Vyloy (zolbetuximab)

CLDN18.2 will be an important target in GAC. Early understanding of how to target CLDN18.2 based on the level of expression (high, moderate, low) will be the key to success in this area. Studying these as separate entities should be considered. Resistance patterns, loss of CLDN18.2 expression, role in the refractory setting, and if any role in localized disease are questions that remain. Other targets for claudin that target claudin six and four are under investigation. Their role in GI malignancies will soon be further clarified.

P1, N=12, Not yet recruiting, Astellas Pharma Global Development, Inc.

P=N/A, N=18, Completed, Astellas Pharma Inc | Phase classification: P1 --> P=N/A

P2, N=393, Active, not recruiting, Astellas Pharma Global Development, Inc. | Recruiting --> Active, not recruiting

Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%...CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials...Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.

Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy...This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours.

Here, we review the exploration of CLDN18.2 as a target in GACs via the use of zolbetuximab (IMAB362). Zolbetuximab is now under priority FDA review for GACs, and we eagerly await the review outcome.

Among them, trastuzumab, as the first targeted drug for gastric cancer, effectively inhibits the proliferation and metastasis of tumor cells by targeting overexpressed HER2, and has become the standard treatment for HER2-positive gastric cancer patients. Ramucirumab, on the other hand, inhibits tumor angiogenesis by targeting VEGFR2 and has been used as second-line therapy for advanced gastric cancer patients. In addition, bemarituzumab targets overexpressed FGFR2, while zolbetuximab targets overexpressed CLDN18.2, significantly extending progression-free survival and overall survival in patients with gastric cancer in clinical trials. This article reviews the roles of tumor driver genes in the progression of gastric cancer; and the treatment strategies for gastric cancer based on targeting HER2, VEGF, FGFR2, CLDN18.2, MET and other tumor driver genes, aiming to provide reference for clinical application of targeted therapy for gastric cancer.

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.

This article summarizes the findings and implications of several important studies published over the past 2 years that are fundamentally changing the way we treat patients with gastroesophageal cancer.

Claudin 18.2 positive colorectal adenocarcinomas (26/576, 5%) are frequently MMR deficient (19/26, 73%) and demonstrate distinct histologic features. Future studies addressing efficacy of zolbetuximab therapy in this subset of colorectal cancers are needed.

For the overall survival (OS) analysis, no statistically significant differences were observed between pembrolizumab [hazard ratios (HR) = 1.00, 95% CI: 0.94-1.07], sintilimab (HR = 0.99, 95% CI: 0.89-1.09), sugemalimab (HR = 0.98, 95% CI: 0.87-1.10), tislelizumab (HR = 0.97, 95% CI: 0.87-1.09), zolbetuximab (HR = 0.98, 95% CI: 0.91-1.07), and nivolumab (HR = 1.00). In addition, anti-claudin-18.2-targeted therapies presented similar OS (HR = 0.99, 95% CI: 0.95-1.04) and PFS (HR = 1.01, 95% CI: 0.91-1.12) compared to immunotherapy, although their toxicity profiles were distinct. Our network meta-analysis showed no significant difference in PFS, OS, or ORR between different checkpoint inhibitors or between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers.

Recent phase III trials have unveiled the efficacy of Zolbetuximab, a CLDN18.2-targeting antibody, in combination with oxaliplatin-based chemotherapy for CLDN18.2-positive metastatic GC. This manuscript reviews the evolving role of CLDN18.2 as a biomarker in GC and explores the current status of CLDN18.2-targeting agents in clinical development. The aim is to provide concise insights into the potential of CLDN18.2 as a therapeutic target and guide future clinical decisions in the management of metastatic GC.

Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further...Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC.

Ongoing efforts to identify novel biomarkers in EGA have led to enhanced subclassification of upper GI cancers. These advances, coupled with the strategic application of targeted therapies and immunotherapy when appropriate, hold promise to further improve patients outcomes.

Recently, zolbetuximab has been proposed as a new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced and metastatic GC/EGJA...Accurate biomarker assessment is essential to ensure the best therapeutic option for patients. In the present review, we provide a comprehensive overview of available evidence on CLDN18.2 testing and its impact on the therapeutic management of patients with GC/EGJA, as well as some practical suggestions for CLDN18.2 staining interpretation and potential pitfalls in the real-world setting.

Trastuzumab (anti-HER2) is recommended in the first line in HER2-positive cancer. Ramucirumab (anti-VEGFR2) is recommended in the second line, in addition to paclitaxel chemotherapy. Zolbetuximab (anti-Claudine 18.2) should also be considered in the first line in Claudine 18.2-positive cancer...Important progress has been made in recent years in the treatment of gastric cancer, especially due to a better understanding of molecular characteristics and heterogeneity of this disease. New targets and therapeutic approaches are being developed, which will very likely lead to changes in the management of gastric cancer.

From these clinically meaningful results, CLDN18.2-targeting therapy including zolbetuximab has attracted a lot of attention. In this review, we summarize the clinical implications of CLDN18.2-positive gastric or GEJ cancer, and CLDN18.2-targeting therapy, mainly for zolbetuximab.

In gastric or gastroesophageal junction (GEJ) cancers, trastuzumab combined with first-line chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive patients and ramucirumab combined with second-line paclitaxel remarkably prolonged overall survival (OS) compared with chemotherapy alone, according to phase 3 trial results. Global phase Ⅲ trials revealed that the addition of zolbetuximab to first-line chemotherapy prolonged OS in CLDN18.2-positive and HER2-negative GC patients. This review summarizes recent clinical trials of CLDN18.2-targeted therapy.

Zolbetuximab, a first-in-class investigational monoclonal antibody (mAb) targeting tumor-associated antigen CLDN18.2 which is highly expressed on gastric cancer cells, was recently reported to meet the primary endpoint in Phase III trial as first-line treatment in CLDN18.2 positive and HER2-negative gastric cancers. Furthermore, PM1032 was generally well tolerated, with no significant abnormalities observed in toxicity studies, including the liver and stomach. In summary, PM1032 demonstrated good PK and an exceptional safety profile in rhesus monkeys supporting further investigation in clinical studies.

The expression characteristics of claudin 18.2 in NENs were characterized, which may provide a clinicopathological reference for targeted therapies in patients with NENs.

The clinical pharmacology of zolbetuximab was well characterized using data from 9 clinical trials. The integrated data support the proposed 800/600 mg/m2 Q3W regimen as well as an 800/400 mg/m2 Q2W regimen in combination with chemotherapy. Clinical trial information: NCT00909025, NCT01671774, NCT03528629, NCT04086758, NCT01197885, NCT01630083, NCT03505320, NCT03504397, NCT03653507.

A systematic literature review of phase 2, 3, or unknown phase randomized, global trials of 1L therapies (capecitabine + cisplatin [CX]; capecitabine + oxaliplatin [CAPOX]; fluorouracil + cisplatin [CF]; oxaliplatin + folinic acid + fluorouracil [FOLFOX]; S-1 + cisplatin [SC]; nivolumab + CAPOX/FOLFOX; pembrolizumab + CF/CAPOX or CX; and zolbetuximab + CAPOX/FOLFOX) in adults with LA unresectable or mG/GEJ adenocarcinoma... This NMA examined the relative benefit of different targeted therapies when combined with chemotherapy. Zolbetuximab + FOLFOX/CAPOX for CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma confers a significant PFS and OS benefit, similar to that achieved with PD-1/PD-L1 inhibitors + CF/CAPOX or FOLFOX/CAPOX. >*Based on pts in ITT populations regardless of PD-L1 CPS status.

In SPOTLIGHT, pts (N = 565) were randomized 1:1 to zolbetuximab + mFOLFOX6 vs PBO + mFOLFOX6... In SPOTLIGHT and GLOW, slower infusion rate and use of antiemetic combinations may have helped to mitigate N/V. These strategies will be important to support continued treatment and allow pts to achieve maximum clinical benefit with zolbetuximab + chemotherapy. Clinical trial information: NCT03504397 and NCT03653507.

Sponsored by No funding sources reported Background: Monoclonal antibody (Nivolumab, Trastuzumab, Bemarituzumab) with chemotherapy has shown benefit for patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. In summary, the use of Zolbetuximab alongside standard chemotherapy reduces mortality and disease progression, although it might increase the risk for grade ≥ 3 treatment-emergent AEs.

More recently, two monoclonal antibodies have demonstrated their efficacy in combination with oxaliplatin-based first-line chemotherapy, nivolumab (anti-PD1) for PD-L1 CPS ≥5 tumors, and zolbetuximab for tumors overexpressing Claudin 18.2. Recent years have seen the emergence of new drugs that have improved patient survival, such as trastuzumab in first-line for HER2-positive tumors, ramucirumab alone or in combination with paclitaxel in second-line, and trifluridine-tipiracil beyond the second-line treatment. Advanced gastric adenocarcinoma is a common disease with a poor prognosis whose treatment has for decades been based on cytotoxic chemotherapy, including platinum salts in first-line, and taxane or irinotecan in second or later line. In addition, regorafenib has been also showed effective in phase 3 trial for heavily pretreated patients. Based on phase 2 studies, trastuzumab-deruxtecan was approved in 2022 by the EMA for HER2-positive pretreated patients. This agent is currently evaluated in phase 3 study (DESTINY-Gastric04 trial), as are several other anti-HER2 (zanidatamab, margetuximab, tucatinib), immune checkpoint inhibitors, or targeted therapies (anti-FGFR2b).

Our findings suggest that FGFR2b-targeted therapy, specifically when used in combination with chemotherapy (bemarituzumab_chemo), exhibited the greatest efficacy. This was followed by immunotherapy-based combination regimens (CPS ≥5, Sintilimab_chemo). Further, targeted combination therapy featuring CLAUDIN 18.2 (zolbetuximab_chemo) appeared beneficial based on individual patient characteristics. In the case of HER2-positive patients, the trastuzumab_chemo regimen is recommended, as most existing studies have excluded this subpopulation. These results have significant implications for both clinical decision-making and patient care in the realm of advanced gastric or gastroesophageal cancer treatment.

CLDN18.2-targeted treatment with zolbetuximab in combination with chemotherapy has recently been assessed in two phase III studies of patients with HER2-negative, locally advanced, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma...It also failed to meet the threshold for accuracy and sensitivity when used on either the Dako or the Leica platforms. These results demonstrate the reliability of IHC testing for CLDN18 expression in gastric tumor samples, when using commercially available platforms with an appropriate methodology and primary antibody selection.

P2, N=143, Recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Jul 2024 --> Dec 2026 | Trial primary completion date: Apr 2024 --> Apr 2025

We explore the impact of monoclonal antibodies targeting HER2, VEGF, PD-1/PD-L1, and Claudin 18.2 (CLDN18.2) on the first-line treatment landscape by talking about key clinical trials. This review emphasizes the importance of biomarker testing for optimal treatment selection and provides practical recommendations based on ASCO guidelines.

Zolbetuximab plus chemotherapy was associated with higher risk of grade 3 and higher AEs, but was generally manageable. https://www.crd.york.ac.uk/prospero, identifier (CRD42023437126).

IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).

The GLOW randomized double-blind phase 3 trial shows that Claudin-18.2 targeting antibody zolbetuximab combined with capecitabine and oxaliplatin improves outcome compared to placebo and chemotherapy as first-line treatment in Claudin-18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas.

Methods Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (every 3 weeks) + mFOLFOX6 IV (D1, 15, 29) for four 42-day cycles or to PBO + mFOLFOX6; pts without progressive disease (PD) continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator's discretion, until PD or discontinuation criteria were met...Most common TEAEs with zolbetuximab + mFOLFOX6 were nausea (zolbetuximab arm: 82.4% vs PBO arm: 61.5%), vomiting (67.4% vs 36.3%), and decreased appetite (48.7% vs 34.9%); incidences of serious TEAEs were similar between arms (47.0% vs 46.4%). Conclusions With longer follow-up, zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant improvement in PFS and OS compared with PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a potential new option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma.

Background The phase 3 GLOW study showed statistically significant improvement with 1L zolbetuximab + capecitabine + oxaliplatin (CAPOX) vs placebo (PBO) + CAPOX in PFS (final; median 8.2 vs 6.8 mo, HR 0.69 [95% CI 0.54, 0.87], P = 0.0007) and OS (interim; median 14.4 vs 12.2 mo, HR 0.77 [95% CI 0.62, 0.97], P = 0.0118) in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. Most common TEAEs with zolbetuximab + CAPOX were nausea (zolbetuximab arm: 68.9% vs PBO arm: 50.2%), vomiting (66.1% vs 31.3%), and decreased appetite (41.3% vs 34.5%); incidences of serious TEAEs were similar between arms (48.0% vs 50.6%). Conclusions Zolbetuximab + CAPOX continued to demonstrate statistically significant improvement in PFS and OS compared with PBO + CAPOX, with no new safety signals, supporting zolbetuximab + CAPOX as a potential new option for 1L treatment of patients with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma.

The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies demonstrated clinically meaningful and statistically significant improvement in progression-free and overall survival with first-line (1L) zolbetuximab (anti-CLDN18.2) + chemotherapy (mFOLFOX6 or CAPOX, respectively) vs placebo + chemotherapy in pts with CLDN18.2+/HER2− disease...Conclusions A high CLDN18.2 prevalence rate (36.4%) was observed in the Asia region which was similar to the global prevalence observed in both the SPOTLIGHT and GLOW phase 3 studies. These data support the relevance of CLDN18.2 as a biomarker in Asian pts with LA unresectable or mG/GEJ adenocarcinoma, for whom zolbetuximab + chemotherapy represents a potential 1L therapy.

Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive G/GEJ adenocarcinoma. These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2 positive. Across cohorts, zolbetuximab treatment was tolerable with no new safety signals.

GLOW (NCT03653507) is a phase 3 global, double-blind study comparing zolbetuximab or PBO with capecitabine and oxaliplatin (CAPOX) as 1L treatment for this pt population... Targeting CLDN18.2 with zolbetuximab combined with CAPOX significantly prolonged PFS and OS in 1L pts with CLDN18.2+/HER2− LA unresectable or mG/GEJ adenocarcinoma. These results align with SPOTLIGHT and establish zolbetuximab + chemotherapy as a potential new standard-of-care option for these pts.

SPOTLIGHT (NCT03504397) is a phase 3 global, double-blind study comparing zolbetuximab + folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) vs placebo + mFOLFOX6 as 1L treatment for pts with CLDN18.2+/ HER2−, LA unresectable or mG/GEJ adenocarcinoma... Targeting CLDN18.2 with 1L zolbetuximab combined with mFOLFOX6 statistically significantly prolonged PFS and OS in pts with CLDN18.2+/HER2−, LA unresectable or mG/GEJ adenocarcinoma. TEAEs were consistent with previous studies. Zolbetuximab + mFOLFOX6 may be a new option for these pts.

Methods Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (every 3 weeks) + mFOLFOX6 IV (D1, 15, 29) for four 42-day cycles or to PBO + mFOLFOX6; pts without progressive disease (PD) continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator's discretion, until PD or discontinuation criteria were met...Most common TEAEs with zolbetuximab + mFOLFOX6 were nausea (zolbetuximab arm: 82.4% vs PBO arm: 61.5%), vomiting (67.4% vs 36.3%), and decreased appetite (48.7% vs 34.9%); incidences of serious TEAEs were similar between arms (47.0% vs 46.4%). Conclusions With longer follow-up, zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant improvement in PFS and OS compared with PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a potential new option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma.

Background The phase 3 GLOW study showed statistically significant improvement with 1L zolbetuximab + capecitabine + oxaliplatin (CAPOX) vs placebo (PBO) + CAPOX in PFS (final; median 8.2 vs 6.8 mo, HR 0.69 [95% CI 0.54, 0.87], P = 0.0007) and OS (interim; median 14.4 vs 12.2 mo, HR 0.77 [95% CI 0.62, 0.97], P = 0.0118) in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. Most common TEAEs with zolbetuximab + CAPOX were nausea (zolbetuximab arm: 68.9% vs PBO arm: 50.2%), vomiting (66.1% vs 31.3%), and decreased appetite (41.3% vs 34.5%); incidences of serious TEAEs were similar between arms (48.0% vs 50.6%). Conclusions Zolbetuximab + CAPOX continued to demonstrate statistically significant improvement in PFS and OS compared with PBO + CAPOX, with no new safety signals, supporting zolbetuximab + CAPOX as a potential new option for 1L treatment of patients with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma.