FDA Issues CRL for Zolbetuximab in Advanced CLDN18.2+ Gastric Cancer

Zolbetuximab received priority review from the FDA as a treatment for CLDN18.2-positive advanced gastric or GEJ adenocarcinoma in July 2023.

The FDA has issued a complete response letter for a biologics license application for zolbetuximab (IMAB362) as a treatment for those with Claudin 18.2 (CLDN18.2)–positive, locally advanced, unresectable or metastatic, HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to a press release from Astellas Pharma Inc.¹

The regulatory agency highlighted that it could not approve the application for zolbetuximab in this indication due to insufficiencies pertaining to a pre-license inspection at a third-party manufacturing site for the agent. Moreover, no additional clinical data or studies were requested to affirm the agent’s efficacy or safety. Developers are collaborating with the FDA and the third-party manufacturer to meet the concerns associated with the inspection.

“We remain confident in zolbetuximab’s clinical profile and potential to fill a significant therapeutic gap for those diagnosed with advanced gastric or GEJ cancer whose tumors are CLDN18.2 positive,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development at Astellas, said in the press release.¹

Zolbetuximab received priority review from the FDA as a treatment for CLDN18.2-positive advanced gastric or GEJ adenocarcinoma in July 2023.² Supporting data for the application came from the phase 3 SPOTLIGHT trial (NCT03504397) as well as the phase 3 GLOW trial (NCT03653507).

Investigators of the SPOTLIGHT trial highlighted a median progression-free survival (PFS) of 10.61 months (95% CI, 8.90-12.48) in the zolbetuximab arm compared with 8.67 months (95% CI, 8.21-10.28) in the placebo arm (HR, 0.75; 95% CI, 0.60-0.94; P = .0066).³ The estimated PFS rates at 12 months were 49% (95% CI, 42%-55%) vs 35% (95% CI, 28%-42%) in each respective arm, and the estimated rates at 24 months were 24% (95% CI, 17%-32%) vs 15% (95% CI, 9%-22%).

In the GLOW trial, zolbetuximab plus capecitabine and oxaliplatin (CAPOX) produced a median PFS of 8.21 months (95% CI, 7.46-8.84) compared with 6.80 months (95% CI, 6.14-8.08) among patients who received placebo plus CAPOX (HR, 0.687; 95% CI, 0.544-0.866; P = .0007).⁴ The PFS rates in the zolbetuximab and placebo arms, respectively, were 35% vs 19% at 12 months and 14% vs 7% at 24 months.

Patients enrolled on the SPOTLIGHT study were assigned to receive zolbetuximab intravenously at 800 mg/m² on day 1 during cycle 1 and at 600 mg/m² on day 22 of cycle 1 or placebo in combination with modified folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6). The trial’s primary end point was PFS, with secondary end points including overall survival (OS), objective response rate, and safety. The trial included those with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.

As part of the GLOW trial, patients received 800 mg/m² of zolbetuximab intravenously on day 1 of cycle 1 plus 600 mg/m² on day 1 of every subsequent cycle once every 3 weeks or matched placebo followed by CAPOX and then 600 mg/m² of zolbetuximab every 3 weeks or placebo plus capecitabine starting on cycle 9. The trial’s primary end point was PFS, and secondary end points included OS, ORR, and time to confirmed deterioration. The trial included those with previously untreated locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma.

References

1. Astellas provides update on zolbetuximab biologics license application in U.S. News release. Astellas Pharma Inc. January 9, 2024. Accessed January 9, 2024. https://rb.gy/bl225f
2. Astellas announces U.S. FDA grants priority review for zolbetuximab biologics license application. News release. Astellas Pharma Inc. July 6, 2023. Accessed January 9, 2024. https://shorturl.at/egzU1
3. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. Published online April 14, 2023. doi:10.1016/S0140-6736(23)00620-7
4. Xu R, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary phase 3 results from GLOW. J Clin Oncol. 2023;41(suppl 36):405736. doi:10.1200/JCO.2023.41.36_suppl.405736