Two phase 1 clinical trials will evaluate EO-3021 (also known as SYSA1801), a differentiated, clinical-stage antibody-drug conjugate (ADC) targeting Claudin 18.2 (a specific isoform of Claudin 18 that is normally expressed in gastric epithelial cells)*, in combination with ramucirumab (Cyramza®;Eli Lilly and Company/ImClone Systems) , a VEGFR2 inhibitor, in second-line patients and in combination with dostarlimab (Jemperli®; GSK), a PD-1 inhibitor, in the front-line setting. Initiate dosing in the combination portion of the Phase 1 trial is expected by year-end 2024. [1]

EO-3021 is being developed by Elevation Oncology for the treatment of advanced gastric or gastroesophageal junction cancer. The clinical trials are scheduled following recently signed clinical supply agreements with Eli Lilly and Company and GSK.

“EO-3021 has the potential to change the treatment paradigm for tumors that express Claudin 18.2, including a majority of gastric and gastroesophageal junction adenocarcinomas,” explained Valerie Malyvanh Jansen, M.D., Ph.D., Chief Medical Officer of Elevation Oncology.

“Based on safety data from preclinical and clinical trials, we believe EO-3021 benefits from a differentiated safety profile and will be readily combinable. We also know that combination-based regimens are a mainstay of cancer care, and that the combination of two therapies with distinct mechanisms of action often enables patients to achieve deeper, more durable responses,” Jansen added.

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“As such, we are excited to begin evaluating EO-3021 together with ramucirumab, a VEGFR2 inhibitor, and with dostarlimab, a PD-1 inhibitor, in the second- and first-line settings, respectively. In parallel, we continue to advance our Phase 1 trial of EO-3021 monotherapy toward initial safety and efficacy data by mid-third quarter,” she concluded.

Clinical Development Plans
EO-3021 is a differentiated, potential best-in-class antibody-drug conjugate (ADC) targeting Claudin 18.2. The investigational agent was designed with site-specific conjugation at glutamine (Q295), with the goal of increasing the stability of the linker-payload and minimizing the potential for free monomethyl auristatin E(MMAE) compared to traditional cysteine-based conjugation. In preclinical studies and the Phase 1 clinical trial conducted by Elevation Oncology’s partner, data showed a favorable tolerability profile, with limited MMAE-related toxicities.

Initial results with EO-3021 presented during the 2023 annual meeting of the American Association for Cancer Research (AACR), demonstrated profound in vivo antitumor activity and outperformed SOC in gastric, pancreatic, and lung cancer models. Results from in vitro and in vivo studies highlight the promising therapeutic potential of EO-3021 for patients with CLDN18.2-expressing cancers.[1]

The initial development of EO-3021 in combination with ramucirumab and dostarlimab explore two regimens for the treatment of gastric or gastroesophageal junction cancer:

  • EO-3021 in combination with ramucirumab in second-line patients: Ramucirumab is a monoclonal antibody that targets VEGFR2 and is approved for use in combination with paclitaxel for the treatment of second-line gastric or gastroesophageal junction cancer with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. With EO-3021, Elevation Oncology aims to introduce a combination agent that, when paired with ramucirumab, can potentially deliver improved safety and efficacy as compared to the approved combination of ramucirumab and paclitaxel.
  • EO-3021 in combination with dostarlimab in front-line patients: Dostarlimab is approved alone and in combination with chemotherapy for certain types of dMMR and MSI-H endometrial cancer in the US; it also has an accelerated approval in certain dMMR solid tumors. By combining EO-3021 and an immune checkpoint inhibitor, Elevation Oncology aims to deliver synergistic benefit, potentially offering patients improved outcomes beyond those seen with existing immunotherapy regimens for gastric or gastroesophageal junction cancer in the front-line setting.

Each combination cohort will include a dose escalation and expansion portion, evaluating the combination of EO-3021 and ramucirumab or EO-3021 and dostarlimab. The primary endpoints will include safety and anti-tumor activity. Elevation Oncology plans to initiate dosing in the combination portion of the Phase 1 trial by year-end 2024.

In June 2024, Elevation Oncology entered into clinical supply agreements with Lilly and GSK to supply their respective compounds for these combination cohorts. Elevation Oncology will sponsor and conduct all clinical development of both combinations and will assume all costs associated with the study. All companies will retain commercial rights to their respective compounds.

Elevation Oncology continues to enroll patients in the monotherapy cohort of its ongoing Phase 1 clinical trial (NCT05980416) and remains on track to share initial safety and efficacy data by mid-third quarter 2024, with additional data in the first half of 2025.

Elevation Oncology has the exclusive rights to develop and commercialize EO-3021 in all global territories outside Greater China.

Note: * Claudin18.2 (CLDN18.2), a tight junction protein normally expressed only on gastric mucosa, is overexpressed in gastric, pancreatic, esophageal, ovarian, lung and other solid tumors. Unlike in normal tissue, CLDN18.2 is exposed on epithelial surfaces in malignancy. There are no approved targeted therapies for CLDN18.2-expressing cancers. [1]

Clinical trials
Study of EO-3021 in Adult Patients With Solid Tumors Likely to Express CLDN18.2 –
ClinicalTrials.gov ID NCT05980416

Highlights of Prescribing information
Ramucirumab (Cyramza®; Eli Lilly and Company/ImClone Systems) [Prescribing information]
Dostarlimab (Jemperli®; GSK) [Prescribing Information]

References
[1] Mo Dan, Xiwu Hui, Yancui Wang, Can Yuan, Thomas O’Hare, Valerie Malyvanh Jansen, Shawn M. Leland, Yang Zhang, David Dornan, Xiaoyan Wang. Therapeutic potential of EO-3021/SYSA1801, a Claudin18.2 antibody-drug conjugate, for the treatment of CLDN18.2-expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6300.

Featured Image: Life scientists researching in laboratory. Courtesy: © 2010 – 2024 Fotolia/Adobe. Used with Permission. Used with permission.

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