Metastatic HER2-negative gastric and gastroesophageal junction (GEJ) adenocarcinoma is notoriously difficult to treat and has a significant unmet need for new efficacious treatments. In contrast to HER2-positive disease (for which HER2-targeted agents such as trastuzumab [Genentech] and ENHERTU® [Daiichi Sankyo] are available), targeted treatment options are more limited for HER2-negative patients. Zolbetuximab would address some of that unmet need as a first-in-class claudin 18.2 (CLDN18.2) inhibitor in oncology as well as first-line metastatic HER2-negative gastric or GEJ adenocarcinoma. CLDN18.2 was found to be highly expressed in ~38% of HER2-negative gastric cancer patients in two phase 3 trials (SPOTLIGHT and GLOW). Zolbetuximab also has the potential to treat pancreatic cancer, in which 50% of cases have CLDN18.2 expression.


  1. Astellas Pharma Inc
  2. CLDN18.2-targeted mAb
  3. Intravenous infusion every three weeks (in combination with chemotherapy) for previously untreated HER2-negative, CLDN18.2-positive unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma
  4. Also being investigated to treat pancreatic cancer
  5. ~88K new cases of previously untreated metastatic HER2-negative gastric or GEJ adenocarcinoma in the G7 markets in 2023

Why is it a drug to watch?

Claudin 18.2 (CLDN18.2) has emerged as an exciting target to treat gastric cancers because alterations in claudin expression can affect signaling pathways and help promote tumors. Zolbetuximab is poised to be the first-in-class CLDN18.2 inhibitor to enter the oncology market and to offer a much-needed biomarker-driven option for first-line treatment of metastatic HER2-negative gastric or GEJ adenocarcinoma. Regulatory submissions were based on the positive results from two phase 3 trials conducted in previously untreated CLDN18.2-positive, HER2-negative, unresectable locally advanced or metastatic gastric or GEJ adenocarcinoma:

  1. SPOTLIGHT: first-line zolbetuximab plus mFOLFOX6 (combination chemotherapy with oxaliplatin, leucovorin and fluorouracil) vs placebo plus mFOLFOX6
  • 24.9% reduction in the risk of progression or death (vs control)
  • Median progression-free survival (PFS) of 10.6 months (vs 8.7 months with control)
  • 25.0% reduction in the risk of death (vs control)
  • Median overall survival (OS) of 18.2 months (vs 15.5 months with control)
  1. GLOW: first-line zolbetuximab plus CAPOX (combination chemotherapy with capecitabine and oxaliplatin) vs placebo plus CAPOX
  • 31.3% reduction in the risk of progression or death (vs control)
  • Median PFS of 8.2 months (vs 6.8 months with control)
  • 22.9% reduction in the risk of death (vs control)
  • Median OS of 14.4 months (vs 12.2 months with control)

The incidence of serious treatment-emergent adverse events (TEAEs) in both studies was similar between the groups and consistent with previous studies.

Review and
approval status

November 2010

  • Orphan drug designation: EMA

November 2012

  • Orphan drug designation: U.S. FDA

September 2022

  • Fast Track designation: U.S. FDA

June 2023

  • MAA accepted: EMA
  • BLA filed: Japan PMDA

July 2023

  • Priority Review granted: U.S. FDA
  • BLA accepted: Mainland China NMPA

January 12, 2024

  • PDUFA date

Expected launch:

  • 2024: European Union, Japan, Mainland China, United States

Patents estimated to expire beginning in 2032

How will zolbetuximab impact the market for gastric and GEJ adenocarcinomas?

  1. There are approximately one million new cases of gastric cancer diagnosed annually worldwide, representing a sizable market.
  2. Approximately 75% of all gastric cancer diagnoses are in Asia, and Japan is a significant market in this setting.
  3. The treatment of gastric cancer remains largely dominated by non-targeted therapies, and platinum/fluoropyrimidine-based chemotherapy regimens remain the standard of care.
  4. The first-line metastatic HER2-negative gastric and GEJ adenocarcinoma drug-treatable patient population is the largest in gastroesophageal cancer, yet HER2-negative patients have fewer treatment options than their HER2-positive counterparts. Therefore, a large commercial opportunity exists for novel agents in the HER2-negative setting.
  5. Zolbetuximab is being evaluated in combination with chemotherapies already commonly used in gastric and GEJ cancer (mFOLFOX6, CAPOX). The demonstration of clear and unequivocal (albeit numerically modest) OS improvements over chemotherapy alone in the two phase 3 trials would likely support rapid uptake for appropriate patients.
  6. Immunohistochemistry testing for CLDN18.2 will be needed to treat with zolbetuximab, but ~38% of gastric cancer patients could be eligible, which would translate into a sizeable market opportunity.

What gaps in treatment does zolbetuximab fill?

Early-stage gastric cancer symptoms frequently overlap with more common stomach-related conditions. As result, gastric cancer is often diagnosed in the advanced or metastatic stage when it has spread to other body tissues or organs. The five-year relative survival rate for patients at the metastatic stage is 6.6%. Despite approvals of targeted therapies and immunotherapies, improving survival in gastric cancer remains a critical unmet need as few patients survive more than 2 years after initiation of front-line therapy. In addition, metastatic HER2-negative gastric or GEJ adenocarcinoma is notoriously difficult to treat. CLDN18.2 has emerged as a promising target for treating gastric cancers, and zolbetuximab could be an important new option in the largely untapped HER2-negative gastric and GEJ adenocarcinoma market segment.

What hurdles might it need to overcome to reach blockbuster status?

  1. The uptake of zolbetuximab will hinge upon wide adoption of CLDN18.2 testing, a biomarker that is not yet integral to diagnostic workups, in routine clinical practice. Increased awareness and education on CLDN18.2 testing will help mitigate this risk.
  2. Several other therapies targeting CLDN18.2 are in clinical development, a few of which were acquired in blockbuster deals. Some of these candidates offer a different modality than mAbs like zolbetuximab, such as antibody-drug conjugates or bispecific agents. If approved, these therapies would be unwelcome competitors for zolbetuximab:
  • TST-001 (osemitamab; Transcenta Therapeutics Co Ltd)
  • ASKB-589 (AskGene Pharma Inc)
  • CMG901 (AstraZeneca)
  • SYSA-1801 (EO-3021; Elevation Oncology Inc)
  • TJ-CD4B (ABL111; I-Mab)
  • TPX-4589 (LM-302; Turning Point Therapeutics)
expected sales in G7 countries for 2029
probability of success for metastatic stomach cancer in the U.S.
Source: Cortellis Competitive Intelligence, Drug Timeline & Success Rates Prediction current as of December 15, 2023

Drug Timeline &
Success Rates

– Source: Cortellis Competitive Intelligence, Drug Timeline & Success Rates Prediction current as of December 15, 2023

Drugs to Watch 2024

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