ATTRACTION-5: adjuvant nivolumab plus chemotherapy did not show relapse-free survival benefit in stage III gastric or GEJ adenocarcinoma

Evidence before this study

We searched PubMed from database inception to Aug 14, 2023, without language or study-type restrictions, using the search terms (“immunotherapy” OR “immune checkpoint inhibitor” OR “PD-1 inhibitor” OR “PD-L1 inhibitor”) AND (“gastric cancer” OR “gastro-oesophageal junction cancer”) AND (“adjuvant” OR “postoperative” OR “perioperative”). On the basis of clinical benefits seen in landmark trials, immune-checkpoint inhibitors have become standard treatment for people with advanced gastric or gastro-oesophageal junction (GEJ) cancer. Meta-analyses have subsequently substantiated the benefits of first-line immune-checkpoint inhibitors in overall survival and progression-free survival, with variable findings related to PD-L1 expression status and other characteristics. These findings have created interest in investigating the potential of adjuvant immunotherapy in combination with chemotherapy for resectable gastric or GEJ adenocarcinoma, for which standard of care of perioperative or postoperative adjuvant chemotherapy can still improve. Numerous phase 2 and 3 clinical studies of immune-checkpoint inhibitors are ongoing for resectable gastric or GEJ cancer, although standard treatment for resectable gastric or GEJ cancer differs between European, North American, and Asian countries. Fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy is the most used perioperative regimen in Europe and North America, two phase 3 studies of perioperative immune-checkpoint inhibitors in combination with chemotherapy are ongoing (KEYNOTE-585 and MATTERHORN). Results of both studies showed improvements in pathological complete response and, although the primary endpoint of event-free survival was not met in KEYNOTE-585, the results of the primary endpoint for MATTERHORN are awaited. Specific studies have also examined the effect of immune-checkpoint inhibitors in subpopulations with microsatellite instability-high or deficient mismatch repair cancers and biomarkers, especially PD-L1 combined positive score, in patient selection.

Added value of this study

To our knowledge, ATTRACTION-5 is the first phase 3 trial to compare the efficacy of adjuvant immune-checkpoint inhibitor plus chemotherapy with placebo plus chemotherapy in patients with pathological stage III gastric or GEJ adenocarcinoma undergoing gastrectomy with D2 or more extensive lymph-node dissection, which is widely used as standard of care for patients with pathological stage III gastric or GEJ cancer in Asia. Adjuvant nivolumab plus chemotherapy did not show clinical benefit in terms of the primary endpoint of relapse-free survival. Overall, the safety profiles noted in this trial were consistent with the known safety profile of nivolumab and each chemotherapy. However, adverse events leading to discontinuation and specific treatment-related adverse events with potential immunological causes (ie, endocrine-related events) occurred more frequently in the adjuvant nivolumab plus chemotherapy group than in the placebo plus chemotherapy group and with higher incidence than in previous studies of people with advanced or recurrent gastric or GEJ cancer.

Implications of all the available evidence

Nivolumab as a monotherapy or when combined with chemotherapy has shown clinical benefit for patients with advanced or recurrent gastric or GEJ cancer. Although the clinical benefit of nivolumab plus chemotherapy seen in the advanced setting has been hypothesised to lead to reduced recurrence when given as postoperative adjuvant therapy, ATTRACTION-5 did not support use of nivolumab plus chemotherapy in the adjuvant setting.

Source: The Lancet Gastroenterology & Hepatology