Zongertinib: A Promising New TKI for HER2-Mutated NSCLC

The FDA recently granted breakthrough therapy designation to zongertinib (BI 1810631; Boehringer), an investigational oral therapy for non-small cell lung cancer (NSCLC) with HER2 mutation.¹ China’s Center for Drug Evaluation has granted the medication a similar status for treatment in patients with advanced NSCLC with tumors that express HER2 mutations who have had treatment with systemic therapy.¹ If approved, the drug would be the first in a new generation of tyrosine kinase inhibitors (TKI) that can treat patients with metastatic, advanced, or unresectable NSCLC with HER2 mutations.

Approximately 85% of patients with lung cancer have NSCLC and among those, 2% to 4% have HER2 mutations. Ekaterina - stock.adobe.com

Approximately 85% of patients with lung cancer have NSCLC and among those, 2% to 4% have HER2 mutations.^1,2 Each year, about 40,000 people globally are diagnosed with HER2-mutated NSCLC.¹ These patients have limited therapy options, even when compared to patients with other types of HER2-positive cancers. This drug may help to meet more of the needs in this patient population.

The discovery and development of TKIs have yielded significant gains in treating various cancers. Because TKIs can be modified or designed for selectivity, and NSCLC encompasses a large variety of oncogenic alterations, TKIs and their outlook remain a strong, viable option for treatment and management of NSCLC. There has been a new and ever-evolving tradition of targeted therapy development since the first EGFR drug was approved almost 2 decades ago.³ Since then, many more oncogenic drivers have been identified, such as RET, ALK, and ROS1, and drugs subsequently have been developed to target those driver mutations, such as selpercatinib (Retevmo; Eli Lilly and Company), alectinib (Alecensa; Genentech), and entrectinib (Rozlytrek; Genentech), respectively. Zongertinib may be another addition.

In a recent presentation at the 2024 World Conference on Lung Cancer, Boehringer presented findings from their phase 1b Beamion LUNG-1 trial (NCT04886804) that demonstrated promising efficacy and tolerability of zongertinib in previously treated patients with HER2-mutated NSCLC.⁴ In the study, 132 patients were treated with 120 mg or 240 mg of zongertinib once a day (n = 75 and n = 57, respectively). There was a confirmed objective response rate (ORR) of 66.7 %, with a 97.5% confidence interval (53.8, 77.5; P < 0.0001) within the cohort 1 group (120 mg) according to blind independent central review (BICR).⁵

Additionally, zongertinib demonstrated brain activity in patients with asymptomatic brain metastases. There was a confirmed ORR of 33% (120 mg; n = 27) and 40% (240 mg; n = 25) per BICR following recommendations for standardized tumor response and progression assessment. Moreover, disease control rates of 74% and 92%, respectively, were noted.⁵

There was considerable tolerability among patients in both dosing groups, reflected by no incidence of fatal treatment-related adverse effects (TRAEs), 11% of patients requiring dose reductions, and only 3% of patients leading to discontinuations. Though 92% and 100% of patients in the 120 mg and 240 mg groups, respectively, experienced any grade of TRAEs, only 17% and 19% of these patients, respectively, had grade 3 or higher TRAEs. The most reported effects were grade 1 or 2 diarrhea (43% and 11%, respectively) and grade 1 or 2 rash (19% and 8%, respectively).⁵

Boehringer has indicated that two-thirds of responding patients remained on therapy after the data cut-off and that they will present data on progression-free survival and duration of response in the near future. The company is currently enrolling for their Beamion LUNG-2 study, a phase 3, open label, randomized, active-controlled study comparing standard-of-care treatment to zongertinib in patients with unresectable, locally advanced, or metastatic non-squamous HER2-positive NSCLC.⁶

The potential of these findings and the prospect of drug approval may preview new first-line therapies in treating HER2-mutated NSCLC, and, more importantly, may further cement TKIs as an essential model on which to build new therapies for current oncogenic targets or oncogenes that have yet to be identified and classified. The versatility of TKIs lends a unique strategy for researchers and clinicians to approach treatment and thus will most likely continue to play larger roles in treatment of NSCLC and in various cancers beyond.

REFERENCES

1. Boehringer Ingelheim to unveil groundbreaking oncology research at WCLC, demonstrating strength of portfolio. News release. Boehringer Ingelheim. August 27, 2024. Accessed October 10, 2024. https://www.boehringer-ingelheim.com/us/human-health/cancer/boehringer-ingelheim-unveil-oncology-research-wclc

2. Yu X, Ji X, Su C. HER2-Altered Non-Small Cell Lung Cancer: Biology, Clinicopathologic Features, and Emerging Therapies. Front Oncol. 2022;12:860313. March 29, 2022. doi:10.3389/fonc.2022.860313

3. Friedlaender A, Perol M, Banna GL, Parikh K, Addeo A. Oncogenic alterations in advanced NSCLC: a molecular super-highway. Biomark Res. 2024;12(1):24. February 12, 2024. doi:10.1186/s40364-024-00566-0

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. Wu Y-L, Opdam F, Barve M, et al. 34P Updated data from Beamion LUNG-1, a phase (ph) Ia/b trial of the HER2-specific tyrosine kinase inhibitor (TKI), zongertinib (BI 1810631), in patients (pts) with HER2 mutation-positive (m+) NSCLC. ESMO Open. 2024;9:102613.

6. Boehringer’s zongertinib shows encouraging efficacy and tolerability profile in previously treated HER2 mutated lung cancer patients. Boehringer Ingelheim. September 9, 2024. Accessed October 10, 2024. https://www.boehringer-ingelheim.com/human-health/cancer/lung-cancer/zongertinib-positive-results-non-small-cell-lung-cancer