Zolbetuximab 100mg powder for solution for infusion vials

Abstract Background The benefit of adding Zolbetuximab to the treatment in patients with Claudin-18 isoform 2 (CLDN18.2)-positive, human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GC/GEJ) is not yet fully elucidated. Methods We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) that investigated Zolbetuximab plus chemotherapy versus chemotherapy alone for GC or GEJ adenocarcinoma. We computed hazard-ratios (HRs) or odds-ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). Results Three studies and 1,233 patients were included. Comparing with Zolbetuximab plus chemotherapy versus chemotherapy alone, progression-free survival (PFS) rate (HR 0.64; 95% CI 0.49–0.84; p < 0.01) and overall survival (OS) rate (HR 0.72; 95% CI 0.62–0.83; p < 0.01) were significant in favor of the Zolbetuximab group. Regarding effectiveness, the Objective Response Rate (ORR) was (OR 1.15; 95% CI 0.87–1.53; p = 0.34). Conclusions In this comprehensive systematic review and meta-analysis of RCTs, the incorporation of Zolbetuximab alongside chemotherapy offers a promising prospect for reshaping the established treatment paradigms for patients diagnosed with advanced CLDN18.2-positive GC/GEJ cancer.

Abstract licence: CC BY 4.0

ObjectiveZolbetuximab is a “first-in-class” chimeric lgG1 monoclonal antibody targeting Claudin18.2 (CLDN 18.2). In recent years, several important trials have been published showing that zolbetuximab is associated with improved prognosis in patients with advanced gastric or gastro-esophageal junction (G/GEJ) adenocarcinoma. This promises great change to the current treatment landscape. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of zolbetuximab for first-line treatment of advanced CLDN 18. 2-positive G/GEJ adenocarcinoma.MethodsThe following databases were searched for relevant studies: PubMed, EMBASE, and Cochrane library (updated 10 June 2023). All randomized trials comparing zolbetuximab plus chemotherapy versus first-line chemotherapy alone for first-line treatment of advanced CLDN 18. 2-positive G/GEJ adenocarcinoma were eligible for inclusion. Data were analyzed using Review Manager 5.4.1 (Cochrane collaboration software). Primary outcomes and measures included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs).ResultsThis systematic review and meta-analysis included three randomized controlled studies involving 1,402 patients (699 receiving zolbetuximab plus chemotherapy and 703 receiving chemotherapy alone). Compared with chemotherapy alone, zolbetuximab plus chemotherapy significantly improved OS (HR = 0.73; 95% CI: 0.68–0.84) and PFS (HR = 0.64; 95% CI: 0.50–0.82), but did not result in a higher ORR (RR = 0.92; 95% CI: 0.82–1.03). Further analysis of CLDN 18.2 expression showed a more significant benefit for OS (HR = 0.69; 95% CI: 0.55–0.87; p = 0.002) and PFS (HR = 0.61; 95% CI: 0.44–0.84; p = 0.003) from zolbetuximab in patients with high expression, while there was significant benefit in patients with lower expression. In terms of AEs, zolbetuximab plus chemotherapy was associated with higher risk of grade 3 and higher AEs, but increased risk of nausea and vomiting were more common.ConclusionThis systematic review and meta-analysis revealed that the effect of zolbetuximab plus chemotherapy was superior to that of chemotherapy alone for first-line treatment of advanced CLDN 18.2-positive G/GEJ adenocarcinoma. Thus, zolbetuximab plus chemotherapy represents a new first-line treatment for these patients. Zolbetuximab plus chemotherapy was associated with higher risk of grade 3 and higher AEs, but was generally manageable.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero, identifier (CRD42023437126).

Abstract licence: CC BY 4.0

IntroductionAdvanced gastric and gastroesophageal junction (G/GEJ) adenocarcinomas are characterized by an aggressive course and a very poor prognosis. Due to the limited benefit of immunotherapy in patients with HER2-negative tumors, new therapeutic targets are sought. Zolbetuximab is a chimeric monoclonal antibody targeting the CLDN18.2 protein, which is overexpressed in 50–80% of gastric cancers.Materials and methodsThis review is based on phase I–III clinical trials, including the pivotal SPOTLIGHT, GLOW, FAST, and ILUSTRO trials. The efficacy and safety of zolbetuximab in combination with chemotherapy were assessed as first-line treatment for adults with locally advanced or metastatic G/GEJ adenocarcinoma, HER2-negative, and highly CLDN18.2-expressing.ResultsEarly phase studies confirmed the clinical activity and tolerability of zolbetuximab. A Japanese phase I study demonstrated the safety and pharmacokinetic profile of zolbetuximab as monotherapy, establishing the recommended dose in subsequent studies. The phase II FAST study demonstrated that the addition of zolbetuximab to EOX chemotherapy significantly improved both PFS (HR 0.44; p=0.0005) and OS (HR 0.55; p=0.0001). The phase II ILUSTRO study demonstrated activity of zolbetuximab both as monotherapy (ORR 9%) and in combination with mFOLFOX6 (ORR 39%), supporting its advancement to phase III. These results were confirmed in two pivotal randomized phase III studies. In the SPOTLIGHT study, the addition of zolbetuximab to mFOLFOX6 reduced the risk of death by 25% (median OS 18.23 vs. 15.54 months), and in the GLOW study, the addition of zolbetuximab to CAPOX reduced the risk of death by almost 23% (median OS 14.39 vs. 12.16 months). The most common adverse events were nausea and vomiting, occurring primarily in the first treatment cycle.ConclusionsZolbetuximab represents a significant advancement in the treatment of patients with advanced G/GEJ adenocarcinoma overexpressing CLDN18.2, addressing an important unmet clinical need. However, optimizing the stringent threshold for CLDN18.2 positivity (requiring staining in ≥75% of cells) and establishing a treatment regimen for patients with concurrent CLDN18.2 and PD-L1 expression remains a significant challenge. The review protocol was prospectively registered in the PROSPERO database (International Prospective Register of Systematic Reviews) under registration number CRD420261383764.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261383764.

Abstract licence: CC BY 4.0

Background/objectiveHER2-negative unresectable advanced or recurrent gastric cancer (GC) has a poor prognosis. This study evaluated the comparative cost-effectiveness of multiple first-line treatment options from the Japanese healthcare payer perspective.MethodsA partitioned survival model was developed to estimate the cost-effectiveness of each regimen. Hazard ratios were derived from a network meta-analysis to project long-term costs and quality-adjusted life years (QALYs) gained. Regimens included pembrolizumab plus chemotherapy (Pem + Chemo); zolbetuximab plus chemotherapy (Zolb + Chemo); nivolumab plus chemotherapy (NIVO + Chemo); 5-fluorouracil, oxaliplatin, and levofolinate (FOLFOX); capecitabine and oxaliplatin (CapeOx); S-1 and oxaliplatin (SOX), capecitabine and cisplatin (Cape + CDDP); and S-1 and cisplatin (S-1 + CDDP). Cost parameters were obtained from a Japanese medical claims database. Incremental cost-effectiveness ratios (ICERs) were calculated for each regimen. Sensitivity analyses were conducted to assess parameter uncertainty. Scenario analysis was conducted by incorporating tislelizumab, which is approved and recommended in countries outside Japan.ResultsOn the basis of the base-case analysis, CapeOx, SOX, Pem + Chemo (5-FU + CDDP, CapeOx), and Zolb + CapeOx were located on the efficiency frontier. The ICER of SOX versus CapeOx was USD 85,649/QALY. Pem + Chemo versus SOX had an ICER of USD 345,103/QALY. Zolb + CapeOx versus Pem + Chemo had an ICER of USD 1,637,571/QALY. Probabilistic sensitivity analysis showed SOX had the highest probability (40.33%) of being the most cost-effective.ConclusionsAt a willingness-to-pay threshold of USD 100,000/QALY (Japan's HTA upper reference), SOX was identified as the most cost-effective first-line treatment for HER2-negative unresectable advanced or recurrent GC in Japan.

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