Zolbetuximab Regimen Prolongs Survival in CLDN18.2+, HER2- Locally Advanced Unresectable, Metastatic Gastric/GEJ Cancers

Initial results from the phase 3 spotlight study show that the study met its primary and key secondary end point of progression-free and overall survival.

Treatment with zolbetuximab plus chemotherapy led to statistically significant progression-free survival (PFS) improvement in patients with 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 study (NCT03504397).1

Results announced in a press release by Astellas Pharma Inc, showed that compared with placebo and modified oxaliplatin, fluorouracil, and folinic acid (leucovorin; mFOLFOX6), zolbetuximab plus mFOLFOX6 also achieved the study’s key secondary end point of overall survival (OS) improvement.

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

Spotlight is a global, multicenter, double-blind, randomized study that is investigating the efficacy and safety of zolbetuximab to provide supportive data for regulatory submissions in the United States, and other countries. Approximately 566 patients have been enrolled in the study. In arm A, patients received zolbetuximab on cycle 1, day 1 at a loading dose followed by a lower dose in subsequent cycles, every 3 weeks. In combination with zolbetuximab, patients receive up to 12 treatments of mFOLFOX6 over at least 4 cycles. After mFOLFOX6 is complete, patients are permitted to receive fluorouracil (5-FU) and folinic acid until the subject meets the study treatment discontinuation criteria. Patients in arm Bare administered matching placebo and mFOLFOX6 and may also receive 5-FU and folinic acid after mFOLFOX6 completion.

Patients included in the study were 18 years or older, with a histologically or radiologically confirmed tumor, an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and adequate laboratory values at baseline. The study excluded patients who had systemic treatment for locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma. In addition, patients who received radiotherapy within 14 days, systemic immunosuppressive agents within 28 days, investigational agents within 28 days, and/or major surgery within 28 days were ineligible to enroll. The study also excluded patients due to comorbidities and active infections that may have interfered with the study treatment.

In addition to survival, the Spotlight study is evaluating objective response rate, duration of response, safety/tolerability, ECOG performance status abnormalities, health-related quality of life, time to confirmed deterioration, pharmacokinetics, and the number of anti-drug antibody-positive patients as secondary end points.

The study is ongoing at 220 locations worldwide. It is expected to be completed in January 2025. In addition to Spotlight, zolbetuximab is also being investigated in combination with capecitabine and oxaliplatin (CAPOX) vs placebo and CAPOX in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma (GLOW; NCT03653507).

"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 [the] development of zolbetuximab for the first-line treatment of patients with locally advanced or metastatic gastric cancer," said Ahsan Arozullah, MD, MPH, senior vice president and head of Development Therapeutic Areas, at Astellas Pharma, Inc. “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."


Astellas announces zolbetuximab meets primary endpoint in phase 3 SPOTLIGHT trial as first-line treatment in Claudin 18.2 positive, HER2-negative locally advanced or metastatic gastric and gastroesophageal junction (GEJ) cancers. News release. Astellas Pharma, Inc. November 17, 2022. Accessed November 17, 2022. https://bit.ly/3Eh65kP

A phase 3 efficacy, safety and tolerability study of zolbetuximab (experimental drug) plus mFOLFOX6 chemotherapy compared to placebo plus mFOLFOX6 as treatment for gastric and gastroesophageal junction (GEJ) cancer (Spotlight). Clinicaltrials.gov. Updated November 17, 2022. Accessed November 17, 2022. https://clinicaltrials.gov/ct2/show/NCT03504397?term=SPOTLIGHT&draw=2&rank=9