The Newsletter of ANZUP Cancer Trials Group Limited
SUMMER 2015
Goldilocks and immunotherapy in GU cancer HOT TOPIC
PEMBROLIZUMAB
MOR PD-L1 PRO E TRIAL S TEIN PD1 PROTEIN
Immunotherapy is transforming the treatment of cancer, with stunning results in patients with a ANDREW WEICKHARDT range of cancer. More recently there has been some very promising preliminary results using these drugs in both bladder and kidney cancers. Historically both bladder and kidney cancer have long been known to respond to immune manipulation. Bladder cancer was the first indication for which an immunotherapy was granted FDA approval when BCG vaccine injected in the wall of the bladder was shown to prevent recurrence of superficial bladder cancer. BCG vaccine leads to recruitment of immune cells and subsequent death of surrounding cancer cells. Advanced kidney cancer was commonly treated in some parts of the world with Interleukin-2 (IL-2) or Interferon-alfa over the last 20 years. While only a small proportion of patients responded to these drugs that activated the immune system, some patients experienced very long lasting control of their cancer. However IL-2 therapy was difficult to administer
OF APY S M R O F W NE HER T O N U M M I ‘JUST R IMPROVED OVERA LL SURVIVALIGHT’
because of the risk of serious side effects due to over activation of immune system and could only be used in very selective patient groups. Interferon-alfa had fewer side effects than IL-2 but it seemed much less effective. New forms of immunotherapy seem to have hit upon the Goldilocks phenomenon – just the right amount of immune activation to treat the cancer (not too cold!), but not too much to cause excessive side effects (not too hot!). These check point inhibitors such as pembrolizumab, nivolumab and atezolizumab block the ability of the cancer cell to dampen the immune response to its presence. The antibodies specifically block an interaction between the PD1 protein on the immune cells and PD-L1 protein on the cancer cell that the cancer uses to induce tolerance in the host immune system. Recent trials in kidney cancer have demonstrated improved overall survival of kidney cancer patients with nivolumab compared to everolimus. Additionally recent trials of similar PD1 inhibitors including pembrolizumab have reported encouraging responses in metastatic bladder cancer, with approximately 1 in 4 patients achieving tumour shrinkage.
More trials are planned to compare these drugs to standard of care. Encouragingly only approximately 1 in 20 patients experienced severe side effects from the drugs. While these are promising early results there are plenty of challenges ahead. How long will patients achieve sustained disease control with these well tolerated drugs? How can we identify which group of patients benefit most from the drugs? Can these drugs be given with standard chemotherapy and or radiation to further expand the group of patients that benefit? We need to be mindful that in the past it has been difficult to get the ‘porridge just right’ – that is long term control of the cancer using the immune system but free of crippling immune related toxicity. ANZUP is happy to announce an upcoming 2016 trial of the combination of pembrolizumab and chemotherapy with radiation for patients with localised bladder cancer, with aim of assessing if the combination is feasible (not too cold!) and still active (not too hot!). Hopefully the outcomes will be as Goldilocks would have it, ‘just right’. ANDREW WEICKHARDT Medical Oncologist
