IMPALA is a randomised phase III study on maintenance treatment with a new agonist of toll-like receptor 9, lefitolimod. This trial included patients that had initially responded to induction chemotherapy, mainly FOLFOX chemotherapy first line, for advanced colorectal cancer. Patients were randomised to either physician’s choice of maintenance or even non-maintenance or lefitolimod. At first progression after maintenance patients were reintroduced with the first line chemotherapy, at least they had continuous chemotherapy as maintenance. In the control group there were three different choices for the physician – continuing with the same regimen, downgrading the regimen without oxaliplatin or discontinuation. The primary objective of the trial was overall survival.
The results of this phase III randomised trial with over 1,000 patients is that it’s a negative trial, no difference in overall survival. In fact, if anything, patients that received chemotherapy maintenance had increased progression free survival. This means that lefitolimod, in spite of having all the pharmacodynamic biomarkers explored positive, it was an active immune modulator, it is an innate response modulator and it did what it had to do in terms of pharmacodynamic biomarkers with activation of monocyte and other interleukins and cytokines, this was not translated into clinical efficacy.
Colon cancer is a very highly immunosuppressed tumour. Advanced colon cancer that is not MSI does not respond to any kind of immunotherapy that has been tested so far. It is a tough tumour for single agent so we hope that having achieved all these pharmacodynamic endpoints, this will open new avenues for future combination therapies involving chemotherapy and other immune modulators.