ORIGINAL REPORTS: Gastrointestinal Cancer

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

  • Kawakami, Hisato MD, PhD2,,
  • Kadowaki, Shigenori MD, PhD3,
  • Makiyama, Akitaka MD, PhD5,
  • Tsuda, Masahiro MD, PhD6,
  • Hirata, Kenro MD, PhD7,
  • Sugimoto, Naotoshi MD, PhD8,
  • Machida, Nozomu MD, PhD9,
  • Hara, Hiroki MD10,
  • Hirano, Hidekazu MD, PhD11,
  • Esaki, Taito MD, PhD12,
  • Komatsu, Yoshito MD, PhD13,
  • Hironaka, Shuichi MD, PhD14,
  • Kobayashi, Yukari BS15
  • Kakimi, Kazuhiro MD, PhD15
  • Chiba, Yasutaka PhD16
  • Boku, Narikazu MD, PhD17,
  • Hyodo, Ichinosuke MD, PhD18,
  • Muro, Kei MD, PhD3,
  • 1Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Japan

  • 2

    Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan

  • 3

    Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan

  • 4

    Cancer Center, Gifu University Hospital, Gifu, Japan

  • 5

    Center for One Medicine Innovative Translational Research, Gifu University, Gifu, Japan

  • 6

    Department of Gastroenterological Oncology, Hyogo Cancer Center, Akashi, Japan

  • 7

    Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Japan

  • 8

    Department of Genetic Oncology, Osaka International Cancer Institute, Osaka, Japan

  • 9

    Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan

  • 10

    Gastroenterology, Saitama Cancer Center, Ina, Japan

  • 11

    Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo-ku, Japan

  • 12

    Department of Gastrointestinal and Medical Oncology, NHO Kyushu Cancer Center, Fukuoka, Japan

  • 13

    Department of Cancer Chemotherapy, Hokkaido University Hospital Cancer Center, Sapporo, Japan

  • 14

    Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan

  • 15

    Department of Immunology, Kindai University Faculty of Medicine, Osaka-sayama, Japan

  • 16

    Clinical Research Center, Kindai University Hospital, Osaka-sayama, Japan

  • 17

    Department of Oncology and General Medicine, Institute of Medical Science Hospital, University of Tokyo, Tokyo, Japan

  • 18

    Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan
Hisato Kawakami, MD, PhD; e-mail: [email protected].
Journal of Clinical Oncology 43(19):p 2184-2195, July 1, 2025. | DOI: 10.1200/JCO-24-02463

PURPOSE

Microsatellite instability–high (MSI-H) advanced gastric or esophagogastric junction cancer (AGC), accounting for 5%-6% of all AGC cases, has shown an enhanced responsiveness to immunotherapy. We performed a single-arm phase II study to evaluate the combination of nivolumab (NIVO) and low-dose (LD) ipilimumab (IPI) for first-line treatment of MSI-H AGC.

PATIENTS AND METHODS

Patients with MSI-H AGC received NIVO (240 mg once every 2 weeks) and IPI (1 mg/kg once every 6 weeks). The primary end point was overall response rate (ORR) assessed by blinded independent central review. Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and biomarker analysis. MSI-H status was confirmed with an MSI-IVD Kit (Falco).

RESULTS

Twenty-nine patients were enrolled. The ORR was 62.1% (95% CI, 42.3 to 79.3), with a complete response rate of 10.3%. The DCR was 79.3% (95% CI, 60.3 to 92.0). Treatment-related adverse events (TRAEs) of any grade occurred in 93.1% of patients, with those of grade ≥3 manifesting in 37.9% of patients. At the data cutoff (median follow-up of 9.0 months), treatment had been discontinued in 21 patients, with such discontinuation being due to TRAEs in 12 (41.4%) patients. However, after exclusion of one patient with progressive disease, the remaining 11 patients showed long-term antitumor efficacy after treatment discontinuation (range of response duration, 0.9+ to 15.6+ months). The median PFS was 13.8 months (95% CI, 13.7 months to not reached [NR]) and the median OS was NR (95% CI, 13.7 months to NR), with a 12-month OS rate of 79.5%.

CONCLUSION

NIVO plus LD-IPI showed robust and durable antitumor efficacy as a first-line treatment for MSI-H AGC. Although TRAEs often led to treatment discontinuation, treatment efficacy was subsequently sustained in most patients.

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