Pharma Strategy Blog

Approaches to improve the efficacy of radiotherapy and chemotherapy in treating various cancers have begun to include the addition of radio- and chemo-sensitisers to the existing regimen. 

One such drug is motexafin gadolinium (MGd, Xcytrin®).  Motexafin is an aromatic macrocycle that has a strong affinity for electrons, i.e., it is easily reduced.  In the presence of oxygen, motexafin accepts electrons from various cellular reducing metabolites and forms superoxide and other reactive oxygen species.  The molecular target for the drug appears to be thioredoxin reductase, which when inhibited, results in cellular redox stress, cytotoxicity and an increase in tumour responsiveness to a variety of treatments. Previous research has shown that motexafin increases cytotoxicity of ionizing radiation and various chemotherapy agents and may be directly cytotoxic to tumour cells under certain conditions.

This latest phase III study was an international large randomised trial. The researchers observed increased median time to neurologic progression from 10 to 15 months with motexafin gadolinium/WBRT over WBRT alone, and a more pronounced increase in those treated promptly after diagnosis (median, 8.8 to 24.2 months).  An interesting finding was found to be crucial for interpreting multicenter studies: delays in randomization (particularly long for EU/Australian contributors) produced statistically worse results.

Overall, the trial demonstrated the benefit of motexafin gadolinium added to whole brain radiotherapy (WBRT) and now offers a treatment option for non-small cell lung cancer (NSCLC) patients who develop brain metastases. Approximately 50% of such lung cancer patients get brain mets.

Mehta, M., Shapiro, W., Phan, S., Gervais, R., Carrie, C., Chabot, P., Patchell, R., Glantz, M., Recht, L., & Langer, C. (2009). Motexafin Gadolinium Combined With Prompt Whole Brain Radiotherapy Prolongs Time to Neurologic Progression in Non–Small-Cell Lung Cancer Patients With Brain Metastases: Results of a Phase III Trial International Journal of Radiation OncologyBiologyPhysics, 73 (4), 1069-1076 DOI: 10.1016/j.ijrobp.2008.05.068