NGR-hTNF Treatment for Malignant Pleural Mesothelioma

by | Jan 1, 2016 | 2010, Cancer, Pleural Mesothelioma

Written by Joyce Smith, BS. NGR-hTNF has low toxicity and potential as a treatment for malignant pleural mesothelioma when used in combination with chemotherapeutic agents.

Tumor necrosis factor (TNFα) is one of multiple proteins capable of inducing necrosis (death) of tumor cells. It is a multifunctional proinflammatory cytokine with a broad spectrum of biological activities that include cell proliferation, differentiation, and apoptosis (programmed cell death). When combined with chemotherapy TNF has had a high success rate in the treatment of melanomas and sarcomas as well as liver cancers that have not yet metastasized (1, 2-5).

Malignant pleural mesothelioma (MPM) is a very aggressive and devastating cancer to treat. A recent randomized trial demonstrated an increased survival time of 3 months using a combination of pemetrexal and cisplatin rather than cisplatin alone (6). In addition, studies have shown that MPM has one of the highest vascular endothelial growth factor levels among solid tumors (7). This increased vascularity encourages proliferation and metastasis of MPM cells and is also an independent poor prognostic factor (8).

Given the natural rapid progression of MPM in which most patients die within on year, researchers felt the need for new treatments was of upmost importance. With this objective in mind they chose to investigate an anti-vascular treatment approach.

Researchers fused TNFα with a peptide ligand called asparagine-glycine- arginine (NGR). NGR binds to an aminopeptidase that is overexpressed in solid tumors (9-12). The resulting NGR-TNF, in preclinical trials, was 10 times more active than TNFα alone and showed significant anti tumor activity in a dose dependent manner (9-12).

Researchers designed a multicenter nonrandomized single-agent phase 2 trial to evaluate the efficacy of low-dose NGR-hTNF with respect to progression free survival (PFS), toxicity and disease control rate (DCR). NGR-hTNF was given at a dose of 0.8 ug/m2 every third week in 43 patients with advanced MPM who had been previously treated with pemetrexel (triweekly cohort). Because of the low toxicity demonstrated in the triweekly cohort, researchers added a subsequent cohort of 14 patients who were also given 0.8 ug/m2 but on a weekly basis to maintain a more constant antivascular effect.

Results:

For the whole study population (n=57)

  • Overall study results included a 1-year survival rate of 51% after a median follow-up time of 17.9 months.
  • Disease control rate (DCR) was 46%, which was maintained for a median progression-free time of 4.7 months, a median progression free survival (PFS) of 2.8 months, and a median overall survival (OS) of 12.1 months.
  • NGR-hTNF was well tolerated in pemetrexel-pretreated patients.
  • The weekly cohort showed no higher toxicity. Also median PFS in patients with disease control was 9.1 months compared to 4.4 months in the triweekly cohort.

Univariate Cox analyses:

  • Progression free survival (PFS) was significantly related to sex (P=0.002)
  • Overall survival (OS) was correlated to patients survival PS (P=0.001)

Multivariate Cox Analyses:

  • Male sex remains associated with longer survival (P=0.022)

In conclusion, disease control was achieved in about half of patients and maintained for a median time of more than 4 months in the triweekly cohort and more than 9 months in the weekly cohort. Toxicity of NGR-hTNF was easily managed. Furthermore, because of its low toxic profile, NGR-hTNF is a good candidate for use in combination with chemotherapeutic agents. Lastly, the potential clinical benefit of NGR-hTNF (0.8 ug/m2 weekly) given either alone or in combination needs to be evaluated in a randomized setting for patients with advanced MPM.

Source: Gregorc, Vanesa, et al. “Phase II study of asparagine-glycine-arginine–human tumor necrosis factor α, a selective vascular targeting agent, in previously treated patients with malignant pleural mesothelioma.” Journal of Clinical Oncology 28.15 (2010): 2604-2611.

© 2017 American Society of Clinical Oncology. All rights reserved.

Posted September 15, 2015. 

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