FDA Grants Fast Track Status to EO-3021 for CLDN18.2-Expressing Gastric or GEJ Cancer

FDA

The FDA has granted fast track designation to EO-3021 (also known as SYSA1801) for use in patients with advanced or metastatic, claudin 18.2 (CLDN18.2)–expressing gastric or gastroesophageal junction (GEJ) cancer that has progressed on or following previous therapy.¹

The safety and activity of the differentiated antibody-drug conjugate (ADC) is under exploration in adult patients with solid tumors likely to express CLDN18.2 as part of an open-label, international, multicenter, phase 1 study (NCT05980416).² Initial data released in August 2024, which had a cutoff date of June 10, 2024, indicated that EO-3021 was generally well tolerated. No grade 4 or 5 treatment-related toxicities were observed in the safety population (n = 32), and fewer than 10% of patients discontinued the drug due to adverse effects (AEs).³

The most common treatment-emergent AEs observed in 20% or more of patients included nausea (56%), reduced appetite (47%), fatigue (41%), and diarrhea (28%). When administered at a dose of 2.9 mg/kg, four dose-limiting toxicities (DLTs) were observed: grade 3 fatigue (n = 1), grade 3 encephalopathy (n = 1), worsening decreased appetite (n = 1), and grade 2 decreased appetite that required a dose reduction at cycle 2 (n = 1). Based on this, investigators selected 2.0 mg/kg and 2.5 mg/kg every 3 weeks for further exploration in the dose-expansion portion of the research.

Initial efficacy findings revealed that in patients with gastric and GEJ cancer and claudin 18.2 expressed in 20% or more of tumor cells at immunohistochemistry (IHC) 2+/3+ (n = 7), the ADC elicited an objective response rate (ORR) of 42.8%, which included three confirmed partial responses. The disease control rate (DCR) was 71.4%. In patients with claudin 18.2 expressed in under 20% of tumor cells at IHC 2+/3+, the ORR was 0% with EO-3021 and the DCR was 50%.

“We are delighted to receive fast track designation for EO-3021, which marks an encouraging recognition of the unmet medical need in patients with Claudin 18.2­–expressing tumors, as well as the potential for EO-3021 to deliver improved therapeutic outcomes,” Joseph Ferra, president and chief executive officer of Elevation Oncology, stated in a news release.¹ “This designation is based on nonclinical and initial clinical data from our ongoing phase 1 clinical trial. As we announced in August, early results showed a confirmed overall response rate of 42.8% in a Claudin 18.2–enriched subset of gastric and GEJ cancer. In addition, we observed differentiated tolerability, with minimal MMAE-associated toxicities, including no neutropenia or peripheral neuropathy/hypoesthesia.”

EO-3021 is comprised of an immunoglobulin G1 monoclonal antibody that targets claudin 18.2 and monomethyl auristatin E payload; its cleavable linker is conjugated to glutamine 295, which translates to a drug-to-antibody ratio of 2.

The phase 1 study enrolled patients with select advanced or metastatic solid tumors determined to be likely to express CLDN18.2, like gastric or GEJ cancer, pancreatic cancer, and esophageal cancer.² Patients were required to be at least 18 years of age, have an ECOG performance of 0 or 1, have at least 1 measurable extracranial lesion by RECIST 1.1 criteria, have acceptable organ function, and have a life expectancy greater than 12 weeks. All patients must have progressed on or following standard treatment, have been intolerant to available standard therapy, or have no standard treatment available.

Patients were excluded if they had symptomatic or untreated brain metastases; previously received CLDN18.2-targeted ADCs or any ADC containing an auristatin payload; have grade 2 or higher peripheral neuropathy; a history of noninfectious pneumonitis or interstitial lung disease; a diagnosis of another malignancy or history of systemic treatment for invasive cancer within 3 years of enrollment; or active ocular surface disease at baseline.

At the data cutoff date of June 10, 2024, a total of 32 patients had received EO-3021 in the dose-escalation portion of the study at 4 dose levels that ranged from 1.0 mg/kg to 2.9 mg/kg administered every 3 weeks.³ The primary outcome measures of the study are to evaluate the incidence of DLTs during the first 21-day cycle, treatment-emergent AEs, serious AEs, clinically significant changes to vital signs, and clinically significant changes in laboratory tests.2 Investigators are also evaluating the preliminary antitumor activity of EO-3021 and the association of CLDN18.2 expression and objective response.

Of the 32 patients who received treatment, 26 had gastric or GEJ cancer. The median patient age was 65 years (range, 45-83). The median number of prior lines of treatment received was 3, with a range of 1 to 7 prior lines.

Data from the dose-escalation portion of the study “suggest that a biomarker patient selection strategy will be an important component of future clinical development,” according to a news release issued in August 2024 by Elevation Oncology, Inc., the drug developer. The company had stated that they were working on identifying the appropriate biomarker threshold, to introduce a biomarker cutoff as part of the dose-expansion portion of the study. In the dose-expansion portion, EO-3021 will be examined at 2.0 mg/kg and 2.5 mg/kg every 3 weeks, to select an optimized dose for further clinical development.

The company also shared plans to expand the study to explore EO-3021 in combination with ramucirumab (Cyramza) in the second-line treatment of patients with metastatic gastric or GEJ cancer and with dostarlimab-gxly (Jemperli) in the first-line setting.

“We are grateful for the opportunity to potentially expedite the delivery of EO-3021 and look forward to advancing through monotherapy dose expansion and reporting additional data from our ongoing trial in the first half of 2025, and to initiating the combination portion of our study later this year,” Ferra stated in the most recent news release.¹

References

1. Elevation Oncology receives fast track designation from the FDA for EO-3021 for the treatment of adult patients with advanced or metastatic gastric or gastroesophageal junction cancer expressing claudin 18.2. News release. Elevation Oncology, Inc. September 23, 2024. Accessed September 24, 2024. https://investors.elevationoncology.com/2024-09-23-Elevation-Oncology-Receives-Fast-Track-Designation-from-the-FDA-for-EO-3021-for-the-Treatment-of-Adult-Patients-with-Advanced-or-Metastatic-Gastric-or-Gastroesophageal-Junction-Cancer-Expressing-Claudin-18-2
2. Study of EO-3021 in adult patients with solid tumors likely to express CLDN18.2. ClinicalTrials.gov. Updated July 12, 2024. Accessed September 24, 2024. https://clinicaltrials.gov/study/NCT05980416
3. 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, Inc. August 6, 2024. Accessed September 24, 2024. https://investors.elevationoncology.com/2024-08-06-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