Today I had the opportunity to present the updated clinical and translational results of the NEOSTAR study which evaluated neoadjuvant nivolumab or nivolumab plus ipilimumab for resectable non-small cell lung cancer patients in the neoadjuvant setting. The rationale for this phase II multi-arm study stems from the evidence that, unfortunately, more than 50% of patients with stage 1-3 resectable non-small cell lung cancer will relapse if treated with surgery alone. And perioperative chemotherapy as a means to prevent tumour recurrence in this population of patients only provides a 5% improvement in five year overall survival as compared to surgery alone.
Immunotherapy is being tested in the neoadjuvant setting with the goal to induce an anti-tumour immune response and eradicate micrometastatic disease, so to prevent this tumour recurrence and potentially improve outcomes in these patients. For this trial the primary endpoint was the major pathological response defined as less than or equal to 10% viable tumour cells in resected specimens following neoadjuvant nivolumab or nivolumab plus ipilimumab. The NEOSTAR was a multi-arm phase II study in which eligible patients with resectable stage 1-3A N2 single stage non-small cell lung cancer were randomised in a one to one ratio to a nivolumab monotherapy arm or a nivolumab plus ipilimumab arm. After 3-6 weeks after the last dose of immunotherapy patients underwent surgery, we assessed radiographic responses with CT scans and PET CT scans and we collected for biomarker analysis baseline tumour specimens, blood samples throughout and post-immunotherapy surgical specimens as well as stool samples.
As part of the statistical design if six or more mPRs were observed after each of the treatment arms then the specific therapy would be considered promising for further evaluation. In the intention to treat population the major pathologic response was 17% in the nivolumab arm and 33% in the nivolumab plus ipilimumab combination and seven patients in the nivolumab plus ipilimumab group achieved mPR and therefore this regimen met the pre-specified efficacy endpoint for being considered promising for further evaluation. We also observed six complete pathologic responses after the combination adjuvant nivolumab plus ipilimumab as compared to only two complete pathologic responses with nivolumab monotherapy. We saw that tumours treated with the combination therapy had less viable tumour cells as compared to nivolumab treated tumours.
We also noticed that there was a positive correlation between overall radiographic responses and overall pathologic responses. The toxicity profile was overall acceptable, however, we are still learning with this trial and with other trials testing immunotherapy in the neoadjuvant setting how to administer these agents to a population of patients with resectable disease. We are learning about the surgical outcomes with these therapies.
Preliminary results of biomarker analysis show positive correlation between elevated baseline levels of PD-L1 and radiographic responses, major pathologic responses and greater tumour pathologic regression. We also saw from evaluation of surgical samples that nivolumab plus ipilimumab was associated with increased T-cell infiltration with a particular subset of T-cells that might be potentially reacting to the tumour and be responsible for an anti-tumour immune response.
How do you think these results will change or influence clinical practice?
This is a very important question. The fact that the combination therapy met the pre-specified trial endpoint to be considered promising tells us that maybe this combination deserves further evaluation, most likely in association with other therapies, chemotherapy or other immune checkpoint inhibitors. This can potentially affect in how many patients with resectable non-small cell lung cancer we can limit tumour recurrence.