Treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) in the neoadjuvant setting plus adjuvant nivolumab resulted in a high rate of pathologic complete response (pCR) in patients with resectable microsatellite instable (MSI)/mismatch repair deficient (dMMR) oeso-gastric junction (OGJ) adenocarcinoma, according to findings from the GERCOR NEONIPIGA clinical trial, which were presented by Thierry André, MD, Professor, Medical Oncology, Sorbonne Université, Hôpital Saint Antoine, Paris, France, at the 2022 ASCO Gastrointestinal Cancers Symposium.
Results showed a pCR rate of 59%, meeting the primary end point of the trial. In addition, 59% of 29 evaluable patients had tumor regression grade (TRG) 1 by Mandard classification, indicating that they experienced complete regression/fibrosis with no tumor cells.
Patients with locally advanced, MSI/dMMR gastric/OGJ adenocarcinoma tend to have a better prognosis than those who have microsatellite stable, proficient mismatch repair disease. Questionable benefit is derived by those with MSI/dMMR disease with the use of perioperative chemotherapy comprised of fluoropyrimidines and platinum salt; in fact, this approach may result in decreased disease-free survival and overall survival, Dr André explained.
Data have indicated that MSI/dMMR status may be used to predict the efficacy of immune checkpoint inhibitors. Investigators have hypothesized that the use of these agents in this population both prior to, and following, radical surgery may result in improved outcomes.
Study Details
The phase 2 GERCOR NEONIPIGA trial enrolled patients with resectable MSI/dMMR, T2-T4 NxM0 gastric/gastroesophageal tumors. Treatment consisted of nivolumab 240 mg every 2 weeks (6 infusions) plus ipilimumab 1 mg/kg every 6 weeks (2 infusions), followed by radical surgery 5 weeks after the last nivolumab infusion. Patients with Becker TRG <3 following neoadjuvant therapy were treated with adjuvant nivolumab 480 mg every 4 weeks (9 infusions). The median time between last infusion and surgery was 35 days. Follow-up was performed every 2 months for 2 years and then every 6 months until 5 years from inclusion.
Among the 32 patients enrolled in the trial, the median age was 65 years (range, 40-84 years), 72% were male, 59% had an Eastern Cooperative Oncology Group performance status of 0, 50% had gastric cancer, and 50% had gastroesophageal junction cancer. All patients had dMMR positivity per immunohistochemistry; 81.25% had loss of MLH1 and/or PMS2, and 18.75% had loss of MSH2 and/or MSH6. All patients also had MSI disease. Nineteen percent of patients had Lynch syndrome.
A total of 29 patients underwent surgery after neoadjuvant treatment whereas 3 did not have surgery; 1 because of metastatic progression and 2 refused because endoscopy showed complete response at biopsy without tumor cells.
Seventeen (59%) patients had a pCR, defined as TRG 1a as per Becker grade and ypT0N0. Four (14%) patients had TRG 1b as per Becker grade (<10% residual tumor per tumor bed), 2 had TRG 2 (10%-50% of residual tumor), and 6 had TRG 3 (>50% of residual tumor) as per Becker grade.
Twenty-five patients went on to receive adjuvant nivolumab; 10 of these patients were still receiving treatment at the time of data cutoff.
With a median follow-up of 12 months, 2 patients died or relapsed. One patient died 3 days after surgery and 1 had progressive metastatic disease after 6 cycles of neoadjuvant therapy (surgery was not performed in this patient).
“Thirty-one patients were alive, 30 without relapse,” said Dr André. “Neoadjuvant therapy with nivolumab and ipilimumab is feasible in patients with MSI/dMMR resectable oeso-gastric adenocarcinoma.”
Safety Profile
Regarding safety, 84% of patients had an any-grade treatment-related adverse event (TRAE) with neoadjuvant treatment; 25% of patients had a grade 3 or 4 TRAE. Sixteen percent of patients experienced a grade 3 or 4 TRAE that resulted in discontinuation.
The most common any-grade AEs included diarrhea (7%), colitis/ileitis (6%), fatigue (28%), pruritus (25%), pyrexia (25%), hepatitis (9%), adrenal insufficiency (3%), vomiting (6%), nausea (6%), rash (12%), hypothyroidism (6%), hyperthyroidism (22%), decreased appetite (9%), pancreatitis (3%), and other (28%).
The most common grade 3 or 4 AEs were diarrhea (3%), colitis/ileitis (6%), adrenal insufficiency (3%), vomiting (3%), decreased appetite (6%), and other (6%).
The overall surgical morbidity rate was 54% (N = 14), related to anastomotic leakage (N = 4), pancreatitis (N = 2), pneumonia (N = 2), and other (N = 6).
“NEONIPIGA raises the question whether surgery can be delayed or avoided for some patients with localized MSI/dMMR oeso-gastric adenocarcinoma if immune checkpoint inhibitors are effective,” concluded Dr André. To be able to avoid surgery would be “a dream” for patients who have no evidence of disease following neoadjuvant treatment, he said, and future studies may incorporate endoscopy and biopsy to identify patients who may safely defer surgery.
