Neoadjuvant nivolumab plus ipilimumab followed by adjuvant nivolumab was associated with sustained long-term survival in patients with localized mismatch repair–deficient/microsatellite instability–high (dMMR/MSI-H) gastric or gastroesophageal junction (GEJ) adenocarcinoma, based on updated findings from the French, multicenter, nonrandomized phase II NEONIPIGA trial published in JAMA Oncology. However, according to Samaille et al, there was no clear evidence of improved survival compared with outcomes reported in other studies of surgery alone in this patient population.
“The high [pathologic complete response] and sustained outcomes raise the question of whether chemotherapy-free, immune checkpoint inhibitor–based approaches could be considered in this setting,” the investigators wrote.
Study Details
The investigators focused on patients with histologically proven cT2–T4NXM0 dMMR/MSI-H gastric or gastroesophageal junction adenocarcinoma who were eligible for surgery; of the 32 patients (median age = 65 years; 72% male; 50% each with gastric or gastroesophageal junction adenocarcinoma), 1 had metastatic disease and was inadvertently included.
In this single-arm trial, patients were assigned to receive six cycles of neoadjuvant nivolumab plus two cycles of ipilimumab, followed by surgery and nine cycles of adjuvant nivolumab. A total of 84% completed neoadjuvant therapy, and 44% completed all planned treatment. Three patients did not undergo surgery, including the one with metastatic disease and two who declined surgery.
The primary endpoint was pathologic complete response, which was previously reported. The current analysis focused on long-term and secondary outcomes, including event-free and overall survival, after a median follow-up of 48.3 months.
Key Findings
In the intention-to-treat population (n = 32), the 4-year overall survival rate was 84.1%. The 4-year event-free survival rate was 83.5% among the 31 patients eligible for surgery. One patient experienced a relapse with cerebral metastases. Overall, six deaths were reported, including two related to gastric cancer or its treatment (one due to postoperative complications and one associated with cerebral metastases) and four from unrelated causes.
All patients who did not undergo surgery achieved a clinical complete response following immune checkpoint inhibitor therapy. One of these patients was among the four who died from causes unrelated to cancer.
Pathologic complete response was achieved in 59% of patients who underwent surgery.
Neoadjuvant and adjuvant therapy–related grade 3 or 4 adverse events occurred in 19% and 17% of patients, respectively, and were previously reported. No further late toxic effects were observed.
“Neoadjuvant nivolumab and ipilimumab followed by adjuvant nivolumab was associated with sustained long-term survival, supporting its use in patients with localized dMMR/MSI-H gastric or gastroesophageal junction adenocarcinoma,” the investigators concluded. “The high [pathologic complete response] rates and durable responses observed may provide useful information for designing future clinical studies….”
Looking ahead, they wrote, “Further studies, including randomized trials, are warranted to refine patient selection, optimize response assessment, and evaluate organ-preserving strategies, including nonoperative management.”
Thierry André, MD, of Hôpital Saint-Antoine, Assistance Publique–Hôpitaux de Paris, is the corresponding author of the article in JAMA Oncology.
Disclosure: The study was supported by BMS, GERCOR, and the ARCAD (Aide et Recherche en Cancérologie Digestive) Foundation. For full disclosures of the study authors, visit jamanetwork.com.
