ESMO 2023: Novel Treatment Options Demonstrate a Growing Impact in Solid Tumor Research

During the annual meeting of the European Society for Medical Oncology (ESMO Congress 2023), held in Madrid, Spain, from October 20-24, 2023, Jazz Pharmaceuticals, along with its corporate partners, will present six abstracts including data from trials of bispecific antibody zanidatamab and Zepzelca^® (lurbinectedin), as well as the study design for a Phase 1 trial of the pan-RAF inhibitor JZP815.

Among the results to presented is updated data from Zanidatamab, a humanized, bispecific monoclonal antibody directed against two non-overlapping domains of HER2, demonstrating clinical potential in HER2-targeted biliary tract and gastric cancers. The investigational agent is being developed by Jazz and BeiGene under a license agreements from Zymeworks, which first developed the molecule.

This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients.

Additional presentations, including a lurbinectedin oral presentation in small cell lung cancer (SCLC), underscore the strength of Jazz’s solid tumor portfolio and the company’s commitment to address difficult-to-treat tumors

Compelling data
“The compelling data being presented at ESMO by Jazz and partners, in particular for zanidatamab in biliary tract and gastric cancers, demonstrate the clinical potential of our solid tumor oncology development programs to raise the standard of care for some of the most difficult-to-treat cancers,” explained Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals.

“Through our expanding research in solid tumors – including targeted therapies and immuno-oncology – Jazz is advancing novel investigational therapies that target specific proteins like HER2 and important signaling pathways such as the RAS-RAF-MAPK pathway,” Iannone added.

Key presentations

• A poster presentation featuring progression-free survival (PFS) and duration of response (DoR) results from a Phase 1b/2 study of zanidatamab plus chemotherapy in combination with tislelizumab for the first-line treatment of HER2-positive gastric/gastroesophageal junction adenocarcinoma (G/GEJC). The study, sponsored by BeiGene, showed zanidatamab plus chemotherapy and tislelizumab produced antitumor activity with a confirmed objective response rate (ORR) of 75.8% and median PFS of 16.7 months; and safety was consistent with previous findings.[1]
• A poster presentation featuring health related quality-of-life (hrQoL) data from a Phase 2b study of zanidatamab for the second-line treatment of HER2-amplified biliary tract cancers (BTC), finding that patients with HER2-positive BTC who responded to zanidatamab reported improved health-related quality of life (HRQoL) compared with baseline. Overall, zanidatamab led to a meaningful clinical benefit, which may reduce disease burden and potentially result in improved patient HRQoL compared with baseline.[2]
• A mini oral presentation highlighting results of the Phase 1/2 LUPER study evaluating the efficacy of lurbinectedin (Zepzelca^®; Jazz Pharmaceuticals under license from PharmaMar)* in combination with pembrolizumab for the second-line treatment of small cell lung cancer (SCLC), which includes the following data: preliminary ORR of 46.4%, median DoR of 11.4 months, median PFS of 5.3 months and median OS of 11.1 months; the combination resulted in a manageable safety profile.[3]  The investigational agen is an alkylating drug that binds guanine residues within DNA. This triggers a cascade of events that can affect the activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in disruption of the cell cycle and eventual cell death.
• During the upcoming ESMO Congress 2023, results from an open-label, first-in-human (FIH) study of JZP815 will be presented. JZP815 is an investigational pan-RAF kinase inhibitor that was discovered and developed using state-of-the-art screening methodologies and medicinal chemistry. The investigational drug targets specific components of the mitogen-activated protein kinase (MAPK) pathway that, when activated by oncogenic mutations, can be a frequent driver of human cancer. JZP815 potently inhibits both monomer- and dimer-driven RAF signaling (e.g., RAS-induced), prevents paradoxical pathway activation induced by BRAF selective inhibition, and is active against class 1, class 2, and class 3 BRAF mutants, as well as BRAF fusions and CRAF mutants.

The Presentations include:

Note: * The FDA approved lurbinectedin under accelerated approval in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The approval is based on overall response rate (ORR) and duration of response demonstrated in an open-label, monotherapy clinical study. In December 2021, Jazz and PharmaMar announced the initiation of LAGOON, a confirmatory Phase 3 clinical trial of lurbinectedin for the treatment of patients with relapsed small cell lung cancer. If positive, LAGOON could confirm the benefit of lurbinectedin in the treatment of small cell lung cancer (SCLC) when patients progress following 1L treatment with a platinum-based regimen and support full approval in the U.S.

Highlights of prescribing information
Lurbinectedin (Zepzelca^®; Jazz Pharmaceuticals under license from PharmaMar) [Prescribing information]

References:
[1] Lee K, et al. Zanidatamab (zani) plus chemotherapy (chemo) and tislelizumab (TIS) as first-line (1L) therapy for patients (pts) with advanced HER2-positive (+) Gastric/gastroesophageal junction adenocarcinoma (GC/GEJC): updated results from a phase 1b/2 study. European Society for Medical Oncology. 2023.
[2] Wasan H, et al. Quality of life (QoL) outcomes in patients (pts) with zanidatamab (zani)-treated HER2-positive (HER2+) biliary tract cancer (BTC) in the Phase 2b HERIZON-BTC-01 study. European Society for Medical Oncology. 2023.
[3] Calles A, et al. Lurbinectedin (LUR) in combination with pembrolizumab (PBL) in relapsed small cell lung cancer (SCLC): the phase 1/2 LUPER study. European Society for Medical Oncology.  2023.

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