With the increasing understanding of the biology of the disease and the development of targeted therapy, there has been a paradigm shift in the treatment of clear cell metastatic renal cell carcinoma ...(mRCC). Traditionally patients with metastatic RCC have been treated with immunotherapy which has limited efficacy. The multikinase inhibitors sunitinib, sorafenib and pazopanib, the VEGF antibody bevacizumab in combination with interferon and the mTOR inhibitor temsirolimus have all been shown to prolong progression-free survival in phase III studies. Here we review another mTOR inhibitor, everolimus (Afinitor(®); Novartis, USA) which was approved in March 2009 by the US FDA for treatment of targeted-therapy refractory metastatic renal cell cancer. The phase III study of everolimus (the RECORD study) was terminated early after a significant difference in efficacy was noted in the treatment arm with everolimus (progression-free survival of 4.0 months in patients on the treatment arm vs 1.9 months in the placebo arm). The most common adverse events were stomatitis, pneumonitis, fatigue and infections. We review Phase I-III data with a particular emphasis on safety data and patient focused outcomes.
G Anandappa, AE Hollingdale, TG EisenDepartment of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKAbstract: With the increasing understanding of the biology of the ...disease and the development of targeted therapy, there has been a paradigm shift in the treatment of clear cell metastatic renal cell carcinoma (mRCC). Traditionally patients with metastatic RCC have been treated with immunotherapy which has limited efficacy. The multikinase inhibitors sunitinib, sorafenib and pazopanib, the VEGF antibody bevacizumab in combination with interferon and the mTOR inhibitor temsirolimus have all been shown to prolong progression-free survival in phase III studies. Here we review another mTOR inhibitor, everolimus (Afinitor®; Novartis, USA) which was approved in March 2009 by the US FDA for treatment of targeted-therapy refractory metastatic renal cell cancer. The phase III study of everolimus (the RECORD study) was terminated early after a significant difference in efficacy was noted in the treatment arm with everolimus (progression-free survival of 4.0 months in patients on the treatment arm vs 1.9 months in the placebo arm). The most common adverse events were stomatitis, pneumonitis, fatigue and infections. We review Phase I–III data with a particular emphasis on safety data and patient focused outcomes.Keywords: metastatic renal cell carcinoma, targeted therapy, mTOR, everolimus
Thai soldiers were vaccinated with a recombinant protein derived from the central repeat region of the circumsporozoite (CS) protein of Plasmodium falciparum conjugated to Toxin A (detoxified) of ...Pseudomonas aeruginosa (R32Tox-A) to evaluate its safety, immunogenicity and efficacy. In a randomized, double-blind manner, 199 volunteers received either R32Tox-A or a control vaccine at 0, 8 and 16 weeks. Immunization was performed in a malaria non-transmission area, after completion of which volunteers were deployed to an endemic border area and monitored closely to allow early detection and treatment of infection. The vaccine was found to be safe and to elicit antibody responses in all vaccinees. Peak CS antibody (IgG) concentrations in malaria-experienced vaccinees exceeded those in malaria-naive vaccinees (mean 40.6 versus 16.1 micrograms ml-1; p = 0.005) as well as those induced by previous CS protein-derived vaccines and observed in association with natural infections. A log-rank comparison of time to falciparum malaria revealed no differences between vaccinated and non-vaccinated subjects. Secondary analyses revealed that CS antibody levels were lower in vaccinee malaria cases than in non-cases, 3 and 5 months after the third dose of vaccine (p = 0.06 and p = 0.014, respectively). Because antibody levels had fallen substantially before peak malaria transmission occurred, the question of whether high levels of CS antibody are protective remains to be resolved.
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