The KEYNOTE-604 trial was a randomised phase III trial looking at the addition of pembrolizumab or placebo to a standard first line platinum etoposide regimen as first line therapy for extensive-stage small-cell lung cancer. KEYNOTE-604 was designed as a definitive randomised phase III trial, placebo controlled, to look at whether pembrolizumab augmented the efficacy of standard platinum etoposide for patients with newly diagnosed extensive-stage small-cell lung cancer. This involved patients with stage 4 small-cell lung cancer, no prior systemic therapy, ECOG performance status 0 or 1. Patients with brain metastases were eligible if those brain metastases were treated and the patient was neurologically stable off of steroids. The randomisation was one to one to platinum etoposide with the physician’s choice of either carboplatinum or cisplatinum. The randomisation was to pembrolizumab at 200mg every three weeks or normal saline placebo control. There were two primary endpoints for the trial – progression free survival and overall survival.
The two really definitive results: progression free survival was achieved, there was a substantial advantage in progression free survival with the addition of pembrolizumab to platinum etoposide with a hazard ratio of 0.75, 95% confidence intervals on that were from 0.61 to 0.91 and that read out with a p-value of 0.0023 with a nice separation of curves in the tail. Overall survival also appeared to favour pembrolizumab with a hazard ratio of 0.80 and 95% confidence intervals that did not cross 1.0 but because of the statistical design of the study this was actually not deemed statistically significant. The p-value was 0.0164 on overall survival but the predefined threshold for causitivity on the OS result needed to achieve a p-value of 0.0128.
So the main conclusion is that adding pembrolizumab to EP as first line therapy for extensive-stage small-cell lung cancer significantly improves progression free survival, again with a hazard ratio of 0.75 and a p-value of 0.0023. The hazard ratio for overall survival favoured pembrolizumab EP but the significance threshold was missed. That did not meet statistical significance.
Pembrolizumab EP provided some durable responses in a subset of patients and we’re very interested in trying to further define the biomarkers that might help us define that subset of patients that really derives long-term benefit from IO in small-cell lung cancer.
The safety profile was as expected and manageable. It was very similar to the toxicities that have been previously observed with pembrolizumab. Overall the data support the benefit of pembrolizumab and further reinforce the value of immunotherapy in first line therapy for small-cell lung cancer.
We’d really like to thank our patients and their families for participating in this trial; their contributions are, of course, essential and we really thank them for their participation.