Perioperative immunotherapy instead of chemotherapy for patients with localised MSI/dMMR oeso-gastric adenocarcinoma

Patients with resectable microsatellite instable (MSI)/mismatch repair deficient (dMMR) oeso-gastric junction (OGJ) adenocarcinoma treated in the phase II GERCOR NEONIPIGA trial demonstrated a 59% pathologic complete response rate upon treatment with neoadjuvant nivolumab plus ipilimumab, meeting the study’s primary end point.

Perioperative chemotherapy is the standard strategy for localised gastric cancers. Nevertheless, this strategy seems to be inefficient for patients with tumours harbouring microsatellite instability (MSI) and/or mismatch repair deficiency (dMMR), a tumour phenotype predictive for the efficacy of immune checkpoint inhibitors. Therefore, the use of immune checkpoint inhibitors before and/or after radical surgery might improve outcomes for patients with gastric and oesogastric junction adenocarcinoma.

NEONIPIGA study design

NEONIPIGA is a single-arm phase II study evaluating the efficacy of neo-adjuvant nivolumab and ipilimumab followed by adjuvant nivolumab in patients with resectable MSI/dMMR, T2-T4 NxM0 gastric cancer. Treatment consisted of nivolumab 240 mg every 2 weeks (6 infusions) and ipilimumab 1 mg/kg every 6 weeks (2 infusions), followed by radical surgery 5 weeks (±1 week) after last injection of nivolumab. Patients with Becker tumour regression grade (TRG) < 3 were treated with adjuvant nivolumab 480 mg every 4 weeks (9 infusions). Once treatment is completed, patients will be followed up every 2 months for 2 years and then every 6 months until 5 years from study inclusion. The primary endpoint of the study was pathological complete response (pCR) rate.

Results

In total, 32 patients were enrolled in the study. Median age of the patients was 65 years, 16 patients had gastric cancer and 16 patients had GEJ cancer. The initial disease stage was usT3Nx for 22 patients, usT2Nx for 4 patients and not evaluable by ultrasound endoscopy for 6 patients. At data lock, all 32 patients had terminated the neo-adjuvant period and 29 patients underwent surgery. Three patients did not proceed to surgery, one because of metastatic progression after cycle 6 and two due to patient’s refusal because endoscopy demonstrated a complete response, with no tumoural cells on biopsy after cycle 6 and adjuvant treatment. Of the 29 patients who underwent surgery, 3.5% had a total oesogastrectomy, 24% had a total gastrectomy, 31% had 4/5 gastrectomy, 38% had a Lewis-Santy procedure, and 3.5% had a pancreaticoduodenectomy. All the 29 patients who underwent surgery had R0 resection: 17 patients (58.6%) had pCR (i.e., TRG 1a as per Becker grade, ypT0N0) and four (13.8%) had TRG 1b as per Becker grade (< 10% residual tumour per tumour bed). Two patients had TRG 2 (10-50% of residual tumour) and six patients had TRG 3 (˃50% of residual tumour) as per Becker grade, per local pathological assessment (central pathological review is awaited). With a median follow-up of 12 months, two patients had events. One patient died at day three post-surgery (history of severe cardio-vascular co-morbidity and sudden death) and one patient had progressive disease with metastatic disease progression after six cycles (surgery not performed). Thirty-one patients are thus still alive, of which 30 without relapse.

The rate of treatment-related adverse events (TRAEs) of grade 3-4 during the neo-adjuvant treatment phase was 25%. The most common grade 3 or 4 AEs were diarrhoea (3%), colitis/ileitis (6%), hepatitis (6%), adrenal insufficiency (3%), vomiting (3%), decreased appetite (6%), and other (6%). Per and/or post-operative complications until 90 days post operation were reported in 17 (58.5%) patients. Overall surgical morbidity was related to fistula (N= 6), pancreatitis (N= 3), ileus (N= 2), pneumonia (N= 2), atrial fibrillation (N= 2), death (N=1) or other causes (N=6).

Conclusion

The primary objective of the study was met with a pathological complete response rate of 59%. Neo-adjuvant nivolumab and ipilimumab is feasible in patients with MSI/dMMR resectable oeso-gastric adenocarcinoma. No new safety concerns were reported and surgical complications were as expected with this type of surgeries. With twelve months of follow-up, 94% of included patients were free of events. Finally, NEONIPIGA raises the question on whether surgery can be delayed or avoided for some patients with localised MSI/dMMR gastric/GEJ adenocarcinoma if immune-checkpoint inhibitors are effective.

Reference

André T, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): The GERCOR NEONIPIGA phase II study. Presented at ASCO GI 2022; Abstract 244.