Targeting HER2 in cancer: The story of zongertinib

According to the World Health Organization, 2.21 million people were diagnosed with lung cancer in 2020, making it the second most common cancer worldwide ¹. Non-small cell lung cancer (NSCLC) accounts for the majority of cases (85%). Among these, 2 to 4% harbor HER2 mutations ^2,3. There remains a high unmet for these patients as they may respond poorly to the current standards of care, including chemotherapy and immunotherapy ^3,4.

HER2 in Cancer

The human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family of tyrosine kinase receptors. These are proteins that are expressed at the surface of cells and activate signaling pathways involved in cell growth and survival ⁵. Alterations in the HER2 gene, including mutation, amplification and overexpression, can turn the HER2 protein into a cancer driver - triggering uncontrolled cell proliferation, inhibiting cell death, and promoting tumor growth and spread ⁶.

Currently available small molecule inhibitors targeting the ErbB family, known as tyrosine kinase inhibitors (TKIs), are limited by poor potency and selectivity - they can bind to HER2 but also to other ErbB family members, such as EGFR (epidermal growth factor receptor) ⁷. Experience from the clinic has shown that inhibiting wild-type/non-mutated EGFR leads to adverse events. These can be so severe that they limit the amount of drug a patient can take, making treatment less effective or even ineffective in patients with certain mutations ⁸. More specifically, HER2 exon 20 insertion mutations, which are the most common type of HER2 mutations, have proven to be extremely challenging to drug. 

“Making molecules that serve a purpose”

Birgit Wilding, Scientific Director in Medicinal Chemistry and her team at Boehringer Ingelheim in Vienna focus on discovering small molecules that inhibit disease causing proteins, such as HER2. “Arguably the biggest challenge in kinase drug discovery is to obtain high selectivity among kinase family members. In this case, the high similarity between HER2 and EGFR, makes it particularly challenging. But our efforts and dedication led us to identify a single amino acid that is different in the compound binding pocket of HER2 and EGFR, and designed compounds addressing this amino acid to achieve selectivity over wild-type EGFR.” explains Wilding. 

“Very early in my career I realized that I enjoy making molecules that serve a purpose. Knowing that a compound we designed, synthesized and tested as a team, can potentially help patients in the clinic is massively motivating” tells Wilding.

On the cusp of discovery: When chemistry meets biology

In drug discovery, chemistry and biology are disciplines that work hand in hand - they provide continuous feedback to each other until a compound has been fully optimized from a pre-clinical perspective. Ralph Neumüller, Head of Cancer Cell Signaling at Boehringer Ingelheim in Vienna, co-led the research team with Birgit Wilding. His team was responsible for the biological aspects of the project, including looking at how specifically a compound inhibits tumor cells (specificity) and how effectively (potency). 

“For targeted therapy, we need quality compounds with a clean profile – the molecule must spare normal cells and inhibit tumor cells dependent on HER2. In addition, it needs to inhibit tumor growth in pre-clinical models and must be optimized for usage in humans. Once all these requirements are met, a molecule can enter the next phase – which is preparation for clinical development. Our goal is to hand over a molecule that, from a pre-clinical standpoint, is ready for clinical development.” explains Neumüller. 

Together, the teams discovered two compounds with such potential. One made it to the clinic. Now known as zongertinib, our investigational HER2 TKI, can specifically bind to the tyrosine kinase domain of both wild-type and mutated HER2 receptors, including difficult-to-target exon 20 insertion mutations. At the same time, it can spare wild-type EGFR signaling ⁷. 

“A culture of trust has been essential to working successfully in a multi-disciplinary project. Trust fosters empowerment, which ultimately facilitates problem-solving and enables data-driven decision-making. The commitment of everyone involved to deliver a high-quality molecule that potentially addresses unmet patient needs was truly remarkable.” adds Neumüller.

Zongertinib is currently being investigated in a phase III clinical trial (Beamion LUNG-2: NCT06151574). Based on encouraging early signals, we increased our efforts to accelerate its development.  

By being innovative in our research and constantly pushing forward, we aim to make a difference - by delivering meaningful advances to people living with cancer.

Together we can change lives

Our purpose is to transform lives for generations. Our curiosity, creativity and passion for science lead us to take the paths scientifically less travelled and the courage to face challenging journeys as we relentlessly pursue the next generation of breakthrough therapies. This is only possible with the support of our exceptional people and global family of partners, who share the same passion for science and enjoy working together to deliver breakthroughs. 

Join us to grow, collaborate, innovate and transform lives for generations.

Explore our career opportunities

Learn about our partnering interests in Oncology
 

References

1. World Health Organisation- Cancer (3 February 2022). https://www.who.int/news-room/fact-sheets/detail/cancer (2022).
2. Arcila, M. E. et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2  (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin. cancer Res.  an Off. J. Am. Assoc.  Cancer Res. 18, 4910–4918 (2012).
3. Mazières, J. et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and  therapeutic perspectives. J. Clin. Oncol.  Off. J. Am. Soc.  Clin. Oncol. 31, 1997–2003 (2013).
4. Maziéres, J. et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: Results from the European EUHER2 cohort. Ann. Oncol. 27, 281–286 (2016).
5. Appert-Collin, A., Hubert, P., Crémel, G. & Bennasroune, A. Role of ErbB receptors in cancer cell migration and invasion. Front. Pharmacol. 6, 1–10 (2015).
6. Wang, S. E. et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 10, 25–38 (2006).
7. Wilding, B. et al. Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling. Nat. Cancer 3, 821–836 (2022).
8. Shah, R. R. & Shah, D. R. Safety and Tolerability of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors in Oncology. Drug Saf. 42, 181–198 (2019).