EO-3021 Generates Responses in Advanced Solid Tumors Likely to Express CLDN18.2

Kohei Shitara, MD

Treatment with the antibody-drug conjugate (ADC) EO-3021 was safe and generated responses in patients with advanced, unresectable or metastatic solid tumors likely to express Claudin 18.2 (CLDN18.2), including gastric, gastroesophageal junction (GEJ), pancreatic, and esophageal cancers, according to initial data from a phase 1 trial (NCT05980416).¹

Findings announced by Elevation Oncology showed that, at a data cutoff of June 10, 2024, 7 of the 15 efficacy-evaluable patients with gastric or GEJ cancers (47%) had tumors with CLDN18.2 expression in at least 20% of tumor cells. In these patients, the objective response rate (ORR) was 42.8%, comprising 3 confirmed partial responses. Two patients had stable disease, and the disease control rate (DCR) in this patient population was 71.4%.

Among 8 patients with a CLDN18.2 expression of less than 20%, the ORR was 0%. Four patients had stable disease, and the DCR was 50%.

Regarding safety, no grade 4 or 5 treatment-related adverse effects (AEs) occurred. The discontinuation rate due to AEs was less than 10%. Among patients evaluable for safety (n = 32), no instances of neutropenia or peripheral neuropathy/hypoesthesia were reported. The most common treatment-emergent AEs reported in at least 20% of patients included nausea (56%), decreased appetite (47%), fatigue (41%), and diarrhea (28%).

Four dose-limiting toxicities (DLTs) were reported, including grade 3 fatigue (n = 1), grade 3 encephalopathy (n = 1), worsening decreased appetite (n = 1), and grade 2 decreased appetite requiring a dose reduction at cycle 2 (n = 1). These DLTs occurred at a dose of 2.9 mg/kg; subsequently, 2.0 mg/kg and 2.5 mg/kg once every 3 weeks were selected as the doses for evaluation in the dose-expansion portion of the trial.

"Gastric and GEJ cancers are devastating diseases, which occur frequently in the United States and globally and which, despite recent advancements, still have high levels of mortality," Kohei Shitara, MD, chief of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East in Kashiwa, Japan, and principal investigator of the phase 1 trial, stated in a news release. "There is a particular need for highly selective therapies that benefit patients with CLDN18.2-expressing tumors. To that end, I am excited by the initial data with EO-3021, which suggest it could change the treatment paradigm for a significant portion of patients with gastric or GEJ cancer. I am excited to evaluate EO-3021 in the expansion portion of this phase 1 clinical trial."

EO-3021 is a differentiated, clinical-stage ADC that features an IgG1 monoclonal antibody targeting CLDN18.2 and a monomethyl auristatin E payload via a cleavable linker. The agent has a drug-to-antibody ratio of 2.

In the ongoing phase 1 trial, investigators are enrolling patients at least 18 years of age with advanced or metastatic solid tumors likely to express CLDN18.2. Patients are required to have progressed on or after standard therapy, be intolerant to standard therapy, or have no standard therapy available. Other key inclusion criteria consist of an ECOG performance status of 0 or 1; at least 1 measurable extra-cranial lesion per RECIST 1.1 criteria; adequate organ function; and a life expectancy of more than 12 weeks.2

Patients are excluded from the study if they have symptomatic or untreated brain metastases; received prior treatment with a CLDN18.2-targeted ADC or any ADC containing an auristatin payload; have grade 2 or higher peripheral neuropathy; or have a history of non-infectious pneumonitis or interstitial lung disease.

During dose escalation, 32 patients received EO-3021 at 1 of 4 dose levels ranging from 1.0 mg/kg to 2.9 mg/kg once every 3 weeks. This portion of the study included 26 patients with gastric or GEJ cancer. The median age in enrolled patients was 65 years (range, 45-83) and patients received a median of 3 prior lines of therapy (range, 1-7).¹

Enrollment in the dose-expansion portion of the study is planned, and EO-3021 will be evaluated at 2.0 mg/kg and 2.5 mg/kg once every 3 weeks.

Safety and the incidence of DLTs are the trial’s primary end points.²

References

1. Elevation Oncology announces promising initial data from phase 1 clinical trial evaluating EO-3021 in patients with advanced unresectable or metastatic solid tumors likely to express Claudin 18.2. News release. Elevation Oncology. August 6, 2024. Accessed August 6, 2024. https://www.prnewswire.com/news-releases/elevation-oncology-announces-promising-initial-data-from-phase-1-clinical-trial-evaluating-eo-3021-in-patients-with-advanced-unresectable-or-metastatic-solid-tumors-likely-to-express-claudin-18-2--302215418.html
2. Study of EO-3021 in adult patients with solid tumors likely to express CLDN18.2. ClinicalTrials.gov. Updated July 12, 2024. Accessed August 6, 2024. https://clinicaltrials.gov/study/NCT05980416