Targeting HER2 mutations in cancer: the story of Boehringer’s investigational Zongertinib
Alterations in the HER2 gene are seen across different cancer types, including breast, gastric and lung cancer.1 Every year, about 40,000 people worldwide are diagnosed with non-small cell lung cancer (NSCLC) with a HER2 mutation.2 While targeted therapy is available for some cancers driven by HER2, people living with HER2 mutation-positive NSCLC have continued high unmet needs. Our scientists discovered a potentially highly selective small molecule inhibitor of HER2. Zongertinib is an irreversible HER2-selective tyrosine kinase inhibitor (TKI) that is currently being investigated in a phase I clinical trial (clinicaltrials.gov identifier: NCT04886804). In 2023, the U.S. Food and Drug Administration (FDA) granted Fast Track Designation for this investigational oral treatment for people with NSCLC whose tumors have a HER2 mutation and with disease progression on or after platinum-based therapy.
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.3 NSCLC accounts for the majority of cases (85%).4 Among these, 2% to 4% harbor HER2 mutations.5,6 There remains a high unmet need for these patients as they may respond poorly to the current standards of care, including chemotherapy and immunotherapy.7 People living with advanced NSCLC can also experience a detrimental physical, psychological and emotional impact on their daily lives.8
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 intracellular signaling pathways involved in cell growth and survival.9 Alterations in the HER2 gene, including mutation, amplification and overexpression, can turn the HER2 protein into a cancer driver by triggering uncontrolled cell proliferation, inhibiting cell death, and promoting tumor growth and spread.10
Currently available small molecule inhibitors known as tyrosine kinase inhibitors target several members of the ErbB family non selectively.11 Designing a compound that selectively binds to HER2 (ErbB2), while sparing EGFR (epidermal growth factor receptor) or ErbB1, potentially avoids EGFR-associated toxicity.12
“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 high-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 may 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 may spare wild-type EGFR signaling.11
“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.
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 curiosity, creativity and passion for science lead us to take the paths scientifically less traveled 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.
This compound is an investigational agent and has not been approved for use by any regulatory authority, including the U.S. Food and Drug Administration (FDA). The efficacy and safety of this investigational compound has not been established.
References
Yu, X. et al. HER2-Altered Non-Small Cell Lung Cancer: Biology, Clinicopathologic Features, and Emerging Therapies. Frontiers in Oncology. https://doi.org/10.3389/fonc.2022.860313.
Chia, P. et al. Prevalence and natural history of ALK positive non-small-cell lung cacner and the clincial impact of targeted therapy with ALK inhibitors. Clinical Epidemiology. http://dx.doi.org/10.2147/CLEP.S69718
World Health Organisation- Cancer (3 February 2022). https://www.who.int/news-room/fact-sheets/detail/cancer (2022).
Molina, J. R. et al. Non-Small Cell Lung Cancer: Epidemiology, Risk Factors, Treatment, and Survivorship. Mayo Clin Proc. 2008 May ; 83(5): 584–594.
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).
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).
Mazières, J. et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Annals of Oncology. doi:10.1093/annonc/mdv573.
Bi, Z et al. Negative correlations of psychological distress with quality of life and immunotherapy efficacy in patients with advanced NSCLC. American Journal Cancer Research. 2022;12(2):805-815 www.ajcr.us /ISSN:2156-6976/ajcr0140896
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).
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).
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).
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).