Emerging HER2-Targeted Therapies in NSCLC: Zongertinib and BAY 2927088

The treatment of non-small cell lung cancer (NSCLC) has dramatically changed with advancements in precision medicine and molecular testing. Since the first targeted therapy was approved in 2013, it is now advised by the National Comprehensive Cancer Network to conduct broad molecular testing to assess for numerous predictive molecular markers with targeted treatment options. This includes testing for HER2, also known as ERBB2 mutation, which is present in about 3% of patients with NSCLC. HER2 mutation is most commonly present in females and never-smokers with non-squamous histology. Unfortunately, HER2 mutation is associated with more aggressive disease and has a higher incidence of brain metastases than other actionable mutations. Brain metastases tend to have a negative prognosis with worse overall survival and decreased quality of life.^1,2

To date there are no approved first-line targeted treatment options for HER2-mutant NSCLC. Image Credit: © Wanlop - stock.adobe.com

To date there are no approved first-line targeted treatment options for HER2-mutant NSCLC. All approved HER2-targeted therapy options are indicated for advanced and metastatic NSCLC in the subsequent line setting. Current first-line therapy options for these patients are dependent on PD-L1 expression and would consist of immunotherapy and/or platinum doublet. Following progression on first-line therapy is when HER2-targeted therapy options can be considered. The current approved HER2-targeted therapies approved for subsequent treatment are fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo), which is preferred, and ado-trastuzumab emtansine (Kadcyla; Lonza). Both agents are HER2-directed antibody drug conjugate therapies. An alternative option for these patients is to consider clinical trials as several new agents are being studied to target HER2 including oral tyrosine kinase inhibitors (TKIs).^1,2

Zongertinib (BI 1810631; Boehringer Ingelheim International GmbH) is one of the few HER2-specific TKIs being studied in NSCLC. Zongertinib selectively and covalently binds to the tyrosine kinase domain of mutated HER2 receptors blocking downstream signaling. The selectivity for HER2 spares wild-type EGFR signaling thus avoiding EGFR-associated toxicities. Zongertinib is being studied in the Beamion LUNG-1 phase 1a/b trial (NCT04886804) for the treatment of adult patients with advanced, unresectable or metastatic NSCLC harboring HER2 mutations who are treatment-naïve (cohort 2) or have received a prior systemic therapy (cohort 1).³

Results were presented for cohort 1 (phase 1b: dose expansion) at the 2024 International Association for the Study of Lung Cancer: World Conference on Lung Cancer. In the phase 1a portion of the study, a maximum tolerated dose was not reached, and a daily dose of 120 mg and 240 mg daily were selected for the dose expansion phase. Patients who received 120 mg (n=75) daily had an objective response rate (ORR) of 66.7% (97.5% CI, 53.8%-77.5%; P <.0001) via blinded independent review. Duration of response and progression-free survival data were immature at time of analysis as roughly 2 thirds of patients remained on treatment at data cut-off. Table 1 shows response rates via central review and Table 2 shows intracranial responses for the 2 doses of zongertinib selected for the dose expansion phase. Overall, zongertinib was well-tolerated with the most common treatment-related adverse effects (TRAEs) being diarrhea (55%, 1.5% grade > 3), rash (26%), elevated aspartate aminotransferase (22%, 6% grade > 3) and elevated aspartate aminotransferase (22%, 9% grade > 3). There was no reported incidence of interstitial lung disease or significant pneumonitis. Dose reductions occurred in 11% of patients, with 3% of patients having to discontinue therapy; there were no reported treatment-related deaths.

Investigators are now enrolling in the Beamion LUNG-2 study (NCT06151574) which is a phase 3, randomized, active-controlled, multi-center trial evaluating orally administered zongertinib compared with standard of care as first-line treatment in patients with unresectable, locally advanced or metastatic non-squamous NSCLC harboring HER2 tyrosine kinase domain mutations. Zongertinib shows it has activity against HER mutant NSCLC even in patients with brain metastases with a tolerable safety profile.⁴

Another oral HER2 targeted therapy under investigation is BAY 2927088 (Bayer), which is being evaluated in the SOHO-01 study (NCT05099172) for patients with unresectable/metastatic pre-treated HER2-mutant NSCLC. BAY 2927088 is an oral, reversible HER2-targeted TKI. Preliminary results for patients receiving the selected dose of 20 mg twice daily (n=43) showed an ORR of 72.1%, and those with the most common HER2 mutation YVMA insertion had an ORR of 90%. Additional outcomes are shown in Table 3. Most common TRAEs include diarrhea 86% (25% grade >3) and rash (43%, no grade >3). Roughly 31.8% of patients required dose reductions and 6.8% patients discontinued therapy. There was 1 reported death due to dyspnea.⁵ BAY 2927088 is another promising treatment option for the treatment on HER2-mutant NSCLC.

Given the poor prognosis of HER2-mutant NSCLC, development of new targeted therapies is imperative to improve outcomes for these patients. To date there are no approved first-line HER2-targeted therapy options for treatment of HER2-mutant NSCLC and no approved HER2 TKIs. Oral TKIs offer the convenience of taking medication at home but still require close monitoring for adverse effect management. Zongertinib and BAY 2927088 are 2 TKIs which show activity against HER2-mutant NSCLC in pre-treated patients. Both agents have been granted breakthrough therapy designation by the FDA.

REFERENCES

1. Non-Small Cell Lung Cancer (Version 9.2024). National Comprehensive Cancer Network. Accessed September 20, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
2. Vathiotis IA, Bafaloukos D, Syrigos KN, Samonis G. Evolving Treatment Landscape of HER2-mutant Non-Small Cell Lung Cancer: Trastuzumab Deruxtecan and Beyond. Cancers (Basel). 2023 Feb 17;15(4):1286. doi:10.3390/cancers15041286
3. Zongertinib. Boehringer Ingelheim. Accessed September 20, 2024. https://pro.boehringer-ingelheim.com/inoncology/our-pipeline/her2-tki#clinical_development
4. Ruiter G, Tu H-Y, Ahn M-J, et al. Phase 1b analysis of Beamion LUNG-1: zongertinib (BI 1810631) in patients with HER2-mutant NSCLC. Presented at the 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract PL04.04.
5. Le X, Girard N, Janne PA, et al. Safety and efficacy of BAY 2927088 in patients with HER2-mutant NSCLC: expansion cohort from the phase I/II SOHO-01 study. Presented at the 2024 IASLC World Conference on Lung Cancer; San Diego, CA, September 7-10, 2024. PL04.03.