FDA Issues Complete Response Letter to Zolbetuximab BLA in GI Cancer

• Two phase 3 clinical trials revealed promising data with zolbetuximab, supporting its biologics license application (BLA) submission for the treatment of patients with first-line, advanced, HER2-negative, Claudin 18.2 (CLDN18.2)-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.
• Zolbetuximab is a first-in-class investigational CLDN18.2-targeted monoclonal antibody.
• This combination represents a potential first-line treatment for this patient population.

The FDA issued a complete response letter (CRL) to the BLA of zolbetuximab for the upfront treatment of patients with locally advanced, unresectable, or metastatic HER2-negative, CLDN18.2-positive gastric or GEJ adenocarcinoma.¹ The agency cannot approve the BLA after it found "unresolved deficiencies" following an inspection of a third-party manufacturer.

This submission of the BLA was supported by data from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies in which the addition of zolbetuximab to a chemotherapy regimen led to significant overall survival (OS) and progression-free survival (PFS) benefits among patients with advanced, HER2-negative, CLDN18.2-positive gastric/GEJ cancer.^2,3 

“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. Astellas is committed to working with the FDA and the third-party manufacturer to address the agency’s feedback, and to bringing zolbetuximab to [Unites States] patients in need, as soon as possible," said Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of immuno-oncology development, Astellas, said in a press release.¹

In the GLOW trial, 507 patients were enrolled and given treatment with zolbetuximab plus oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6; n = 254) or placebo plus mFOLFOX6 (n = 253). The median follow-up was 12.62 months in the experimental arm and 12.09 months in the comparator arm. At this time, the median PFS in the experimental arm was 8.21 months (95% CI, 7.46-8.84 months) vs 6.80 months (95% CI, 6.14-8.08 months), respectively (HR, 0.687; 95% CI, 0.544-0.866; P =.0007), the 12-month PFS rates were 35% vs 19% with placebo/CAPOX, and the 24-month PFS rates were 14% vs 7%.²

For OS, patients treated with zolbetuximab plus CAPOX had a median OS of 14.39 months (95% CI, 12.29-16.49 months) vs 12.16 months (95% CI, 10.28-13.67 months) among those in the comparator arm (HR, 0.771; 95% CI, 0.615-0.965; P = .0118). At 12 months, OS rates were 58% and 51% in the zolbetuximab/CAPOX arm vs placebo/CAPOX arm, and the 24-month OS rates were 29% and 17%.

Looking at safety, the addition of zolbetuximab to CAPOX was tolerable with manageable adverse events (AEs).

In SPOTLIGHT, 565 patients with advanced, HER2-negative, CLDN18.2-positive gastric/GEJ cancers were evaluated and treated with zolbetuximab plus mFOLFOX6 or with placebo plus mFOLFOX6. The median PFS rates were 10.61 (95% CI, 8.90-12.48) vs 8.67 months (95% CI, 8.21-10.28) in the experimental vs comparator arms. The 12- and 24-month PFS rates were 49% and 24% in the zolbetuximab arm and 35% and 15% in the placebo arm, respectively.

There was also an improvement regarding OS with the combination of zolbetuximab and mFOLFOX6 at 18.23 months (95% CI, 16.43-22.90) vs 15.54 months (95% CI, 13.47-16.53) in the placebo/mFOLFOX6 arm (HR, 0.750; 95% CI, 0.601-0.936; P = .0053). At 12-, 24-, and 26-months, the OS rates in the experimental arm vs the control arm were 68% vs 28%, 60% vs 21%, and 39% vs 9%, respectively.

REFERENCES:

1. Astellas provides update on zolbetuximab biologics license application in U.S. News release. Astellas. January 9, 2024. Accessed January 9, 2024. http://tinyurl.com/35544h2w

2. Xu RH, 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. Presented at: 2023 March ASCO Plenary Series. Abstract 405736

3. Shitara K, Lordick F, Bang Y-J, 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 April 12, 2023. doi:10.1016/S0140-6736(23)00620-7