Zolbetuximab Has Benefit in Targeting CLDN18.2 in Gastrointestinal Cancers

After assessment of Claudin 18.2–targeting therapies for gastrointestinal (GI) cancers for some time, 2 clinical trials have displayed benefit among patients with Claudin 18.2-positive disease, according to John L. Marshall, MD.

CancerNetwork® spoke with Marshall, physician executive director of the MedStar Washington DC Integrated Hematology-Oncology Division and the Otto J Ruesch Center for the Cure of GI Cancers, and chief medical officer of the Lombardi Comprehensive Cancer Center at Georgetown University, about what the FDA approval of zolbetuximab-clzb (Vyloy) plus fluoropyrimidine- and platinum-based chemotherapy will mean for patients with locally advanced or unresectable Claudine 18.2–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.¹

Marshall emphasized a desire within the GI cancer field to develop therapies that treat new targets. He expressed a belief that the approval of zolbetuximab combination therapy in this patient population may benefit outcomes based on 2 clinical trials: the phase 3 SPOTLIGHT (NCT03504397) and phase 3 GLOW (NCT03653507) trials.^2,3 He additionally highlighted an excitement to incorporate the therapy into practice in light of delays to the approval process.

Data from the phase 3 SPOTLIGHT trial published in The Lancet showed a median progression-free survival (PFS) benefit with zolbetuximab plus modified folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6) vs FOLFOX6 alone; 10.61 months (95% CI, 8.90-12.48) and 8.67 months (95% CI, 8.21-10.28), respectively (HR, 0.75; 95% CI, 0.60-0.94; P = .0066). Additionally, 12-month PFS rates were 49% (95% CI, 42%-55%) vs 35% (95% CI, 28%-42%) in the respective arms; 24-month PFS rates were 24% (95% CI, 17%-32%) vs 15% (95% CI, 9%-22%).

Results from the phase 3 GLOW trial published in Nature Medicine showed a median PFS benefit with zolbetuximab plus capecitabine (Xeloda) and oxaliplatin (CAPOX) vs CAPOX alone; 8.21 months and 6.80 months, respectively (HR, 0.687; 95% CI, 0.544-0.866; P = .0007). In each respective arm, the 12-month PFS rates were 35% vs 19%, and the 24-month PFS rates were 14% vs 7%.

Transcript:

In GI cancers, we have been longing for new targets. We have been longing for new therapies. Finally, we are getting one. Claudin 18.2 has been out there for a while, and drug development targeting this has been going on for a while. Two big, randomized studies now support benefit [of zolbetuximab] in this patient population. Now, we are going to get the drug [approval]. We have been delayed a while by some other issues that have slowed the approvals, but we are excited, and we are all looking forward to incorporating [zolbetuximab] into our treatment paradigm.

References

1. Astellas’ VYLOY™ (zolbetuximab-clzb) approved by U.S. FDA for treatment of advanced gastric and GEJ cancer. News release. Astellas Pharmaceuticals. October 18, 2024. Accessed October 23, 2024. https://tinyurl.com/5745k9a8
2. 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
3. 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;29:2133-2141. doi:10.1038/s41591-023-02465-7