Zolbetuximab Plus mFOLFOX6 Improves Survival in Claudin 18.2+ Gastric or GEJ Cancers

The addition of zolbetuximab (IMAB362) to oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) significantly improved progression-free survival (PFS) vs mFOLFOX6 alone in patients with Claudin 18.2 (CLDN18.2)–positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, meeting the primary end point of the phase 3 SPOTLIGHT trial (NCT03504397).¹

The zolbetuximab combination also significantly improved overall survival (OS) vs mFOLFOX6 alone in this population, meeting the secondary end point of the trial.

Moreover, the most common treatment-emergent toxicities observed with the investigative regimen were nausea, vomiting, and decreased appetite.

Additional data from the trial will be submitted for publication and shared at a future medical meeting.

“I am excited by the potential for a new treatment option to help patients with advanced-stage gastric cancer or GEJ cancer,” Kohei Shitara, MD, primary investigator of the SPOTLIGHT trial and chief of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, stated in a press release. “Gastric and GEJ cancers still have very limited treatment options available for patients with advanced diagnosis.”

A chimeric IgG1 monoclonal antibody, zolbetuximab, binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.² Preclinical data with the agent in combination with chemotherapy induced improved antitumor activity over chemotherapy alone in xenografted mice.

Frontline zolbetuximab plus epirubicin, oxaliplatin, and capecitabine (EOX) demonstrated a statistically significant improved survival benefit over EOX alone in this patient population. Moreover, zolbetuximab monotherapy resulted in a clinical benefit rate of 23% in those with recurrent or refractory locally advanced or metastatic CLDN18.2-positive gastric/GEJ cancer who had previously received at least 1 line of chemotherapy.

The SPOTLIGHT trial enrolled adult patients with a histologically and radiologically confirmed diagnosis of locally advanced unresectable or metastatic gastric or GEJ cancer with measurable disease by RECIST v1.1 criteria with CLDN18.2 positivity, HER2 negativity, and who did not receive prior treatment with chemotherapy for metastatic disease.

Exclusion criteria included having received systemic immunosuppressive therapy or other investigational agents or devices within 28 days before the first dose of study treatment.

Study participants (n = 566) were randomly assigned 1:1 to receive mFOLFOX6 plus placebo (n = 275) or intravenous zolbetuximab at a loading dose of 800 mg/m2 on day 1 of cycle 1 followed by 600 mg/m2 on day 22 of cycle 1, and 600 mg/m2 on days 1 and 22 of each 42-day cycle thereafter (n = 275).

Stratification factors included region (Asia vs non-Asia), number of organs with metastatic sites (0 to 2 vs 3 or more), and previous gastrectomy (yes vs no).

Treatment was administered until disease progression per independent review committee confirmation, toxicity requiring study treatment cessation, the initiation of another anticancer treatment, or until other discontinuation criteria were met.

PFS served as the primary end point of the research and OS served as a key secondary end point. Other secondary objectives included objective response rate, duration of response, and safety. Investigators also evaluated pharmacokinetics and immunogenicity of zolbetuximab; they will also examine quality of life.

“We’re delighted and excited about the positive topline results from the SPOTLIGHT trial of zolbetuximab in combination with mFOLFOX6, and we have increased confidence in advancing development of zolbetuximab for the first-line treatment of patients with locally advanced or metastatic gastric cancer,” Ahsan Arozullah, MD, MPH, senior vice president and head of Development Therapeutic Areas at Astellas Pharma Inc, stated in a press release. “These topline results further support the role of CLDN18.2 as an emerging biomarker in gastric and GEJ cancer. We look forward to presenting the full results at a scientific congress in the near future.”

References

1. Astellas announces zolbetuximab meets primary endpoint in phase 3 SPOTLIGHT trial as first-line treatment in Claudin 18.2 positive, HER2-nergative locally advanced or metastatic gastric and gastroesophageal junction (GEJ) cancers. News release. Astellas Pharma Inc. November 16, 2022. Accessed November 16, 2022. http://bit.ly/3EDdEnb
2. Shitara K, Al-Batran E-R, Bang Y-J, et al. 198TiP SPOTLIGHT: phase III study of zolbetuximab + mFOLFOX6 versus placebo + mFOLFOX6 in first-line Claudin18.2+/HER2- advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ). Ann Oncol. 2020;31(suppl 6):S1317. doi:10.1016/j.annonc.2020.10.462