This study assessed the potential benefit of combining neoadjuvant and adjuvant chemotherapy with immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma. Despite observing an improvement in pathological complete response with the addition of pembrolizumab, this did not translate into a significant improvement in event-free survival for these patients.
Gastric cancer is one of the leading causes of cancer-related deaths worldwide. For locally advanced disease, adjuvant or neoadjuvant therapy is usually implemented in combination with surgery. However, the potential benefit of combining neoadjuvant and adjuvant chemotherapy with immune checkpoint inhibition has not been explored in patients with locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma. To address this gap, this study assessed the antitumour activity of neoadjuvant and adjuvant pembrolizumab plus chemotherapy in these patients.
The phase III KEYNOTE-585 study was conducted across 143 medical centres in 24 countries. Eligible patients were aged 18 years or older with untreated, locally advanced, resectable gastric or gastro-oesophageal adenocarcinoma, and an Eastern Cooperative Oncology Group performance status 0-1. Patients were randomly assigned (1:1) to receive neoadjuvant pembrolizumab 200 mg intravenously or placebo (saline) plus cisplatin-based doublet chemotherapy (main cohort) every 3 weeks for 3 cycles, followed by surgery, adjuvant pembrolizumab or placebo plus chemotherapy for 3 cycles, then adjuvant pembrolizumab or placebo for 11 cycles. A small cohort was also randomly assigned (1:1) to pembrolizumab or placebo plus fluorouracil, docetaxel, and oxaliplatin (FLOT)-based chemotherapy (FLOT cohort) every 2 weeks for four cycles, followed by surgery, adjuvant pembrolizumab, or placebo plus FLOT for four cycles, then adjuvant pembrolizumab or placebo for 11 cycles. Primary endpoints were pathological complete response (pCR), event-free survival (EFS), and overall survival (OS).
The results of the main cohort are reported in this article.
In total, 804 patients were randomly assigned to the main cohort and received pembrolizumab plus chemotherapy (n=402) or placebo plus chemotherapy (n=402). After a median follow-up of 47.7 months, pembrolizumab significantly improved the pCR rate compared to placebo (12.9% vs. 2%; difference 10.9% (92%CI: 7.5%-14.8%; p<0.00001). While the median EFS was longer with pembrolizumab than with placebo (44.4 months vs. 25.3%, respectively; HR[95%CI]: 0.81[0.67-0.99]; p=0.0198), it did not meet the threshold for statistical significance (p=0.0178). Median OS was reported at 60.7 vs. 58.0 months in the pembrolizumab and placebo groups, respectively.
Grade 3 or worse adverse events (AEs) of any cause occurred in 78% vs. 74% of patients in the pembrolizumab group and placebo groups, respectively. The most common were nausea (60% vs. 62%), anaemia (42% vs. 40%), and decreased appetite (41% vs. 43%). Treatment-related serious AEs were reported in 26% vs. 24% of patients. Treatment-related AEs that led to death occurred in four (1%) patients in the pembrolizumab group (interstitial ischaemia, pneumonia, decreased appetite, and acute kidney injury [n=1 each]) and two (<1%) patients in the placebo group (neutropenic sepsis and neutropenic colitis [n=1 each]).
In this study, neoadjuvant and adjuvant pembrolizumab plus chemotherapy improved pCR in patients with untreated, locally advanced resectable gastric or gastro-oesophageal cancer. However, this pCR benefit did not translate into a significant improvement in EFS.
Reference
Top
