Decoding Approval: Moitreyee Chatterjee-Kishore from Astellas in an Exclusive Conversation with PharmaShots

Shots:

Recently EC granted Marketing Authorization to Astellas’ VYLOY (zolbetuximab) in combination with chemotherapy for the treatment of patients with advanced gastric and GEJ cancers

Zolbetuximab, a monoclonal antibody designed to target gastric tumor cells that express CLDN18.2 biomarker

Today, at PharmaShots we have Dr. Moitreyee Chatterjee-Kishore the Head of Development, Immuno-Oncology and Cancer Cell Therapy at Astellas in an exclusive dialogue exchange on the recent approval

Saurabh: Could you explain how zolbetuximab, when used alongside chemotherapy, offers a different approach compared to the current treatments for advanced gastric cancer? 

Moitreyee: Unlike many chemotherapies and treatments for gastric and gastroesophageal (GEJ) cancers which frequently have a systemic effect, zolbetuximab is a monoclonal antibody specifically designed to target gastric tumor cells that express the biomarker claudin 18.2 (CLDN18.2). CLDN18.2 is an important component of tight junction proteins that regulate tissue permeability, paracellular transport and signal transduction. Pre-clinical studies have shown that CLDN18.2 becomes more exposed and accessible to antibodies as gastric tumors develop.

In both the SPOTLIGHT and GLOW Phase 3 clinical trials, approximately 38% of patients screened had tumors that were CLDN18.2 positive, defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 immunohistochemical staining, assessed and confirmed using an in-vitro companion diagnostic test or medical device. As the first therapy to specifically target CLDN18.2, zolbetuximab offers a more targeted approach to cancer treatment. By binding to CLDN18.2 expressed on tumor cell membranes, zolbetuximab results in antibody-dependent cellular cytotoxicity, complement dependent cytotoxicity and tumor growth inhibition.

Saurabh: Could you share the key findings from the Phase 3 SPOTLIGHT and GLOW clinical trials that supported the European Commission’s approval of zolbetuximab? 

Moitreyee: Results from the Phase 3 clinical trial program have shown the benefits the targeted treatment zolbetuximab in combination with chemotherapy can offer to patients with locally advanced unresectable or metastatic HER-2 negative, CLDN18.2 positive gastric or GEJ cancers. Statistically significant improvements in progression-free survival (PFS) and overall survival (OS) were seen with zolbetuximab in combination with fluoropyrimidine- and platinum-containing chemotherapy compared to standard of care chemotherapies.

In the SPOTLIGHT trial, zolbetuximab was administered in combination with mFOLFOX6 and compared to placebo plus mFOLFOX6. Statistically significant improvements in PFS were achieved (median 10.61 months versus 8.67 months with zolbetuximab plus mFOLFOX6 compared to placebo plus mFOLFOX6 respectively), reducing the risk of progression or death by 24.9%. The median OS was 18.23 months versus 15.54 months, showing that zolbetuximab plus mFOLFOX6 reduced the risk of death by 25.0%.

Similar efficacy findings were seen in the GLOW trial when zolbetuximab was administered in combination with CAPOX. Statistically significant improvements in PFS were achieved (median 8.21 months versus 6.80 months with zolbetuximab plus CAPOX compared to placebo plus CAPOX respectively), reducing the risk of progression or death by 31.3%. The median OS was 14.39 months versus 12.16 months, showing that zolbetuximab plus CAPOX reduced the risk of death by 22.9%.

In both the SPOTLIGHT AND GLOW trials, the incidence of serious treatment emergent adverse events (TEAEs) was similar in the zolbetuximab treatment arm compared to the chemotherapy-only control arm. The most common all-grade TEAEs reported in the zolbetuximab treatment arms were nausea, vomiting and decreased appetite. Guidance to support clinicians with adverse event management, including recommendations on infusion rates, infusion interruptions and the administration of antiemetics which can particularly help to manage nausea and vomiting, will be provided in the treatment label and through healthcare professional educational resources.

Saurabh: What are some of the biggest challenges that patients with advanced gastric cancer face, and how does zolbetuximab help meet those needs? 

Moitreyee: Gastric and GEJ cancers have a very poor outlook. Often diagnosed at a late stage due to overlapping symptoms with more common conditions, the average five-year survival rate in Europe across all stages of the disease is only 26%. Gastric cancer is the sixth most common cause of cancer-related mortality in the European region, driving the need for new, effective and targeted therapeutic options that can slow disease progression and extend patients’ lives.

The Phase 3 clinical trial program for zolbetuximab showed that the treatment, in combination with chemotherapy, improved outcomes by successfully extending progression-free survival and overall survival in adult patients with locally advanced unresectable or metastatic HER-2 negative, CLDN18.2 positive gastric or GEJ cancers.

Saurabh: Could you talk about the collaboration between Astellas and Roche on the VENTANA® CLDN18 (43-14A) RxDx Assay and how it plays a role in treatment with zolbetuximab? 

Moitreyee: Astellas is collaborating with Roche on the VENTANA® CLDN18 (43-14A) RxDx Assay, an immunohistochemistry (IHC) based companion diagnostic (CDx) test for zolbetuximab. The test is intended to be used by a pathologist or laboratory to identify patients eligible for targeted treatment with zolbetuximab, specifically those with CLDN18.2 positive tumor status defined as ≥75% of tumor cells demonstrating moderate to strong membranous CLDN18 immunohistochemical staining.

Saurabh: With zolbetuximab having been approved in Japan earlier this year and now in Europe, what insights or lessons from the Japanese market could shape its introduction in the EU and other regions? 

Moitreyee: As the first approved CLDN18.2 monoclonal antibody, zolbetuximab has introduced a new targeted approach to the first-line treatment of advanced gastric and GEJ cancers. With any shift in treatment comes a need to educate clinicians and build familiarity. For example, we have been working to build clinician awareness of how to conduct testing for CLDN 18.2 in Japan to support identification of patients with advanced gastric or GEJ cancers who may be eligible for treatment.

Real-world clinical experience from Japan is also helping to optimize the care of patients treated with zolbetuximab, providing guidance on adverse event management to enable patients to gain the greatest benefits from treatment. The learnings from Japan will help to shape our launch plans for zolbetuximab across the European region and beyond, and will also better support patient care once regulatory approvals are received.

Saurabh: What are Astellas' plans for continuing research and development on zolbetuximab or similar targeted therapies for other cancers or medical conditions in the future? 

Moitreyee: Astellas continues to explore the unmet needs of patients with advanced gastric and GEJ cancer as a basis for further trials in this population.

Beyond gastric cancer, an expanded Phase 2 trial of zolbetuximab in metastatic pancreatic adenocarcinoma is currently in progress. The trial is a randomized, multi-center, open-label study, evaluating the safety and efficacy of investigational zolbetuximab in combination with gemcitabine plus nab-paclitaxel as a first-line treatment in patients with metastatic pancreatic adenocarcinoma with CLDN18.2 positive tumors.

The treatment of pancreatic adenocarcinoma is an area of significant unmet need where patient survival outcomes are particularly poor. The primary outcome of the trial is expected in 2025 and Astellas plans to share the results with the research community to advance understanding on the role of CLDN18.2 targeting in metastatic pancreatic cancer. More information on the study can be found at www.clinicaltrials.gov under the identifier NCT03816163.

Image Source: Canva

About the Author:

Moitreyee Chatterjee-Kishore

Dr. Moitreyee Chatterjee-Kishore is the Head of Development, Immuno-Oncology and Cancer Cell Therapy at Astellas. A seasoned pharmaceutical business leader and drug developer with more than 20 years of pharmaceutical experience, she previously was the

Head of Research and Early Development R&D Strategy and Planning at Bristol Myers Squibb and has also held important development and early pipeline leadership roles at Janssen, AbbVie and Wyeth and served as a research scientist at the research institutes such as the Cleveland Clinic Foundation and Friedrich Miescher Institut. She has led programs across a breadth of modalities, platforms and therapy areas from the discovery through late phase clinical development, but her primary experience is in oncology and immune-oncology. Dr. Moitreyee Chatterjee-Kishore holds a Ph.D. in Medical Genetics from the Sanjay Gandhi Post Graduate Institute of Medical Sciences and a MBA from Purdue University Daniels School of Business.