Frontline Zolbetuximab Plus CAPOX Meets PFS, OS End Points in Claudin 18.2+ Gastric or GEJ Cancers

The addition of zolbetuximab (IMAB362) to capecitabine and oxaliplatin (CAPOX) resulted in a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) vs placebo/CAPOX in patients with Claudin 18.2 (CLDN18.2)–positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal (GEJ) cancers, meeting the primary and secondary end points of the phase 3 GLOW trial (NCT03653507).¹

Moreover, the treatment-emergent toxicities that were most reported with the frontline regimen were nausea and vomiting.

Detailed findings from the trial will be shared at a future scientific congress, according to drug developer Astellas Pharma, Inc. The data will also be submitted for publication.

“Zolbetuximab has the potential to be an innovative therapeutic option for patients with locally advanced unresectable or metastatic gastric or GEJ cancer, a difficult disease for which treatment options are still limited,” Ruihua Xu, MD, PhD, primary investigator of the study and professor in the Department of Medical Oncology at Sun Yat-Sen University Cancer Center, Guangzhou, China, stated in a press release. “I am so pleased with the topline results from GLOW that establish PFS and OS in patients with zolbetuximab plus CAPOX.”

A first-in-class chimeric IgG1 monoclonal antibody, zolbetuximab, binds to the transmembrane protein CLDN18.2 and mediates cancer cell death through 2 key pathways: antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.²

Preclinical findings have indicated that chemotherapy serves to sensitize gastric/GEJ cancer cell lines to zolbetuximab by boosting CLDN18.2 expression. Xenografted mice that received zolbetuximab and chemotherapy experienced better antitumor activity than the mice given chemotherapy alone.

The agent, when given as a monotherapy or in combination with chemotherapy, has also demonstrated antitumor activity in patients with CLDN18.²-positive gastric or GEJ cancer. Zolbetuximab monotherapy resulted in a clinical benefit rate of 23% in those with recurrent/refractory locally advanced or metastatic disease who received at least 1 previous line of chemotherapy, according to findings from the phase 2a MONO trial (NCT01197885).³

Additionally, data from the phase 2 FAST trial (NCT01630083) demonstrated that frontline zolbetuximab plus epirubicin, oxaliplatin, and capecitabine (EOX) significantly improved PFS and OS vs EOX alone in those with advanced disease, with hazard ratios of 0.44 (95% CI, 0.29-0.67; P < .0005) and 0.55 (95% CI, 0.39-0.77; P < .0005), respectively.4 Early findings from cohort 2 of the phase 2 ILUSTRO study (NCT03505320) showed that when zolbetuximab was paired with 5-fluorouracil, folinic acid, and oxaliplatin (mFOLFOX6), the objective response rate (ORR) was 63.2% (95% CI, 38.4%-83.7%) in patients with advanced gastric or GEJ cancer and high CLDN18.2 expression.⁵

The global, multicenter, double-blind GLOW trial enrolled 507 patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric/GEJ cancer who did not receive prior chemotherapy. Those who received systemic immunosuppressive therapy or other investigational drugs or devices within 28 days before their first dose of study treatment were excluded.

Study participants were randomly assigned 1:1 to zolbetuximab plus CAPOX or placebo plus CAPOX. Zolbetuximab was given intravenously (IV) at a loading dose of 800 mg/m2 on day 1 of cycle 1, and then at 600 mg/m2 on day 1 of each 21-day cycle thereafter. CAPOX chemotherapy was comprised of IV oxaliplatin given at 130 mg/m2 on day 1 of each 21-day cycle for up to 8 cycles and oral capecitabine given at a twice-daily dose of 1000 mg/m2 on days 1 to 14 of each 21-day cycle. For cycle 9 and onward, capecitabine was given per investigator discretion.

Treatment was given until disease progression, intolerable toxicity, the start of another anticancer treatment, or other discontinuation criteria were met.

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

The primary end point of the research is PFS, and secondary end points include OS, ORR, duration of response, safety and tolerability, and quality-of-life parameters

“We are extremely pleased to share positive topline results from GLOW following the positive SPOTLIGHT trial readout last month. This further confirms the potential role of zolbetuximab in gastric cancer treatment, an important milestone in our gastric cancer development program,” Ahsan Arozullah, MD, MPH, senior vice president and head of Development Therapeutic Areas, at Astellas Pharmaceuticals, added in the press release.

He added that the company intends to discuss the results with regulatory authorities.

References

1. Astellas announces zolbetuximab meets primary endpoint in phase 3 GLOW trial as first-line treatment in Claudin 18.2 positive, HER2-negative locally advanced unresectable or metastatic gastric and gastroesophageal junction (GEJ) cancers. News release. Astellas Pharma Inc. December 15, 2022. Accessed December 16, 2022. https://bit.ly/3HGydB4
2. Shah MA, Ajani JA, Al-Batran S-E, et al. Zolbetuximab + CAPOX versus CAPOX in first-line treatment of claudin18.2+/HER2- advanced/metastatic gastric or gastroesophageal junction adenocarcinoma: GLOW phase 3 study. J Clin Oncol. 2022;40(suppl 4):TPS365. doi:10.1200/JCO.2022.40.4_suppl.TPS365
3. Türeci O, Sahin U, Schulze-Bergkamen H, et al. A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann Oncol. 2019;30(9):1487-1495. doi:10.1093/annonc/mdz199
4. Sahin U, Ö Türeci, Manikhas G, et al. FAST: a randomized phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32(5):609-619. doi:10.1016/j.annonc.2021.02.005
5. Klempner SJ, Lee K-W, Metges J-P, et al. Phase 2 study of zolbetuximab plus mFOLFOX6 in claudin 18.2-positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ): ILUSTRO cohort 2. J Clin Oncol. 2021;39(suppl 15):e16063. doi:10.1200/JCO.2021.39.15_suppl.e16063