PharmaShots Interview: Astellas' Dr. Andrew Krivoshik Shares Insights on P-II FAST Study of Zolbetuximab

In an interview with PharmaShots, Dr. Andrew Krivoshik, Senior Vice President and Oncology Therapeutic Area Head at Astellas, shared his views on the P-II FAST study result published in the journal Gastric Cancer and highlights the data published in Annals of Oncology.

Shots:

The data from P-II FAST study evaluating zolbetuximab + EOX in 1L patients with advanced gastric and GEJ cancer were published in peer-reviewed journals, Gastric Cancer and Annals of Oncology
PROs data were published in the Gastric Cancer that determine health related QoL and symptom burden related to treatment with zolbetuximab + EOX
The primary results of P-II FAST study including the data of PFS and OS in patients with advanced CLDN18.2-positive gastric and GEJ cancers were published in Annals of Oncology

Tuba: Discuss the study design of Astellas P-II FAST Study.

Andrew: The FAST study was a randomized, multi-center, open-label study, which evaluated the efficacy and safety of zolbetuximab, an investigational anti-claudin 18.2 (CLDN18.2) monoclonal antibody, in combination with epirubicin, oxaliplatin, and capecitabine (EOX) in first-line patients with advanced gastric and gastroesophageal junction (GEJ) cancer. The study was conducted at 49 centers across six countries (primarily Eastern Europe and Russia). Patients over the age of 18 years were eligible if they had histologically confirmed, locally advanced, inoperable, recurrent, or metastatic gastric, GEJ, and esophageal cancer that was positive for CLDN18.2 and was assigned to receive either EOX or zolbetuximab plus EOX. The primary endpoint was progression-free survival (PFS), with overall survival (OS) as a secondary endpoint.

Tuba: What are the key points of PRO published in the journal Gastric Cancer?

Andrew: Patient-reported outcomes (PROs) from the phase 2 FAST study were analyzed to determine health-related quality of life and symptom burden related to treatment with zolbetuximab plus EOX.

Tuba: Why is studying the health-related quality of life important in gastric cancer?

Andrew: Maintaining a good health-related quality of life and low symptom burden is essential in gastric cancer, where survival is very short, and the disease burden is high.

Tuba: Highlight the data published in the journal Annals of Oncology and the investigational findings of the FAST study thus far.

Andrew: The data published in the Annals of Oncology highlighted PFS and OS data from the Phase 2 FAST study in patients with advanced gastric and GEJ cancer that was positive for CLDN18.2. The publication analyzed both the overall population and patients with moderate-to-strong CLDN18.2 expression in =70% of tumor cells.

Across all patients, there was a statistically significant reduction in the risk of a PFS event following treatment with zolbetuximab plus EOX versus EOX (HR=0.44; 95% CI: 0.29-0.67) and median PFS was 7.5 months with zolbetuximab plus EOX and 5.3 months with EOX alone. In patients with moderate-to-strong CLDN18.2 expression in =70% of tumor cells, median PFS was 9 months in patients treated with zolbetuximab plus EOX and 5.7 months in patients treated with EOX.

Treatment with zolbetuximab plus EOX was also associated with a longer median OS and statistically significant reduction in the risk of death (HR=0.55; 95% CI, 0.39-0.77). Across all patients, the median OS was 13.0 months for the zolbetuximab plus EOX arm compared to 8.3 months with EOX alone. In the population with moderate-to-strong CLDN18.2 expression in =70% of tumor cells group, the median OS was 16.5 months for patients treated with zolbetuximab plus EOX compared to 8.9 months with EOX alone.

The most common adverse events (AEs; =10%) that occurred more frequently in patients treated with zolbetuximab and EOX were nausea, vomiting, anemia, neutropenia, weight loss, fatigue, alopecia, asthenia, decreased appetite, abdominal pain, thrombocytopenia, palmar-plantar syndrome, paresthesia, peripheral edema and increased gamma-glutamyltransferase (GGT).

Tuba: Why do you think targeting the claudin pathway would be an effective way of treating GEJ and gastric adenocarcinomas?

Andrew: Claudins are a family of tight junction molecules involved in the regulation of permeability, barrier function, and polarity of epithelial layers.[i] Claudin 18.2 is a gene variant of claudin-18, whose expression is associated with tumor development and progression.[ii] Studies have shown a significant portion of gastric tumors have a high expression of Claudin 18.2.[iii]

Zolbetuximab is an anti-CLDN18.2 monoclonal antibody, which is thought to bind to Claudin 18.2 on the surface of tumor cells and is thought to induce cancer cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.[iv]

The Phase 2 study met its primary endpoint and based on clinical results observed in the overall population and patients with moderate-to-strong CLDN18.2 expression in =70% of tumor cells, Astellas is currently evaluating zolbetuximab in phase 3 studies.

Tuba: How this therapy is unique from the competitor therapies available in the market or the clinical phase?

Andrew: There are no head-to-head clinical trials comparing zolbetuximab to other investigational therapies. Comparisons cannot be made due to differences in trial populations and designs for each treatment.

However, we are encouraged by the Phase 2 FAST study results and look forward to evaluating the zolbetuximab through our ongoing phase 3 studies.

Tuba: When can we expect the launch of this product in the US, EU, and other geographies?

Andrew: Phase 3 studies surrounding zolbetuximab's potential in CLDN18.2-positive gastric cancer are ongoing. We plan to discuss the results with relevant global health authorities once the data becomes available.

Tuba: Is there anything else from this study that you would like to highlight with our readers?

Andrew: Gastric cancer can be aggressive with a high mortality rate only 6% of people whose cancer has spread to a distant part of the body will survive five years post-diagnosis and there is a need for effective targeted therapies for patients that are HER2-negative. [v] Astellas is committed to exploring the potential of zolbetuximab and CLDN18.2 as a predictive biomarker in these cancers and looks forward to sharing future research surrounding this investigational therapy.

References:

[i] Ding L., Lu Z., Lu Q., Chen Y.H., The claudin family of proteins in human malignancy: a clinical perspective. Cancer Manag Res. 2013; 5: 367-375

[ii] Niimi, Tomoaki, et al. 'Claudin-18, a Novel Downstream Target Gene for the T/EBP/NKX2.1 Homeodomain Transcription Factor, Encodes Lung- and Stomach-Specific Isoforms through Alternative Splicing. 'Molecular and Cellular Biology, vol. 21, no. 21, 2001, pp. 7380'7390., doi:10.1128/mcb.21.21.7380-7390.2001.

[iii] Sahin U. Koslowski M. Dhaene K. et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008; 14: 7624-7634

[iv] O. Türeci, U. Sahin, H. Schulze-Bergkamen, Z. Zvirbule, F. Lordick, D. Koeberle, P. Thuss-Patience, T. Ettrich, D. Arnold, F. Bassermann, S.E. Al-Batran, K. Wiechen, K. Dhaene, D. Maurus, M. Gold, C. Huber, A. Krivoshik, A. Arozullah, J.W. Park, M. Schuler, A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower esophagus: the MONO study, Annals of Oncology, vol. 30, no. 9, 2019, pp. 1487-1495, ISSN 0923-7534

[v] Stomach Cancer - Statistics. Cancer.Net, American Society of Clinical Oncology, Jan. 2020, www.cancer.net/cancer-types/stomach-cancer/statistics.

About Author:

Andrew Krivoshik is the Senior Vice President and Oncology Therapeutic Area Head at Astellas with success in leading global multi-disciplinary cross-functional teams to bring new medicines to oncology patients. Krivoshik has expertise in global clinical development including authoring and implementing novel and innovative clinical trial designs and regulatory submissions spanning the life cycle of clinical development and has been an invited speaker and session chair at international scientific congresses. He and his team have successfully submitted multiple NDA and BLA applications leading to the approvals of new oncology medicines.