Zongertinib is an investigational drug for cancer treatment that belongs to a class of medicines known as tyrosine kinase inhibitors (TKIs). TKIs are designed to interfere with specific cellular processes that fuel cancer growth. This drug is in advanced clinical development, with a primary focus on treating certain forms of non-small cell lung cancer (NSCLC).
Zongertinib’s Mechanism of Action
Zongertinib functions as a highly specific tyrosine kinase inhibitor. Tyrosine kinases are enzymes that act as on/off switches for many cellular functions, including cell growth and division. They add a phosphate group to proteins in a process called phosphorylation, which activates or deactivates them. In some cancers, mutations cause these enzymes to become stuck in the “on” position, leading to uncontrolled cell proliferation.
This drug specifically targets human epidermal growth factor receptor 2 (HER2) and, to a lesser extent, epidermal growth factor receptor (EGFR). It works by selectively binding to the site on these mutated kinase enzymes where their energy source, ATP, would normally attach. By blocking this site, zongertinib prevents phosphorylation from occurring, shutting down the signaling pathways that tell cancer cells to grow and survive. This targeted approach allows it to inhibit cancer cells while minimizing damage to healthy cells.
Unlike some other inhibitors that block all members of this enzyme family, zongertinib is highly selective for HER2. This selectivity is a notable feature because it spares the wild-type, or non-mutated, EGFR. By avoiding inhibition of normal EGFR, it aims to reduce certain side effects commonly associated with less selective drugs.
Cancers Targeted by Zongertinib
The main focus for zongertinib’s development is a specific subtype of non-small cell lung cancer (NSCLC). It is intended for patients whose tumors have specific mutations in the HER2 gene, found in approximately 2-4% of NSCLC cases. These mutations are most often located in a region of the gene known as exon 20 and involve the insertion of extra genetic material.
This specific type of mutation, an exon 20 insertion, results in an altered HER2 protein that promotes aggressive cancer growth. Tumors with these mutations have historically been difficult to treat and often show poor responses to chemotherapy and immunotherapy. Zongertinib is designed to address this challenge by inhibiting the mutated HER2 enzyme driving the cancer’s growth.
While its primary indication is for this subset of lung cancer, the drug has also been studied in other advanced or metastatic solid tumors that harbor HER2 alterations. Preclinical studies have suggested potential activity in other cancer types, but the most robust clinical data has been generated in patients with previously treated, HER2-mutated NSCLC.
Clinical Trial Performance
Zongertinib’s performance was evaluated in clinical studies, most notably the Phase Ia/Ib BEAMION LUNG-1 trial. This study assessed the drug’s safety and efficacy in patients with advanced solid tumors harboring HER2 alterations, with a focus on those with NSCLC. The trial explored different dosing schedules to find a balance between effectiveness and tolerability.
In the trial, zongertinib demonstrated antitumor activity. The overall response rate (ORR), the percentage of patients whose tumors shrank, was 30% across all tumor types. For the 54 patients with NSCLC, the ORR was 35%. These responses were also durable, with a median duration of response lasting 12.7 months.
These results are notable for patients with HER2-mutated NSCLC, a population with limited effective treatment options. The drug showed activity even in patients who had previously received other HER2-directed therapies. The median progression-free survival, the time patients lived without their cancer worsening, was 17.2 months for NSCLC patients on the once-daily dose.
Known Side Effects
Like most cancer therapies, treatment with zongertinib is associated with side effects, or treatment-related adverse events (TRAEs). These effects are consistent with other drugs in the tyrosine kinase inhibitor class. The most frequently reported TRAEs included:
- Diarrhea
- Rash
- Anemia (a low red blood cell count)
- Decreased appetite
- An increase in liver enzymes
The majority of these side effects were reported as mild to moderate. In the BEAMION LUNG-1 study, diarrhea was the most common event, occurring in 50% of patients, but only 1% of cases were severe. Rash was observed in 16% of patients, with 2% experiencing a severe form. These common side effects are managed with supportive care or by adjusting the dose of zongertinib.
The safety analysis showed a relatively low rate of severe side effects. Across the study population, severe TRAEs occurred in about 10% of patients. This manageable safety profile is attributed to the drug’s selectivity for HER2 while sparing normal EGFR, which is often implicated in these specific toxicities.