The clinical trial that we’re presenting here at ASCO in Chicago is a randomised phase II study sponsored by the NCI and conducted by ECOG-ACRIN, EA6194. This is a randomised phase II study where patients are allocated to either immunotherapy with pembrolizumab as monotherapy or the combination of pembrolizumab and vidutolimod. It is a neoadjuvant clinical trial meaning treatment is started before the definitive surgical approach and then we continue as adjuvant therapy following recovery from surgery.
There have been major advances in the neoadjuvant space recently but there continues to be an important need for us to investigate new, novel combinations that may lead to enhanced efficacy while minimising systemic toxicity.
The experimental agent, vidutolimod, is a TLR9 agonist. TLR9 is an endosomal receptor that is expressed by B-cells and plasmacytoid dendritic cells. TLR9 activation leads to the stimulation of type 1 interferon and therefore leads to the induction of potent innate and adaptive anti-tumour immune responses. Recent data have demonstrated clinical activity in the PD-1 refractory setting of metastatic melanoma and this encouraged us to investigate this combination in the neoadjuvant setting as well.
The primary endpoint for the study was pathologic complete response, we also looked at major pathologic response, which is either complete response or near-complete response. We investigated other efficacy and safety endpoints, including the endpoint of event free survival which takes into account disease progression, recurrence after surgery or death from disease or treatment. The study met the primary endpoint, meaning the pathologic complete response was 71%, the major pathologic response was 79% and the one-year event free survival rate was 89%. These compared very favourably when compared to the control arm of PD-1 blockade as monotherapy as well as to historical controls. Therefore, it justifies proceeding with a definitive phase III clinical trial.
We also have ongoing biomarker and mechanistic analysis through an NCI funded mechanism and in collaboration with the CIMAC and CIDC laboratories, results of which we will update at future meetings.
What are the clinical implications of these findings?
The key questions being investigated by this study are a novel immunotherapeutic combination that may ultimately improve efficacy while minimising systemic toxicity, understanding that vidutolimod is actually given intratumourally, therefore minimising the systemic impact of type 1 interferon secretion and activation and so on. Therefore we hope that with phase III testing we would validate the results seen and hopefully will translate into improved outcomes for these patients in terms of efficacy but also in terms of tolerability and reducing the serious immune-mediated adverse events.
