FDA Grants Fast Track Designation to Givastomig for Frontline HER2-Negative Metastatic Gastric Cancer

The FDA has granted fast track designation to givastomig in combination with nivolumab (Opdivo) and chemotherapy for patients with previously untreated HER2-negative advanced or metastatic gastroesophageal adenocarcinomas whose tumors are both claudin 18.2 (CLDN18.2)- and PD-L1–positive.¹

Givastomig is a first-in-class, Fc-silenced CLDN18.2 × 4-1BB bispecific antibody that conditionally activates T cells in the tumor microenvironment (TME) only upon binding CLDN18.2-expressing tumor cells, a mechanism designed to avoid the systemic hepatotoxicity that has limited conventional 4-1BB agonists. Phase 1 monotherapy results supporting the designation were published in Clinical Cancer Research,² and a registrational phase 3 trial is expected to begin as early as the fourth quarter of 2026.¹

In the first-in-human phase 1 study (NCT04900818), givastomig demonstrated an objective response rate (ORR) of 16% among 43 efficacy-evaluable patients with CLDN18.2-positive gastric or gastroesophageal carcinoma (GEC) who received doses of 5 to 18 mg/kg. Seven partial responses (PRs) were observed across a broad range of tumor CLDN18.2 expression (11% to 100% of tumor cells).

Across all 73 efficacy-evaluable patients in the broader FIH population, the confirmed ORR was 11% (8 PRs; 95% CI, 4.9-20.5), and the disease control rate (DCR) was 37% (19 stable disease events; 95% CI, 26.0-49.1). In the CLDN18.2-positive GEC subgroup, the DCR reached 49% (95% CI, 33.3-64.5). Among the seven GEC responders, the median time to response was 1.7 months (95% CI, 0.9-1.84), median duration of response was 9.4 months (95% CI, 3.2-not available), and median progression-free survival was 1.7 months (95% CI, 1.71-2.83). Locally determined PD-L1 combined positive score data were available for five of the seven GEC responders; two had a combined positive score of 5 or higher, and three had a score below 5, including one patient with a score of 0. One additional PR was observed in a patient with head and neck squamous cell carcinoma of unknown CLDN18.2 status.

Higher CLDN18.2 expression correlated with greater response depth. Among patients across all doses and tumor types, ORR was 14% in those with CLDN18.2 expression of 50% or higher versus 4% in those with expression below 50%. The DCR was 48% in the CLDN18.2-high group versus 23% in the CLDN18.2-low group.

"Fast Track Designation is a valuable step forward for givastomig and for patients with first-line HER2-negative metastatic gastric cancer," Phillip Dennis, MD, PhD, chief medical officer of NovaBridge, stated in a news release.¹ "Phase 1b results demonstrate robust efficacy and favorable overall tolerability in combination with immunochemotherapy. Responses were deep and durable across a broad patient population, with marked improvement relative to historical benchmarks for the standard of care."

Safety of Givastomig

No dose-limiting toxicities were observed at any dose level up to 18 mg/kg, and a maximum tolerated dose was not reached. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 21% of patients; those reported in at least two patients were anemia (5%), lymphocyte count decrease (5%), white blood cell count decrease (4%), aspartate aminotransferase increase (3%), neutropenia (3%), and upper GI hemorrhage (3%).

The most common all-grade TRAEs occurring in 10% or more of patients were nausea (21%), anemia (15%), fatigue (13%), white blood cell count decrease (13%), vomiting (12%), and alanine aminotransferase increase (11%). Grade 3 nausea or vomiting was observed in 1% of patients, with no grade 4 events reported for either; neither toxicity was associated with dose interruptions or treatment withdrawal.

Treatment-related serious adverse events were reported in 17% of patients, and TRAEs leading to study drug withdrawal occurred in 5%. Twenty patients (27%) experienced treatment-emergent adverse events resulting in death; 18 (90%) were attributable to disease progression, and 2 were fatal sepsis events not considered related to the study drug. Nine patients required dose interruptions due to givastomig-related events, and the protocol did not permit dose reductions.

Study Design and Patient Characteristics

The phase 1 FIH study enrolled 75 patients at sites in the United States and China across 9 sequential dose levels ranging from 0.1 to 18 mg/kg administered intravenously. During dose escalation, 38 patients with metastatic or locally advanced unresectable solid tumors regardless of CLDN18.2 expression were treated using a Bayesian optimal interval design. Dose levels of 5, 8, 12, and 15 mg/kg were expanded to include additional patients with CLDN18.2-positive advanced or metastatic gastric, gastroesophageal junction, or gastroesophageal adenocarcinoma, with a subsequent expansion cohort of 15 patients treated at 12 mg/kg.

The median patient age was 63 years (range, 27-82), and most patients were White (57%), male (56%), and had an ECOG performance status of 1 (69%). The population was heavily pretreated, with a median of 3 prior lines of therapy (range, 1-9); 53% had received prior PD-(L)1 therapy. The most common tumor types were gastric or gastroesophageal junction cancer (56%), pancreatic cancer (19%), and esophageal cancer (9%), with smaller representation from colorectal cancer (5%), non-small cell lung cancer (3%), ovarian cancer (3%), and rare histologies including cholangiocarcinoma, head and neck squamous cell carcinoma, synovial sarcoma, and uterine carcinosarcoma.

At baseline, 36% of patients had liver metastases and 25% had peritoneal metastases; 75% of all enrolled patients were CLDN18.2-positive per the trial definition. Based on pharmacokinetic and pharmacodynamic data, 12 mg/kg every 2 weeks was selected as the recommended phase 2 monotherapy dose, and a dose range of 5 to 12 mg/kg was chosen for the ongoing combination portion of the trial.

REFERENCES

1. NovaBridge Biosciences receives FDA fast track designation for givastomig in first-line HER2-negative metastatic gastric cancer. News release. NovaBridge Biosciences. June 16, 2026. Accessed June 17, 2026. https://tinyurl.com/y88jwspp

2. Ku G, Shen L, Dayyani F, et al. A first-in-human study of givastomig, a CLDN18.2 and 4-1BB bispecific antibody, as monotherapy in patients with CLDN18.2-positive advanced or metastatic solid tumors. Clin Cancer Res. 2025;31(23):4855-4866. doi:10.1158/1078-0432.CCR-24-4280