FDA Issues CRL to Zolbetuximab for Advanced HER2–, CLDN18.2+ Gastric/GEJ Cancer

The FDA has issued a complete response letter (CRL) regarding the biologics license application (BLA) seeking the approval of zolbetuximab for the treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are Claudin18.2 (CLDN18.2) positive.¹

The FDA stated that the agency cannot approve the BLA by the Prescription Drug User Fee Act action date on January 12, 2024, because of unresolved deficiencies following its pre-license inspection of a third-party manufacturing facility for zolbetuximab. The FDA did not cite any concerns related to the clinical data for zolbetuximab and is not requesting additional clinical trials.

Astellas is working alongside the FDA and the third-party manufacturer to establish a timeline to quickly resolve the agency’s feedback.

“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 U.S. patients in need, as soon as possible,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development, Astellas, said in a news release.

In July 2023, the FDA granted a priority review to zolbetuximabfor the first-line treatment of patients with unresectable, locally advanced or metastatic, HER2-negative, gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive.²

The BLA was based on data from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials. In SPOTLIGHT, the addition of zolbetuximab to mFOLFOX6 (leucovorin calcium, fluorouracil, and oxaliplatin) led to a significant improvement in progression-free survival (PFS) and overall survival (OS) vs placebo plus mFOLFOX6. 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), the median PFS was 10.61 months (95% CI, 8.90-12.48) with zolbetuximab/mFOLFOX6 vs 8.67 months (95% CI, 8.21-10.28) with placebo/mFOLFOX6 (HR, 0.75; 95% CI, 0.60-0.94; P = .0066).^3,4

Additionally, zolbetuximab plus mFOLFOX6 led to a median OS of 18.23 months (95% CI, 16.43-22.90) at a median follow-up of 22.14 months vs 15.54 months (95% CI, 13.47-16.53) with mFOLFOX6 alone (HR, 0.75; 95% CI, 0.60-0.94; P = .0053) at a median follow-up of 20.93 months,.

Updated findings from the trial, which were presented at the 2023 ESMO Congress with an additional 9.7 months of follow-up, showed that the addition of zolbetuximab to mFOLFOX6 continued to provide a statistically significant improvement in PFS (HR, 0.730; 95% CI, 0.587-0.907; P =.0022) and OS (HR, 0.778; 95% CI, 0.637-0.949; P =.0067) vs placebo plus mFOLFOX6.⁵

In GLOW, zolbetuximab added to CAPOX (capecitabine plus oxaliplatin) produced a statistically significant improvement in PFS and OS vs placebo plus CAPOX. At a median follow-up of 12.62 months for the zolbetuximab arm (n = 254) and 12.09 months for the placebo arm (n = 253), patients treated with zolbetuximab plus CAPOX achieved a median PFS of 8.21 months (95% CI, 7.46-8.84) vs 6.80 months (95% CI, 6.14-8.08) for those treated with placebo plus CAPOX (HR, 0.687; 95% CI, 0.544-0.866; P = .0007). The median OS in the experimental arm was 14.39 months (95% CI, 12.29-16.49) vs 12.16 months (95% CI, 10.28-13.67) in the control arm (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).⁶

Updated findings from the trial were also presented at the 2023 ESMO Congress with an additional 8.7 months of follow-up, showing continued statistically significant improvements in PFS (HR, 0.682; 95% CI, 0.545-0.854; P =.0004) and OS (HR, 0.771; 95% CI, 0.624-0.952; P =.0079) with zolbetuximab plus CAPOX vs placebo plus CAPOX.⁷

In both trials, nausea, vomiting, and decreased appetite were the most common treatment-emergent adverse effects in the zolbetuximab arms.^5,7

References

1. Astellas provides update on zolbetuximab biologics license application in US. News release. Astellas Pharma. January 9, 2024. Accessed January 9, 2024. https://www.astellas.com/en/news/28731
2. Astellas announces US FDA grants priority review for zolbetuximab biologics license application. News release. Astellas. July 6, 2023. Accessed January 9, 2024. https://www.astellas.com/en/system/files/news/2023-07/81743d9407/20230706_en_1.pdf
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. 2023;401(10389):1655-1668. doi:10.1016/S0140-6736(23)00620-7
4. Shitara K, Lordick F, Bang Y-J, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT study. J Clin Oncol. 2023;41(suppl 3):LBA292. doi:10.1200/JCO.2023.41.3_suppl.LBA292
5. Ajani JA, Lordick F, Bang YJ, et al. Updated efficacy and safety results from phase III SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients with claudin18.2 isoform 2-positive (CLDN18.2+), HER2–, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Ann Oncol. 2023;34(suppl 2):S1322. doi:10.1016/j.annonc.2023.10.083
6. 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
7. Lordick F, Shah MA, Shitara K, et al. Updated efficacy and safety results from phase III GLOW study evaluating zolbetuximab + CAPOX as first-line (1L) treatment for patients with claudin-18 isoform 2-positive (CLDN18.2+), HER2–, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Ann Oncol. 2023;34(suppl 2):S1321. doi:10.1016/j.annonc.2023.10.082