New Paper Alert: NO LIMIT Trial. First-Line Nivolumab Plus Low-Dose Ipilimumab in MSI-High Advanced Gastric and GEJ Cancer

The NO LIMIT (WJOG13320G) Phase II trial investigates a novel, chemotherapy-free first-line approach using nivolumab plus low-dose ipilimumab in patients with microsatellite instability–high (MSI-H) advanced gastric or gastroesophageal junction (GEJ) cancer. Given the poor prognosis associated with advanced HER2-negative gastric cancer and the immunogenic nature of MSI-H tumors, this study addresses a critical gap in prospective data for this biomarker-defined population. With standard therapy evolving to include immune checkpoint inhibitors, the NO LIMIT trial provides important insights into whether dual checkpoint blockade can deliver durable responses without the added toxicity of cytotoxic chemotherapy.

Title: Phase II Study (NO LIMIT, WJOG13320G) of First-Line Nivolumab Plus Low-Dose Ipilimumab for Microsatellite Instability–High Advanced Gastric or Esophagogastric Junction Cancer

Authors: Hisato Kawakami, MD, PhD, Shigenori Kadowaki, MD, PhD Akitaka Makiyama, MD, PhD, Masahiro Tsuda, MD, PhD, Kenro Hirata, MD, PhD, Naotoshi Sugimoto, MD, PhD, Nozomu Machida, MD, PhD, Hiroki Hara, MD, Hidekazu Hirano, MD, PhD, Taito Esaki, MD, PhD ,Yoshito Komatsu, MD, PhD Shuichi Hironaka, MD, PhD, Yukari Kobayashi, BS, Kazuhiro Kakimi, MD, PhD, Yasutaka Chiba, PhD, Narikazu Boku, MD, PhD, Ichinosuke Hyodo, MD, PhD and Kei Muro, MD, PhD

Published in JCO , May 2025 

Background

Despite the introduction of immune checkpoint inhibitors (ICIs) in gastrointestinal oncology, the prognosis for patients with advanced gastric or gastroesophageal junction cancer (AGC) remains limited, especially in the microsatellite instability–high (MSI-H) subset, which accounts for 5–6% of AGC cases. MSI-H status is a known predictor of favorable response to ICIs, but prospective data for MSI-H AGC are lacking. The NO LIMIT (WJOG13320G) Phase II trial aimed to evaluate a chemotherapy-free first-line regimen using nivolumab (anti–PD-1) combined with low-dose ipilimumab (anti–CTLA-4) in patients with MSI-H AGC.

Methods

The study enrolled patients with histologically confirmed MSI-H AGC or GEJ cancer who were treatment-naïve in the advanced setting. MSI-H status was confirmed centrally using the MSI-IVD Kit. Patients received:

• Nivolumab 240 mg IV every 2 weeks
• Ipilimumab 1 mg/kg IV every 6 weeks

Treatment continued for up to 24 months or until disease progression or unacceptable toxicity. Tumor response was assessed via RECIST 1.1 by blinded independent central review (BICR), and adverse events were monitored per CTCAE v5.0.

Study Design of No Limit Trial

This was a single-arm, multicenter phase II trial conducted in Japan. The primary endpoint was objective response rate (ORR) by BICR, with key secondary endpoints including disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and treatment-related adverse events (TRAEs). A sample size of 28 patients was planned, targeting an ORR of 65% based on prior colorectal cancer trials.

Results of No Limit trial

A total of 29 patients were enrolled between November 2020 and August 2022. The median age was 75 years (range, 54–84), and 55% were female. All tumors were HER2-negative or non-evaluable.

• Confirmed ORR (BICR): 62.1% (95% CI, 42.3–79.3)
• Complete responses: 10.3%
• Partial responses: 51.7%
• Disease Control Rate: 79.3%
• Median Progression-Free Survival (PFS): 13.8 months (95% CI, 13.7–NR)
• 12-month PFS and OS rates: 73.3% and 79.5%, respectively
• Median OS: Not reached at median follow-up of 9.0 months

Treatment responses were often durable, with tumor shrinkage seen in 24 of 27 evaluable patients. Notably, 11 of 12 patients who discontinued therapy due to TRAEs maintained disease control after discontinuation.

Key Findings

The NO LIMIT study is the first prospective trial to assess nivolumab plus low-dose ipilimumab in MSI-H AGC, and the results are highly encouraging. With an ORR of 62.1% and median PFS of 13.8 months, this combination offers a compelling chemotherapy-free option in this biomarker-defined subgroup. Immune-related toxicities are not negligible but appear manageable and do not preclude long-lasting responses. These findings support further development of dual ICI regimens as first-line therapy in MSI-H gastrointestinal malignancies.

• The ORR of 62.1% surpassed the pre-specified threshold (35%), confirming robust efficacy of nivolumab plus low-dose ipilimumab in MSI-H AGC.
• Median PFS of nearly 14 months compares favorably to historical data for chemotherapy and prior immunotherapy combinations.
• TRAEs occurred in 93.1% of patients, with grade ≥3 events in 37.9%. The most frequent TRAEs included pruritus, pneumonitis, and endocrine toxicities.
• Treatment discontinuation due to TRAEs occurred in 41.4% of patients, but efficacy was generally sustained in these cases.
• Genomic analyses showed that B2M mutations were associated with improved response (ORR: 100% vs 52.6%; P = .026).
• High baseline serum albumin (≥2.3 g/dL) predicted better outcomes, with significant differences in both OS and PFS.

Key Takeaway Messages

• Nivolumab plus low-dose ipilimumab shows strong and durable first-line activity in MSI-H advanced gastric and GEJ cancers.
• The regimen avoids cytotoxic chemotherapy, offering a meaningful therapeutic alternative with immune-based durability.
• Though toxicities were frequent and led to treatment discontinuation in some patients, responses were often maintained.
• Biomarkers such as albumin levels and B2M mutations may help identify patients most likely to benefit.

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