3f595bf423bbb19c5a52599165d
8. tnf- ｦ-in-18 | MedChemExpress (MCE) Life Science Reagents, accessed September 24, 2025, https://www.medchemexpress.com/tnf-+%C2%A6-in-18.html
9. Ngr-htnf (Тенгонермин) Производители API | GMP, accessed September 24, 2025, https://pharmaoffer.com/ru/api-excipient-supplier/other-substances/ngr-htnf
10. Data Sheet (Cat.No.T76983) - TargetMol, accessed September 24, 2025, https://www.targetmol.com/attachment/DataSheet/64416316521447567/T76983
11. Tengonermin (ARENEGYR) | Vascular-Targeting Agent, accessed September 24, 2025, https://www.medchemexpress.com/tengonermin.html
12. Tengonermin | MedPath, accessed September 24, 2025, https://trial.medpath.com/drug/60525aa07bdd56f8/tengonermin?page=2&tab=clinical_trials
13. Improving the antitumor activity of R-CHOP with NGR-hTNF in ..., accessed September 24, 2025, https://ashpublications.org/bloodadvances/article/4/15/3648/461722/Improving-the-antitumor-activity-of-R-CHOP-with
14. Study of NGR-hTNF in Combination With Doxorubicin in Solid Tumors | ClinicalTrials.gov, accessed September 24, 2025, https://clinicaltrials.gov/study/NCT00305084
15. Phase Ib study of NGR–hTNF, a selective vascular targeting agent ..., accessed September 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2720203/
16. US20230181719A1 - Ngr conjugates and uses thereof - Google Patents, accessed September 24, 2025, https://patents.google.com/patent/US20230181719A1/en
17. Phase I and pharmacodynamic study of high-dose NGR-hTNF in patients with solid tumors., accessed September 24, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT82039
18. Phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) trial of NGR-hTNF given at high doses in patients with refractory solid tumors. - ASCO, accessed September 24, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT99572
19. Phase I Study of NGR-hTNF, a Selective Vascular Targeting Agent, in Combination with Cisplatin in Refractory Solid Tumors - AACR Journals, accessed September 24, 2025, https://aacrjournals.org/clincancerres/article/17/7/1964/12203/Phase-I-Study-of-NGR-hTNF-a-Selective-Vascular
20. Safety and anticancer activity of low dose regimen of NGRhTNF, a new vascular targeting agent, in solid advanced malignancies (NGR002 phase I trial) - ASCO Publications, accessed September 24, 2025, https://ascopubs.org/doi/10.1200/jco.2007.25.18_suppl.3540
21. NGR-hTNF as second-line treatment in malignant pleural mesothelioma (MPM). - ASCO, accessed September 24, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT95828
22. APN x TNFR - Drugs, Indications, Patents - Synapse, accessed September 24, 2025, https://synapse.patsnap.com/target/860b377e0d4d3db2af26424d4a2d26a1
23. Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma, accessed September 24, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2966632/
24. Tengonermin Completed Phase 2 Trials for Metastatic Adult Soft, accessed September 24, 2025, https://go.drugbank.com/drugs/DB16689/clinical_trials?conditions=DBCOND0037580&phase=2&purpose=treatment&status=completed
25. Lung Cancer Small Cell Lung Cancer (SCLC) Completed Phase 2 Trials for Tengonermin (DB16689) | DrugBank Online, accessed September 24, 2025, https://go.drugbank.com/indications/DBCOND0046917/clinical_trials/DB16689?phase=2&status=completed
26. Tengonermin Completed Phase 2 Trials for Non-Small Cell Lung Cancer (NSCLC) Treatment | DrugBank Online, accessed September 24, 2025, https://go.drugbank.com/drugs/DB16689/clinical_trials?conditions=DBCOND0034130&phase=2&purpose=treatment&status=completed
27. NGR-hTNF Combined With Investigator Choice of Therapy in ..., accessed September 24, 2025, https://ascopost.com/issues/august-25-2018/ngr-htnf-combined-with-investigator-choice-of-therapy-in-malignant-pleural-mesothelioma/
28. Pharmacokinetic results over the first three cycles. NGR-hTNF ..., accessed September 24, 2025, https://www.researchgate.net/figure/Pharmacokinetic-results-over-the-first-three-cycles-NGR-hTNF-concentration-time-profiles_fig1_49822902
29. Improving the antitumor activity of R-CHOP with NGR-hTNF in primary CNS lymphoma: final results of a phase 2 trial | Blood Advances, accessed September 24, 2025, https://ashpublications.org/bloodadvances/article-abstract/4/15/3648/461722
30. Doxorubicin Completed Phase 2 Trials for Ovarian Cancer Treatment | DrugBank Online, accessed September 24, 2025, https://go.drugbank.com/drugs/DB00997/clinical_trials?conditions=DBCOND0028213&phase=2&purpose=treatment&status=completed
31. NCT01358071 | Phase II Study of NGR-hTNF in Combination With Doxorubicin in Platinum-resistant Ovarian Cancer | ClinicalTrials.gov, accessed September 24, 2025, https://clinicaltrials.gov/study/NCT01358071
32. Pharmacokinetic parameters of NGR-hTNF after the first cycle by dose... - ResearchGate, accessed September 24, 2025, https://www.researchgate.net/figure/Pharmacokinetic-parameters-of-NGR-hTNF-after-the-first-cycle-by-dose-levels-upper-table_tbl1_49822902
33. Chromogranin A Restricts Drug Penetration and Limits the Ability of NGR-TNF to Enhance Chemotherapeutic Efficacy | Cancer Research - AACR Journals, accessed September 24, 2025, https://aacrjournals.org/cancerres/article/71/17/5881/568752/Chromogranin-A-Restricts-Drug-Penetration-and
34. Tengonermin | MedPath, accessed September 24, 2025, https://trial.medpath.com/drug/60525aa07bdd56f8/tengonermin
35. European Medicines Agency (EMA), accessed September 24, 2025, https://www.ema.europa.eu/en/medicines
36. Australian Register of Therapeutic Goods (ARTG), accessed September 24, 2025, https://www.tga.gov.au/products/australian-register-therapeutic-goods-artg