FDA Acknowledges BLA of Zolbetuximab in HER2–, CLDN18.2+ Gastric/GEJ Cancer

• The FDA has acknowledged the resubmitted biologics license application (BLA) for zolbetuximab (Vyloy) as a first-line treatment for locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are claudin (CLDN) 18.2 positive.
• Zolbetuximab is a first-in-class investigational CLDN18.2-targeted monoclonal antibody.
• A new target action date of November 9, 2024, has been set under the Prescription Drug User Fee Act.

The FDA acknowledged the resubmitted BLA for zolbetuximab (Vyloy) for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive.¹

On May 9, 2024, the BLA for zolbetuximab was resubmitted after a complete response letter (CRL) was issued on January 4, 2024 by the FDA. The CRL was put in place after third-party manufacturing deficiencies were identified during the prelicense inspection of the facility. However, the FDA did not raise any concerns related to the clinical data of zolbetuximab, and no additional studies to support the approval of this BLA were requested.

The submission of the BLA is supported by data from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies.

"Astellas is committed to introducing new targeted therapies for hard-to-treat cancers. Those living with advanced gastric or GEJ cancer often face great unmet needs, and the FDA acknowledgment of the zolbetuximab BLA resubmission brings us one step closer to offering this important treatment option to eligible patients in the US facing this deadly disease," said Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of immuno-oncology development, Astellas, in a press release.

With this acknowledgment from the FDA, a new target action date of November 9, 2024, has been set.

In the SPOTLIGHT study, zolbetuximab plus oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) was compared with placebo plus mFOLFOX6, and in the GLOW study, experts evaluated zolbetuximab plus capecitabine and oxaliplatin (CAPOX) vs placebo plus CAPOX.

Adding zolbetuximab to a chemotherapy regimen significantly improved overall survival (OS) and progression-free survival (PFS) in patients with advanced, HER2-negative, CLDN18.2-positive gastric/GEJ cancer in these 2 studies.^2,3

A total of 507 patients were enrolled in the GLOW trial and treated with zolbetuximab plus capecitabine and oxaliplatin (CAPOX; n = 254) or placebo plus CAPOX (n = 253). At a median follow-up of 12.62 months in the experimental arm and 12.09 months in the comparator arm, the median PFS rates were 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). At 12 months, the PFS rates were 35% vs 19% with placebo/CAPOX, and at 24 months, these rates were 14% vs 7%.²

Of those given zolbetuximab with CAPOX, the median OS was 14.39 months (95% CI, 12.29-16.49 months) compared with 12.16 months (95% CI, 10.28-13.67 months) of those given the placebo combination (HR, 0.771; 95% CI, 0.615-0.965; P = .0118). Twelve-month 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%, respectively.

The addition of zolbetuximab to CAPOX was shown to be tolerable and adverse events were manageable.

The SPOTLIGHT study enrolled 565 patients with advanced, HER2-negative, CLDN18.2-positive gastric/GEJ cancers who were given either zolbetuximab with mFOLFOX6 or placebo with mFOLFOX6.³ In the experimental vs active comparator arms, the median PFS rates were 10.61 (95% CI, 8.90-12.48) vs 8.67 months (95% CI, 8.21-10.28), and at 12 and 24 months, PFS rates were 49% and 24% in the zolbetuximab arm and 35% and 15% in the placebo arm, respectively.

OS improvements were also seen in the combination arm at 18.23 months (95% CI, 16.43-22.90) compared with 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). OS rates at 12-, 24-, and 26-months in the experimental arm vs the control arm were 68% vs 28%, 60% vs 21%, and 39% vs 9%, respectively.

In both studies, approximately 38% of patients who were screened had CLDN18.2-positive tumors, which was defined as ≥75% of tumor cells demonstrating moderate-to-strong membranous CLDN18 staining, as determined by a validated immunohistochemistry assay.¹

Previously on March 26, 2024, Japan's Ministry of Health, Labour and Welfare (MHLW) granted approval to zolbetuximab. With this, zolbetuximab was made the first and only CLDN18.2-targeted treatment approved for patients with CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer. Applications for zolbetuximab have also been sent to regulatory agencies globally, and reviews are ongoing.

REFERENCES:

1. U.S. FDA acknowledges Astellas' resubmission of biologics license application for zolbetuximab and sets new action date. News release. Astellas Pharma Inc. May 30, 2024. Accessed May 31, 2024. https://tinyurl.com/yszrrjrc

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