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Anti-CLDN18.2 ADC

CompoundSonesitatug vedotin (AZD0901)

Area under investigation

Advanced solid tumors, Gastric/GEJ cancer, Pancreatic cancer

Scientific PillarAntibody-Drug Conjugates

Target Overview

Claudin 18 is a trans-membrane protein and is an important component of the tight junction complexes that regulate cell-cell adhesion, cell permeability, and cell polarity. Alternative splicing of Claudin 18 transcripts results in 2 isoforms: CLDN18.1, which is expressed in the lung and CLDN18.2, which is restricted to the gastric epithelium. In normal tissues, CLDN18.2 expression is restricted to the gastric mucosa. In tumor tissues, CLDN18.2 is widely overexpressed in a variety of cancers such as gastric cancer (GC), gastroesophageal junction cancer (GEJC), pancreatic ductal adenocarcinoma (PDAC), and adenocarcinoma of esophagus.1

Compound Overview

Sonesitatug vedotin (AZD0901) is an ADC that consists of a humanized monoclonal antibody against CLDN18.2, conjugated to a potent microtubule inhibitor, monomethyl auristatin E (MMAE) via a protease cleavable linker.

Sonesitatug vedotin is designed to target and deliver the cytotoxic agent, MMAE, inside cancer cells that express CLDN18.2 and reduce systemic exposure to the cytotoxic payload compared to the way chemotherapy is commonly delivered.

The released MMAE payload also exerts bystander antitumor activity through cytotoxic activity in both the target cells and neighboring tumor cells, owing to its high cell membrane permeability.

Mechanism of Action

  • Mechanism of Action

References

1. Sahin U, Koslowski M, Dhaene K, et al. Clin Cancer Res. 2008;14(23):7624-7634.

 

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CLARITY-Gastric01 trial overview

Tumor

Advanced or metastatic gastric or GEJ adenocarcinoma expressing Claudin18.2, ≥2L

Trial Identifier

NCT06346392

Phase

III

Regimen

Sonesitatug vedotin (different doses); investigator's choice of chemotherapy

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Study Design

Inclusion criteria

The key inclusion criteria1,2 are-

  • Age ≥18 years
  • Histologically confirmed unresectable, locally advanced or metastatic GC/GEJC (adenocarcinoma of the gastric, gastroesophageal junction or distal esophagus) with positive CLDN18.2 expression
  • Disease progression on or after ≥ 1 prior regimen for advanced or metastatic disease, which included a fluoropyrimidine and a platinum-based chemotherapy
  • ⩾1 measurable or evaluable lesion assessed by the investigator, based on RECIST version 1.1
  • ECOG PS of 0 or 1

References:

1. Study NCT06346392. ClinicalTrials.gov website.

2. Shitara K, et al. Poster presented at: ESMO Gastrointestinal Cancers (ESMO GI) Congress; June 26-29, 2024; Poster #495TiP.

Exclusion criteria

The key exclusion criteria1,2 are-

  • Known HER2-positive status (per local HER2 testing)
  • Significant or unstable gastric bleeding and/or untreated gastric ulcers
  • Central nervous system (CNS) metastases or CNS pathology
  • Prior exposure to any MMAE-based ADC and any CLDN18.2-targeted agents, except anti-CLDN18.2 monoclonal antibodies
  • Persistent toxicities (Common Terminology Criteria for Adverse Events Grade ⩾2) caused by previous anticancer therapy, Grade ⩾2 peripheral neuropathy at screening and history of thromboembolic events
  • Known clinically significant corneal disease (eg, active keratitis or corneal ulcerations)

CLARITY-Gastric01 Overview Modal

CLARITY-Gastric01 trial overview

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Abbreviations

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  • 1L

    first line

  • 5-FU

    5-fluorouracil

  • ADA

    anti-drug antibodies

  • ADC

    antibody drug conjugate

  • CAPOX

    capecitabine and oxaliplatin

  • CLDN18.1

    Claudin 18.1 isoform

  • CLDN18.2

    Claudin 18.2

  • CPS

    combined positive score

  • CNS

    central nervous system

  • CTCAE

    Common Terminology Criteria for Adverse Events

  • DoR

    duration of response

  • DNA

    deoxyribonucleic acid

  • DPD

    dihydropyrimidine dehydrogenase

  • ECOG

    eastern cooperative oncology group

  • EAC

    esophageal adenocarcinoma

  • FLOT

    docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil

  • FOLFOX

    5-fluorouracil, leucovorin, and oxaliplatin

  • GC

    gastric cancer

  • GEJ

    gastroesophageal junction

  • GEJC

    gastroesophageal junction cancer

  • GI

    gastrointestional

  • HBV

    Hepatitis B Virus

  • HER2

    human epidermal growth factor receptor 2

  • HIV

    human immunodeficiency virus

  • ICF

    informed consent form

  • ICI

    immune checkpoint inhibitor

  • IHC

    immunohistochemistry

  • MMAE

    monomethyl auristatin E

  • ORR

    objective response rate

  • OS

    overall survival

  • PD-L1

    programmed death-ligand 1

  • PFS

    progression-free survival

  • PK

    pharmacokinetic

  • PO

    per oral (by mouth)

  • PROs

    patient-reported outcomes

  • RECIST

    Response Evaluation Criteria in Solid Tumors

  • T-DXd

    fam-trastuzumab deruxtecan-nxki in US only; trastuzumab deruxtecan in other regions of world

Some compounds herein refer to selected AstraZeneca pipeline products still under development. AstraZeneca pipeline products are investigational products and, as such, are not approved by the US Food & Drug Administration (FDA), the European Medicines Agency (EMA) or any other regulatory agency for the uses under investigation. Information regarding these investigational products should, under no circumstances, be regarded as a recommendation for their use or of their safety or efficacy.

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Veeva ID: Z4-84958 US-109129 DE-92568 Last Updated October 20263/26
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