Oesophageal cancer is a major cancer worldwide but there are few treatment options for the metastatic cases. 5FU and cisplatin is the standard of care for the disease in first line chemotherapy for oesophageal cancer. Indeed, taxane based chemotherapy is the second line standard of care. Recently immune checkpoint inhibitors, nivolumab and pembrolizumab, were approved for the second line treatment of oesophageal cancer but there is no evidence for the combination with chemotherapy with immune checkpoint inhibitors for the first line chemotherapy for oesophageal cancer.
The KEYNOTE-590 study is an international phase III study to evaluate the superiority of chemo plus pembrolizumab over the chemo plus placebo arm for the first line treatment of oesophageal cancer including GEJ adenocarcinoma.
Tell us more about the study design?
The KEYNOTE-590 study is a phase III study comparison of chemo consisting of 5FU and cisplatin repeated every three weeks plus/minus pembrolizumab. The eligibility criteria were oesophageal squamous cell carcinoma and oesophageal adenocarcinoma and oesophageal gastric junction adenocarcinoma with metastatic cases and a PS 0-1.
The patients were stratified by their and histology type and the palpable mass status. The primary endpoint of this trial is progression free survival and overall survival.
What were the results?
More than 370 patients were enrolled for each arm and the patient background was well-balanced for each arm. Half of the patients enrolled from other countries and 70% of the patients were squamous cell carcinoma. Half of the patients had a PD-L1 CPS score more than 10.
The primary endpoint of overall survival was analysed for the population with EACC and the PD-L1 CPS over 10 population and EACC population and CPS over 10 population and all patients. The whole analysis shows a significant improvement with the chemotherapy plus pembrolizumab arm with significance. The hazard ratio is 0.51-0.73 for each population. For example, for all patients the median survival time for the pembrolizumab plus chemo arm was 10.4 months and 8.8 months for the chemotherapy plus placebo arm. Also for the primary endpoint, progression free survival shows also significance. There is superiority of the chemo plus pembrolizumab arm and statistical significance was seen in the EACC cohort and the PD-L1 CPS more than 10 cohort and in all patients. The hazard ratio was also shown around 0.5-0.65. There is an obvious clinically meaningful difference was seen in all efficacy endpoints.
Indeed, the Forest plot shows the subgroup analysis and the a better tendency of the pembrolizumab plus chemo arm. The hazard ratio was the same in the adenocarcinoma subgroup and the squamous cell carcinoma subgroup. The response rate was 45.0% for the pembrolizumab chemo arm and 29.3% for the chemo plus placebo arm. The duration of response is longer in the pembrolizumab plus chemo arm.
The safety signal is similar between the two arms and there are no new signs for the immune checkpoint, immune mediated adverse events, in the pembrolizumab plus chemo arm. The larger proportion of the immune checkpoint mediated AEs was seen in the pembrolizumab arm but they were mostly grade 1/2 and only 7% of the severe immune related adverse events were seen in the pembrolizumab plus chemo arm.
What is the impact of these results?
From the read-out of KEYNOTE-590 the overall survival and the progression free survival was obviously better in the pembrolizumab plus chemotherapy arm in all populations, including squamous cell carcinoma and adenocarcinoma. So I’d like to conclude from the KEYNOTE-590 that the standard of care should be changed from the 5FU plus cisplatin to 5FU plus cisplatin plus pembrolizumab for all patients with oesophageal cancer, including oesophageal gastric adenocarcinoma.
Is there anything you would like to add?
I’d like to say more. For a long time there were not so many phase III trials conducted in the oesophageal cancer area but by the immune checkpoint inhibitors the of the 5FU cancer treatment was proceeding to the new era. Now the clinical trials to evaluate the efficacy of the immune checkpoint inhibitor for the perioperative and neoadjuvant or adjuvant use of the immune checkpoint inhibitor are ongoing and the combination trial of the immune checkpoint inhibitors plus other targeted therapy or immune combinations. So I’d like to see the results of these trials and I hope that new treatment options will be held for oesophageal cancer patients. Thank you.