A new drug in development, Afinitor (everolimus, RAD001) appears to extends life without tumour growth by almost 5 months compared to 1.9 months with placebo. In addition, a quarter of the patients in the study remained progression free beyond 10 months of treatment. This is the first therapy to show significant benefit after failure with initial tyrosine kinase therapy (Sutent or Nexavar). It is currently being reviewed by the FDA for treatment of advanced kidney cancer after failure of initial therapy.
Initial therapy with kinase inhibitors has demonstrated signifcant progression free survival (PFS). Nexavar, for example, demonstrated a doubling of median PFS in patients with no prior
cytokine therapy of 25 weeks vs. 12 weeks with placebo. Sutent was compared to interferon-alpha and demonstrated a PFS of 47.3 weeks compared to 22 weeks with interferon-alpha.
What makes Afinitor different and why does it appear to work well, even in patients who have failed stand therapy? Well, the answer lies in it's mechanism of action. Both Sutent and Nexavar are multiple kinase inhibitors, principally of Vascular Endothelial Growth Factor (VEGF), that appears to be important in renal cell cancer. Solid cancers survive by extending their network of tumour vasculature, a process known as angiogenesis. Inhibiting VEGF therefore inhibits the tumours ability to grow. They also inhibit Platelet Derived Growth Factor (PDGF), which is important in cell proliferation.
Afinitor, on the other hand, inhibits the mammalian target of rapamycin (mTOR) is an intracellular protein that
acts as a central regulator of multiple signaling pathways (IGF, EGF,
PDGF, VEGF, amino acids) that mediate abnormal growth, proliferation,
and angiogenesis in cancer. mTOR is a critical component of the PI3K/AKT pathway, a key signaling pathway that is frequently dysregulated in many cancers.
Image courtesy of Novartis Oncology
By targeting a different pathway, the activity of the tumour can be further reduced, even after patients have stopped responding to their initial therapy. This is one of the new key approaches to attacking cancer – find multiple inhibitors of different critical pathways and then determine the best sequencing for the regimens, thereby improving survival.
All three drugs mentioned so far are oral therapies, which are convenient and easy for cancer patients to take each day. Another drug approved for renal cancer is Torisel (temsirolimus), a mTor inhibitor that is given by intravenous infusion over 30-60 minutes on a weekly basis. This drug significantly extended survival in renal cancer patients compared to interferon-alpha treatment (10.9 vs. 7.3 months). When standardised in weeks to enable comparison to Sutent, this means the PFS was approx. 49 weeks compared to 47 for Sutent.
It should be noted that rare bowel perforations are possible with these therapies, a class effect of inhibiting the VEGF pathway. Sutent and Nexavar have also been asssociated with raised blood pressure and hypertension, whereas Torisel may result in hyperglycemia and hyperlipemia. This may result in the need
for an increase in the dose of, or initiation of, insulin and/or oral
hypoglycemic agent therapy and/or lipid-lowering agents, respectively.
Additional new results with these agents are expected at the Annual Society of Clinical Oncology meeting in mid 2009. Afinitor is currently being evaluated by the FDA and EMEA for approval and could be available on the market by March-April 2009.