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Neoadjuvant nivolumab plus ipilimumab followed by adjuvant nivolumab elicited positive pathologic complete response rates in patients with locally advanced resectable mismatch repair–deficient and/or microsatellite instability–high gastric or gastroesophageal junction adenocarcinoma.
Neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) followed by adjuvant nivolumab elicited positive pathologic complete response (pCR) rates in patients with locally advanced resectable mismatch repair–deficient (dMMR) and/or microsatellite instability–high (MSI-H) gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to data from the phase 2 NEONIPIGA study (NCT04006262).1
In this trial, 58.6% (n = 17; 95% CI, 41.8%-74.1%) of patients who received surgery in addition to perioperative immunotherapy achieved a pCR in the primary tumor and lymph nodes.
“Perioperative nivolumab and low-dose ipilimumab immunotherapy is feasible and associated with a high rate of pCR in dMMR/MSI-H gastric/GEJ adenocarcinoma,” lead study author, Thierry André, MD, a professor of medical oncology at Sorbonne University and a senior physician and the head of the Medical Oncology department at the Saint Antoine Hospital in Paris, France, and colleagues, wrote.
The standard of care for resectable gastric adenocarcinoma is perioperative chemotherapy and surgery. However, dMMR/MSI-H status was shown to be a negative predictor of chemotherapy efficacy in terms of disease-free survival in findings from recently published meta-analyses.
The single-arm, multicenter NEONIPIGA trial investigated the efficacy of neoadjuvant nivolumab and ipilimumab followed by surgery and adjuvant nivolumab in patients with locally advanced resectable dMMR/MSI-H gastric or GEJ adenocarcinoma.
Eligible patients included those aged 18 to 75 years with histologically confirmed locally advanced gastric or GEJ adenocarcinoma. Patients needed to have nonmetastatic tumors at clinical stages T2 to T4, dMMR and/or MSI-H status, an ECOG performance status of 0 or 1, adequate organ function, and surgical eligibility.
Patients were excluded if they had received previous therapy for gastric/GEJ adenocarcinoma, if they required corticosteroids or other immunosuppressive medications within 2 weeks prior to treatment, or if they had a history of malignancy within the past 5 years, excluding cured localized cancers.
Thirty-two patients enrolled to the study and received the multimodality treatment schedule from October 23, 2019, to June 4, 2021. Half of patients had gastric tumors and 50% had GEJ adenocarcinoma. Additionally, 1 patient with metastatic disease was wrongly included.
Patients received intravenous (IV) neoadjuvant nivolumab at 240 mg over 30 minutes once every 2 weeks for 6 doses and IV ipilimumab at 1 mg/kg over 30 minutes once every 6 weeks for 2 doses in cycles 1 and 4. Patients then received surgery 4 to 6 weeks after their last treatment cycle. Four to 8 weeks following surgery, patients received adjuvant IV nivolumab at 480 mg over 30 minutes once every 4 weeks 4 to 8 weeks following surgery, for a total of 9 cycles. Adjuvant treatment was administered by investigator decision, depending on efficacy, treatment tolerance, and the patient’s postoperative condition.
The primary end point of this trial was pCR rate, defined as complete disappearance of tumor cells at pathological examination in the primary tumor surgical specimen and in the lymph nodes.
Secondary end points included event-free survival, defined as the time from the first treatment dose to progression or death from any cause, and overall survival, defined as the time from the first treatment dose to death from any cause.
At a data cutoff of February 28, 2022, and at a median follow-up of 14.9 months (range, 3.4-25.8; 95% CI, 10.6-17.6), 32 patients had received neoadjuvant immunotherapy. Twenty-seven (84%) patients completed all cycles, 3% (n = 1) completed 5 cycles, 6% (n = 2) completed 3 cycles, and 6% (n = 2) completed 2 cycles.
Twenty-nine (91%) patients received surgery in the form of an R0 resection and 23 (79%) received adjuvant nivolumab. Of those 23 patients, 5 patients discontinued treatment because of treatment-related adverse effects (TRAEs), and 3 discontinued based on investigator decision. Nine patients received all 9 cycles of adjuvant nivolumab, and 6 were still receiving treatment at the data cutoff.
Additionally, 3 patients did not receive surgery and instead had complete endoscopic response with tumor-free biopsies and a normal computed tomography (CT) scan. Of those, 2 refused surgery and 1 had metastatic disease at enrollment. The 2 who refused surgery received adjuvant nivolumab as per the study protocol; the patient with metastatic disease did not. All 3 showed CR on a CT scan and complete endoscopic response after 6 cycles of neoadjuvant treatment and had tumor-free biopsies; esophagogastric endoscopic ultrasounds were performed in 2 of those patients and were normal in both. These findings indicate the feasibility of a watch-and-wait approach that may be explored as an alternative to surgery in patients with dMMR/MSI-H gastric/GEJ adenocarcinoma.
According to a RECIST v1.1 evaluation conducted prior to surgery and after neoadjuvant treatment, 5 patients achieved a CR, 12 achieved a partial response, 11 had stable disease, and 4 were not evaluable. Additionally, 2 patients had T0 disease, but with some tumoral cells in 1 node, and were not considered to have a pCR.
Moreover, 31 patients were included in a per-protocol survival analysis (excluding the wrongly-included patient with metastatic disease), which showed that at the data cutoff date, 97% (n = 30) were alive and free of recurrence or progression; 1 patient died 3 days after surgery. The patient who had metastatic disease at inclusion was event-free at the data cutoff after a 9.4-month follow-up.
Six (19%) patients experienced grade 3 or 4 TRAEs, defined as adverse effects with potential immunologic etiology. The most common neoadjuvant grade 3/4 TRAEs were colitis/ileitis (n = 2) and hepatitis (n = 2). Of the patients who experienced TRAEs, 5 discontinued treatment before surgery because of colitis/ileitis (n = 2), hepatitis (n = 1), gastritis (n = 1), and stenosis of the pylorus related to a pseudoprogression with pCR at biopsy during endoscopy with vomiting (n = 1).
A total of 16 patients experienced at least 1 surgical complication within 90 days post-surgery. The role of the immunotherapy combination in these complications is undetermined. The rate of surgical morbidity was 55%, and 1 postoperative death occurred from a cardiovascular comorbidity not related to the neoadjuvant treatment.
“Although not practice changing at the present time, these findings pave the way for other studies to change the standard of care in this group of patients. Translational studies to identify and validate biomarkers predictive of response to immunotherapy and the development of tools with the ability to diagnose pCR without the surgical specimen of the primary tumor should be a priority,” the study authors concluded.
Thierry A, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability–high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase II study. J Clin Oncol. Published online August 15, 2022. doi:10.1200/JCO.22.00686