Givastomig Yields Safety, Efficacy in Gastroesophageal Carcinoma

Results from the phase 1 first-in-human clinical trial (NCT04900818) found that givastomig (TJ033721/ABL111) has a manageable safety profile and encouraging antitumor activity in patients with CLDN18.2-positive gastroesophageal carcinoma.^1,2

Givastomig monotherapy demonstrated encouraging antitumor activity in this heavily pretreated patient population. Among 73 efficacy-evaluable patients, the confirmed objective response rate (ORR) was 11% (95% CI, 4.9%–20.5%), including 8 partial responses (PRs). The disease control rate (DCR) was 37% (95% CI, 26.0%–49.1%), including 27 patients with PRs or stable disease (SD). 

In the key cohort of 43 patients with CLDN18.2-positive gastroesophageal carcinoma treated with doses from 5 to 18 mg/kg, the clinical activity was more pronounced. The confirmed ORR was 16%, including 7 PRs. The DCR was 49%, including 21 PRs and SDs. The median time to response was 1.7 months. The median duration of response was 9.4 months. 

A critical finding was that responses were observed across a broad range of CLDN18.2 tumor cell expression, from as low as 11% up to 100%. This suggests givastomig could benefit patients with lower CLDN18.2 expression levels who are not candidates for zolbetuximab (Vyloy), which is restricted to patients with high expression (>75% of tumor cells).

“Whereas clinical efficacy data in this study should be considered exploratory, several interesting observations can be made,” stated Ku G, author of the study.¹ “First, based on our preclinical data, we allowed enrollment of patients with a broad range of CLDN18.2 expression (1+ or greater in ≥1% of tumor cells). We observed response and/or SD in CLDN18.2-low expressors, with a monotherapy ORR of 16% in patients with CLDN18.2-positive [gastroesophageal carcinoma] (n = 43). Although tested in slightly different patient populations, and with all the caveats of cross-trial comparisons, the ORR in this study is numerically higher than the 9% ORR seen with single-agent zolbetuximab in previously treated [gastroesophageal carcinoma] with a substantially higher cutoff (CLDN18.2 2+/3+ intensity in ≥ 50% tumor cells) in the MONO trial [NCT01197885].”³

Safety Profile of Givastomig

Givastomig demonstrated a manageable safety profile. No dose-limiting toxicities were observed up to 15 mg/kg every 2 weeks and 18 mg/kg every 3 weeks, and the maximum tolerated dose was not reached.

The most common treatment-related adverse events (TRAEs) occurring in ≥10% of patients were generally low-grade and included nausea, anemia, fatigue, decreased white blood cell count, vomiting, and increased alanine aminotransferase.

Rates of nausea and vomiting were notably low. All-grade nausea occurred in 21% of patients, with grade 3 nausea in only 1% (n = 1). All-grade vomiting occurred in 12% of patients, with grade 3 in 1% (n = 1). These rates compare favorably to other CLDN18.2-directed therapies.

Grade ≥3 TRAEs were reported in 21% of patients. TRAEs resulting in study drug withdrawal occurred in 5% of patients.

Study Design and Patient Characteristics

The phase 1 study was designed to evaluate givastomig monotherapy in patients with advanced solid tumors. A total of 75 patients were enrolled in part 1.

Of the total patients, 38 had metastatic or advanced unresectable solid tumors and received escalating doses from 0.1 to 18 mg/kg, regardless of CLDN18.2 expression. 

Additional cohorts of patients with CLDN18.2-positive gastroesophageal carcinoma (defined as ≥1+ intensity on ≥1% of tumor cells) were enrolled at doses of 5, 8, 12, and 15 mg/kg.

The 12 mg/kg cohort was further expanded with 15 patients with CLDN18.2-positive gastroesophageal carcinoma to better characterize its activity.

The study population was heavily pretreated, with a median of 3 prior lines of therapy. Over half of the patients (53%) had received prior anti-PD-L1 therapy.

The median age of patients was 63 years (range, 27–82 years). Of the patients, 42 were male and 33 were female. Most of the patients were White (n = 43), 26 were Asian, 2 were Black, and 4 did not report. The majority of patients had an ECOG performance status of 1 (n = 52). More than half of the patients had a CLDN18.2-positive expression (n = 56). Of the total patients, 27 had liver metastases. The majority of patients had gastric tumors (n = 42), 14 had pancreatic tumors, and 7 had esophageal tumors. 

The exposure of givastomig (both C_max and area under the curve) increased with dose. At levels of 5 mg/kg and higher, exposure increased in a dose-proportional manner. The mean half-life for doses above 5 mg/kg ranged from 108 to 160 hours.

The study confirmed givastomig’s intended mechanism of action. An increase in soluble 4-1BB (s4-1BB), a marker of target engagement, was observed and correlated with both higher CLDN18.2 tumor expression and better clinical outcomes. Critically, there was no evidence of systemic immune activation, supporting the hypothesis of localized T-cell activation within the tumor microenvironment.

These favorable results provide a strong rationale for the ongoing part 2 of the study, which is evaluating givastomig in combination with standard chemotherapy (5-FU/oxaliplatin) and nivolumab (Opdivo) in patients with first-line metastatic HER2-negative gastroesophageal carcinoma.

REFERENCES

1.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): 4944–4952. Published and accessed December 1, 2025. doi: 10.1158/1078-0432.CCR-24-4280

2.Study of TJ033721 (givastomig) in subjects with advanced or metastatic solid tumors. ClinicalTrials.gov. Updated January 3, 2025. Accessed December 1, 2025. https://clinicaltrials.gov/study/NCT04900818 

3.Efficacy and safety study of multiple doses of IMAB362 in patients with advanced gastroesophageal cancer. ClinicalTrials.gov. Updated June 13, 2025. Accessed December 1, 2025. https://clinicaltrials.gov/study/NCT01197885