Neoadjuvant Checkpoint Inhibitor Doublet Yields Complete Responses in Gastroesophageal Cancers

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In patients with resectable microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) gastric and gastroesophageal junction adenocarcinoma, dual checkpoint inhibition with ipilimumab and nivolumab given as neoadjuvant therapy led to a pathologic complete response rate of 58.6%, meeting the primary endpoint of the phase II NEONIPIGA trial.1

“The primary objective was met, and neoadjuvant nivolumab plus ipilimumab was found to be feasible in patients with MSI-H/dMMR, resectable gastric or gastroesophageal junction adenocarcinoma,” said Thierry André, MD, of Sorbonne University and Saint-Antoine Hospital, Paris, at the 2022 ASCO Gastrointestinal Cancers Symposium. The findings of NEONIPIGA raise the question of whether surgery can be delayed or avoided for such patients, given the magnitude of efficacy of immune checkpoint inhibitors demonstrated in the trial, he said.

The primary objective was met, and neoadjuvant nivolumab and ipilimumab was found to be feasible in patients with MSI-H/dMMR, resectable gastric or gastroesophageal junction adenocarcinoma.
— Thierry André, MD

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As Dr. André pointed out, patients with locally advanced MSI-H/dMMR gastric or gastroesophageal junction cancer tend to have a better prognosis than patients with microsatellite-stable/mismatch repair–proficient disease. For the former group, the benefit derived from perioperative chemotherapy comprising fluoropyrimidines and platinum is questionable; in fact, a conventional chemotherapy strategy may result in decreased disease-free and overall survival in this subset. Since MSI-H/dMMR status predicts the efficacy of checkpoint inhibitors, the study’s investigators hypothesized that immunotherapy given before and following surgery could improve outcomes.


The phase II NEONIPIGA trial enrolled 32 previously untreated patients with T2 to T4 Nx M0 gastric adenocarcinoma (50%) or tumors of the gastroesophageal junction (50%) with MSI-H and dMMR status. Among these patients, 81.3% had loss of MLH1 and/or PMS2 expression, and 18.8% had loss of MSH2 and/or MSH6 expression.

Study participants received neoadjuvant nivolumab at 240 mg every 2 weeks in combination with ipilimumab at 1 mg/kg every 6 weeks for a total of six cycles, totaling 12 weeks of neoadjuvant treatment. Approximately 5 weeks later, they underwent surgery, followed by adjuvant treatment with single-agent nivolumab at 480 mg every 4 weeks for nine cycles, totaling 9 months of adjuvant therapy.

All 32 patients received neoadjuvant treatment, and 29 patients completed surgery. A total of 25 patients received adjuvant nivolumab, with 10 still on treatment at the time of data cutoff. Among 15 patients no longer on nivolumab, 9 received the full nine cycles, 2 withdrew due to a serious adverse event, and 2 discontinued therapy per investigator decision.

A total of 94% of patients are free of events with 12 months of follow-up.
— Thierry André, MD

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Key Findings

Pathologic complete response equated to tumor regression grade (TRG) 1 by the Mandard classification, indicating complete regression or fibrosis of tumor with no residual tumor cells, was achieved by 17 of 29 patients (58.6%) who completed surgery after neoadjuvant nivolumab plus ipilimumab. In addition, 13.8% had TRG 2 (fibrosis with scattered tumor cells), 6.9% had TRG 3 (fibrosis and tumor cells with a dominance of fibrosis), 13.8% had TRG 4 (fibrosis and tumor cells with a dominance of tumor cells), and 6.9% had TRG 5 (no evidence of tumor regression).

Per the Becker grading system, 58.6% of patients had TRG 1a following treatment, indicating complete tumor regression without residual tumor. Additionally, 13.8% of patients had TRG 1b (< 10% of residual tumor per tumor bed), 6.9% had TRG 2 (10%–50% of residual tumor following treatment), and 21.7% had TRG 3 (> 50% of residual tumor cells), he reported.

With a median follow-up of 12 months, one patient died after surgery and one (who did not undergo surgery) died of metastatic disease progression after five cycles of neoadjuvant therapy. At data cutoff, a total of 30 patients were still alive and had not yet relapsed, Dr. André said.

Safety Profile

Grade 3 or 4 treatment-related adverse events related to neoadjuvant therapy occurred in 25% of patients; for 16%, these events led to treatment discontinuation. The most common grade 3 or 4 adverse events were diarrhea (3%), colitis/ileitis (6%), adrenal insufficiency (3%), vomiting (3%), decreased appetite (6%), and “other” (6%).

Of the 29 patients who underwent surgery, 22 had a postoperative general complication. Complications included fistula (n = 6), pancreatitis (n = 3), ileus (n = 2), pneumonia (n = 2), atrial fibrillation (n = 2), death (n = 1), and one undefined (n = 6). “No new safety concerns were observed, and surgical complications were as expected with these types of surgeries,” Dr. André concluded. “A total of 94% of patients are free of events with 12 months of ­follow-up.” 

DISCLOSURE: Dr. André disclosed financial relationships with AstraZeneca, ­Astellas, Bristol Myers Squibb, Gritstone Oncology, GlaxoSmithKline, HalioDx, Merck & Co, Pierre Fabre, Seagen, Servier, Transgene, AstraZeneca, Roche/Ventana, Sanofi, Clovis, and Kaleido Biosciences. 


1. André T, Tougeron D, Piessen G, et al: Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma: The GERCOR NEONIPIGA phase II study. 2022 ASCO Gastrointestinal Cancers Symposium. Abstract 244. Presented January 20, 2022. 


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