CMG901 Demonstrates Encouraging Efficacy in Gastric/GEJ Cancer

Rui-hua Xu, MD, PhD

Treatment with CMG901, an anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate, showed promising clinical efficacy in CLDN18.2-positive patients with gastric/gastroesophageal junction (GEJ) cancer in a phase 1 trial (NCT04805307), according to findings presented by Rui-hua Xu, MD, PhD from Sun Yat-sen University Cancer Center in Guangzhou, China, during the ASCO Plenary Series: November 2023 Session.¹

As of July 24, 2023, 113 patients with gastric/GEJ cancer were enrolled and treated with CMG901 at doses of 2.2 mg/kg (n = 31), 2.6 mg/kg (n = 42), and 3.0 mg/kg (n = 16). Six patients from part A and 107 pts from part B were included. Among those enrolled, the median prior lines of systemic therapy were 2 (range 1-6).

A total of 89 patients who were CLDN18.2-positive were evaluable, and their confirmed overall response rate (ORR) was 32.6%. After a median follow-up of 5.98 months, the median progression-free survival (PFS) was 4.76 months (95% CI, 3.35-6.14) among all 93 patients who were CLDN18.2-positive. Further, the median overall survival (OS) was not reached, and the OS rate at 9 months was 56.4%.

“Of 89 patients with CLDN18.2-positive tumors that were response evaluable, most had tumor shrinkage with a confirmed ORR of 30% observed across 3 dose cohorts, and there was a 42% ORR in 2.2 mg/kg cohort,” explained Xu in the presentation. “The progression-free survival and overall survival rates were encouraging in this heavily pretreated population. The median PFS in the overall population was 4.76 months, and the median overall survival was not reached.”

The median age among all of the patients enrolled was 56 years (range, 44-64). Most patients (52%) were male, had an ECOG performance status of 1 (84%), and all were Asian. Gastric was the primary site of disease for 90% of patients, 89% of patients had low or no HER2 expression, and the median lines of prior therapy was 2 (range, 1-6). Additionally, 74% had prior anti-PD-1/PD-L1 therapy, 64% had prior taxane therapy, and 4% had prior anti-CLDN18.2 therapy.

Complete responses were seen in 2 patients in the 3.0 mg/kg cohort, and partial responses and stable disease were observed in 19 and 3 patients in the 2.2 mg/kg cohort, 12 and 16 patients in the 2.6 mg/kg cohort, and 6 and 5 patients in the 3.0 mg/kg cohort. The overall disease control rate was 70.8%.

CMG901 also demonstrated a manageable safety profile. All patients enrolled had a treatment-emergent adverse event (TEAEs; 100%). The most common TEAEs included anemia (62.8%), vomiting (57.5%), and hypoalbuminemia (57.5%). The most frequent grade ≥3 TEAEs were neutrophil count decreased (18.6%) and anemia (13.3%). Treatment discontinuation due to TEAEs occurred in 8% of patients and all were drug-related.

These results support further evaluation of CMG901 in patients with CLDN18.2-positive gastric/GEJ cancer.

“CMG901 demonstrated positive clinical efficacy in patients with CLDN18.2-positive gastric/GEJ cancer. Clinical activity was observed across all of the subgroups,” added Xu.

CMG901 is an Claudin 18.2-targeted agent which binds to Claudin 18.2-positive cells. The agent then goes into the lysosome by tumor cells and releases the cytotoxic payload. The process halts the cell cycles as well as the apoptosis of the tumor cells. Cellular and soluble immune effectors have previously been stimulated with CMG901 to limit activation of antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, killing Claudin 18.2-positive cells.

In April 2022, the FDA granted fast track designation to single-agent CMG901 for the treatment of patients with unresectable or metastatic gastric and gastroesophageal junction cancer who have relapsed and/or are refractory to approved therapies.,

This phase 1a trial is the first to assess the efficacy and safety of CMG901 for the treatment of patients with advanced gastric or GEJ cancer. The study took place in China and included a dose-escalation phase (part A) which evaluated CMG901 at doses ranging from 0.3-3.4 mg/kg, and a dose-expansion phase (part B) with doses of 2.2, 2.6, and 3.0 mg/kg. Treatment with CMG901 was given to patients via intravenous infusion every 3 weeks until disease progression or unacceptable toxicity.

Though CLDN18.2 expression was not required for entry in part A of the study, patients with gastric/GEJ cancer required CLDN18.2 expression of ≥2+ membrane staining intensity in ≥5% tumor cells to be enrolled in part B.

Primary end points included safety, tolerability, and maximum tolerated dose for part A, and in part B, these end points were objective response rate, a reduction in tumor size, and investigators aimed to determine the recommended phase 2 dose.

REFERENCES
1. Xu RH. A phase 1 trial of claudin 18.2-specific antibody-drug conjugate CMG901 in patients with advanced gastric/gastroesophageal junction cancer. Presented at: 2023 November ASCO Plenary Series. Abstract 434420:

2. Safety, tolerability, pharmacokinetics, and preliminary efficacy, phase 1 study of CMG901. ClinicalTrials.gov. Updated December 28, 2022. Accessed November 7, 2023. https://tinyurl.com/5883mz6d