FDA Accepts BLA Resubmission for Zolbetuximab in CLDN18.2+ Advanced Gastric/GEJ Adenocarcinoma

The FDA has accepted the resubmission of a biologics license application (BLA) seeking the approval of zolbetuximab for the first-line treatment of adult patients with locally advanced unresectable or metastatic, Claudin18.2 (CLDN18.2)–positive, HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.¹

The target action date under the Prescription Drug User Fee Act for the resubmitted BLA is November 9, 2024.

In January 2024, the FDA issued a complete response letter (CRL) for the initial BLA seeking the approval of zolbetuximab for this patient population.² The CRL was issued because of third-party manufacturing deficiencies identified during the pre-license inspection of the facility. Notably, the regulatory agency did not identify any concerns regarding the efficacy or safety data for zolbetuximab, and no additional clinical studies were requested to support the BLA approval.¹

“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 United States facing this deadly disease,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development at Astellas, stated in a news release.¹

The resubmitted BLA is supported by data from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials.

SPOTLIGHT

The global, randomized, placebo-controlled, double-blind study investigated zolbetuximab plus mFOLFOX6 vs placebo plus mFOLFOX6 in previously untreated patients at least 18 years of age with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. CLDN18.2 positivity was defined as at least 75% of tumor cells showing moderate-to-strong membranous CLDN18 staining. Key inclusion criteria included radiologically evaluable disease per RECIST 1.1 criteria; an ECOG performance status score of 0 or 1; and adequate organ function.³

Patients were randomly assigned 1:1 to receive zolbetuximab at 800 mg/m² as a loading dose followed by 600 mg/m² every 3 weeks plus mFOLFOX6 every 2 weeks; or placebo plus mFOLFOX6.

Progression-free survival (PFS) per RECIST 1.1 criteria as assessed by independent review committee (IRC) assessment served as the trial’s primary end point. Key secondary end points included overall survival (OS) and time to confirmed deterioration.

Findings showed that at a median follow-up of 12.94 months for the zolbetuximab group (n = 283) and 12.65 months for the placebo group (n = 282), zolbetuximab plus mFOLFOX6 elicited a median PFS of 10.61 months (95% CI, 8.90-12.48) compared with 8.67 months (95% CI, 8.21-10.28) for placebo plus mFOLFOX6 (HR, 0.75; 95% CI, 0.60-0.94; P = .0066). An OS benefit was also observed in the zolbetuximab group (HR, 0.75; 95% CI, 0.60-0.94; P = .0053).

No new safety signals were identified in the zolbetuximab arm. Grade 3 or higher treatment-emergent adverse effects (AEs) were reported in 87% of evaluable patients in the zolbetuximab group (n = 279) vs 78% of patients in the placebo group (n = 278). The most common any-grade AEs in the zolbetuximab arm included nausea, vomiting, and decreased appetite. The rates of treatment-related deaths were 2% in the zolbetuximab arm compared with 1% in the placebo arm.

GLOW

The global, double-blind, phase 3 study enrolled patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma, who were randomly assigned to received zolbetuximab plus CAPOX or placebo plus CAPOX. CLDN18.2 positivity was defined as at least 75% of tumor cells with moderate-to-strong membranous CLDN18 staining. Other inclusion criteria consisted of radiologically evaluable disease per RECIST 1.1 criteria; an ECOG performance status score of 0 or 1; and adequate organ function.⁴

PFS per RECIST 1.1 criteria as assessed by IRC served as the trial’s primary end point. Key secondary end points included OS and time to confirmed deterioration.

The study met its primary end point, zolbetuximab plus CAPOX reduced the risk of progression or death by 31.3% compared with placebo plus CAPOX (HR, 0.687; 95% CI, 0.544-0.866; P = .0007). Patients treated in the experimental arm (n = 254) achieved a median PFS of 8.21 months compared with 6.80 months for those given placebo plus CAPOX (n = 253). The respective 12- and 24-month PFS rates were 35% and 14% in the zolbetuximab arm, compared with 19% and 7%, respectively, in the placebo arm.

The median OS was 14.39 months for the experimental arm vs 12.16 months for the control arm (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).

Regarding safety, grade 3 or higher treatment-emergent AEs occurred in 72.8% of patients given the zolbetuximab regimen vs 69.9% of patients given the placebo regimen.

References

1. U.S. FDA acknowledges Astellas’ resubmission of biologics license application for zolbetuximab and sets new action date. News release. Astellas Pharma. May 31, 2024. Accessed May 31, 2024. https://www.astellas.com/en/news/29186
2. Astellas provides update on zolbetuximab biologics license application in US. News release. Astellas Pharma. January 9, 2024. Accessed May 31, 2024. https://www.astellas.com/en/news/28731
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 [published correction appears in Lancet. 2023;402(10398):290. doi:10.1016/S0140-6736(23)00620-7
4. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7