Thank you very much Dr Schilsky. Good morning everyone. First of all I would like to thank the scientific committee on behalf of all my co-authors, the scientific committee as well as the press committee, for allowing us to present the initial results of KEYNOTE-062, a randomised phase III study evaluating the effect of pembrolizumab in the first line treatment for patients with gastric or gastroesophageal junction adenocarcinoma.
Patients with gastric cancer and gastroesophageal cancer when they have advanced disease have really a very poor prognosis. The current gastric and gastroesophageal junction guidelines recommend to treat these patients with a combination of a platin and a fluoropyrimidine as the backbone chemotherapy in the first line setting. Pembrolizumab has shown anti-tumour activity and manageable safety in patients with advanced gastric and gastroesophageal junction, especially in the refractory setting, in patients with PD-L1 combined positive score more than 1.
So the KEYNOTE-062 study was an international multicentre randomised study, as mentioned, evaluating the role of pembrolizumab in the first line setting of patients with locally advanced or metastatic gastric or gastroesophageal adenocarcinoma, HER2 negative and PD-L1 CPS1 positive. Patients were stratified according to their geographical region, the extent of the disease and the chemotherapy backbone of the fluoropyrimidine that they received.
The study was aimed to include a total of 750 patients in three different arms. The first experimental arm was with pembrolizumab at the recommended doses as monotherapy. The second experimental arm was a combination of pembrolizumab at the recommended doses plus standard chemotherapy with cisplatin and a fluoropyrimidine, either 5-fluorouracil or capecitabine. Finally, the third arm, the control arm, was conventional chemotherapy plus placebo. Patients were treated until progression of the disease, unacceptable toxicity or consent withdrawal. The primary endpoints of the study were overall survival and progression free survival and secondary endpoints included overall response rate and safety.
This slide summarises the most important statistical considerations of this complex study. The hypotheses that are seen in the first row of the slide were tested first and in parallel and only the remaining hypotheses in the second row could be only tested if the first hypotheses were demonstrated to be statistically significant. The final analysis of this study was planned to be done when 415 overall survival events were observed in the pembrolizumab plus chemotherapy or the chemotherapy arms, all in patients with PD-L1 positive, CPS >1.
The study was considered to have met the primary endpoint if any of the overall survival or progression free survival hypotheses were significant. This was achieved with the first comparison, the first comparison of overall survival, non-inferiority of pembrolizumab versus chemotherapy in the CPS >1 population. Actually I will start presenting the data for the comparison of pembrolizumab versus chemotherapy.
As mentioned before, the study met the primary endpoint. The analysis of non-inferiority for overall survival of pembrolizumab versus chemotherapy was positive for pembrolizumab with an upper bound of 99.2% confidence interval for the hazard ratio of 1.18, this figure being lower than the pre-specified non-inferiority figure of 1.2. The hazard ratio was 0.91 and the median survival of the two arms were different – as you can see the median survival of pembrolizumab was 10.6 months and the median survival for chemotherapy was 11.1 months. The two year survival rate favoured also the pembrolizumab arm, being 27% in those patients receiving pembrolizumab and 19% in those patients receiving chemotherapy.
In looking at the forest plot for potential subgroups of patients that could benefit more from the treatment, there were no measured differences for the different subgroups according to the baseline characteristics and the stratification factors except for perhaps a slight increase in the benefit of pembrolizumab over chemotherapy for the Asiatic population.
If we focus now in the population of patients that had CPS >10, and this accounts for around 37% of the patients of the total population included in the study, we can see even a more profound benefit for pembrolizumab over chemotherapy with a hazard ratio of 0.69, a difference in the median survivals of 17.4 months for pembrolizumab and 10.8 months for chemotherapy and a two year survival rate of 39% for pembrolizumab and 22% for chemotherapy. However, inferential analysis for the statistical hypothesis could not be done because of the stepwise statistical model that I mentioned before.
If we look now at the comparison of pembrolizumab and chemotherapy versus chemotherapy the study did not meet the primary endpoint of superiority of pembrolizumab plus chemotherapy over chemotherapy, although there was a trend for a better benefit in those patients receiving the combination with the median of pembrolizumab plus chemotherapy being 12.5 months and the median for chemotherapy being 11.1 months. The same effect was seen in the population of patients with CPS >10, accounting again for 37% of the patients with a similar benefit in the hazard ratio or in the medians, as you can see in this slide.
In looking at the treatment related adverse events, when we compare patients that received pembrolizumab with those patients that received chemotherapy actually patients receiving pembrolizumab had less any treatment related adverse events and also less grade 3-5 events. Also, less patients led to discontinuation because of treatment related adverse events. When we did a comparison between those patients that received pembrolizumab and chemotherapy with those that received chemotherapy you can see that the treatment related adverse events were comparable at both any grade and grade 3 and 5 events. Around 22% of the patients that received pembrolizumab had any kind of immune mediated and infusion reactions, mainly grade 1 and 2, and no new safety events were seen.
To conclude, pembrolizumab was not inferior to chemotherapy for overall survival in patients with advanced gastric or gastroesophageal junction cancer with PD-L1 expression CPS1 equal or more than 1. There was a clinically meaningful improvement in overall survival for those patients that received pembrolizumab compared to those that received chemotherapy in the population of patients that was PD-L1 CPS > 10. Pembrolizumab plus chemotherapy was not superior to chemotherapy in respect to overall survival in patients with advanced gastric and gastroesophageal junction cancer in the first line setting. Finally, there was an improved safety profile with pembrolizumab over chemotherapy in this population of patients. Thank you for your attention.