Zongertinib Could Alter SOC in HER2-Mutated Advanced NSCLC

John V. Heymach, MD, PhD

The HER2-selective TKI zongertinib (BI 1810631) displayed efficacy in patients with HER2-mutated advanced non–small cell lung cancer (NSCLC), leading to excitement among investigators that the agent could soon become a new standard-of-care option in the field, according to John V. Heymach, MD, PhD.

“HER2 mutations occur in [approximately] 2% to 4% of patients with lung cancer, [and] in over 20 tumor types [overall],” Heymach said in an interview with OncLive®. “To date, we haven’t been able to [develop] a successful HER2-targeted oral TKI for these patients [with NSCLC]. Right now, the only option is fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu], which is a HER2[-targeted] antibody-drug conjugate [ADC]. Having an oral option that’s hopefully more effective would be a huge advance for these patients.”

Heymach is the chair of and a professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. He is also the David Bruton, Jr Chair in Cancer Research in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine at MD Anderson.

During the 2025 AACR Annual Meeting, Heymach presented data from the phase 1b Beamion LUNG-1 trial (NCT04886804)evaluating zongertinib in patients with HER2-altered solid tumors, including NSCLC.1 Patients with previously treated NSCLC harboring tyrosine kinase domain (TKD) HER2 mutations treated with zongertinib in cohort 1 (n = 75) achieved an overall response rate (ORR) of 71% (95% CI, 60%-80%), including a complete response (CR) rate of 7%.

Additionally, patients in cohort 3 with NSCLC harboring non-TKD HER2 mutations (n = 20) experienced an ORR of 30% (95% CI, 15%-52%), comprised of all partial responses. In cohort 5, patients previously treated with platinum-based chemotherapy with or without immunotherapy who also received a prior HER2-directed ADC (n = 31) achieved an ORR of 48% (95% CI, 32%-65%) with a CR rate of 3%. Notably, patients in this cohort previously treated with T-DXd (n = 22) had an ORR of 41% (95% CI, 23%-61%).

In February 2025, the FDA granted priority review to the new drug application (NDA) seeking the approval of zongertinib for the treatment of adult patients with unresectable or metastatic NSCLC harboring HER2 mutations who have received prior systemic therapy.2 Prior data from Beamion LUNG-1 supported the NDA submission.

In the interview, Heymach discussed the background of Beamion LUNG-1, the findings from the trial he presented during the meeting, and the potential role for zongertinib in the treatment of patients with HER2-mutated advanced NSCLC.

OncLive: What were the notable design features of Beamion LUNG-1?

Heymach: This was a phase 1a/b study. In part 1a, which we reported [data from] earlier, we did something that doesn’t happen very often; we found no maximum tolerated dose. [Zongertinib] was well tolerated up to [a dose of] 300 mg, but we ended up selecting 120 mg and 240 mg as the doses to study further.

In part 1b, we selected 120 mg [once daily] based on [data from] the interim analysis. We [presented data at AACR] from 3 cohorts [from part 1b]. The main cohort [included] patients who previously received chemotherapy or other systemic therapy.

What were the key findings from the updated data you presented during AACR?

In cohort 1, which was the primary cohort, the ORR was 71%, and the median progression-free survival [PFS] was 12.4 months [95% CI, 8.2-not evaluable]. This is a substantial advance compared with [drugs] we have had before. Other drugs that have been [previously tested in the space displayed a median PFS of [approximately] 5 months and an ORR [of approximately] 20%. [Zongertinib] is a game changer, and [it had] dramatically better tolerability than the other pills that have been tested before.

Cohort 5, which included patients who received T-DXd or other [HER2-directed] ADCs [after platinum-based chemotherapy with or without immunotherapy], had an ORR of 48%, but [this was] a bit lower than in those who had not received [ADCs]. Cohort 3 included patients who had [non-TKD HER2 mutations]. Most [HER2] mutations are in the TKD, and that’s what zongertinib was designed to inhibit. In cohort 3, the ORR was 30%.

Were there any safety concerns observed with zongertinib?

This drug was remarkably well tolerated overall. Earlier drugs tested in HER2-mutated [NSCLC displayed] rates of grade 3 diarrhea from [approximately] 8% all the way up to 26% and grade 3 rash up to [approximately] 49%. In contrast, this drug had a very manageable safety profile. [In cohort 1], the most common [any-grade] adverse effect [AE] was diarrhea, but there was only one patient with grade 3 diarrhea, which is a low rate. Five percent of patients had [grade 3] increased aspartate aminotransferase [levels] and 8% had a [grade 3] rise in alanine aminotransferase [levels]. However, that was not something that was symptomatic or that progressed for those patients.

Otherwise, the AEs were usually grade 1, [including] dry skin or pruritus. Only 7% required a dose reduction [due to an AE]; with earlier drugs in the space, up to 50% of patients needed a dose reduction. There were 2 patients who discontinued the drug due to AEs, and we’re used to [a figure] closer to 10% with other pills.

What are the next steps in the development of zongertinib in this patient population?

[Zongertinib] is under priority review for potential FDA approval, and we’ll hear [the result] of that [in the third quarter of 2025] based on the Prescription Drug User Fee Act action date. Moving forward, the randomized phase 3 Beamion LUNG-2 trial [NCT06151574] is examining the agent in the first-line setting to see if it can [outperform] chemotherapy, which is still the standard first-line treatment. If so, this would become the [standard] first-line agent for this space.

There are [also] some combination regimens that are being tested. In the future, this drug may move to become the first-line treatment for patients with HER2-mutated [NSCLC], and we look forward to combinations that could improve the efficacy further.

References

1. Heymach JV, Ruiter G, Ahn M-J, et al. Zongertinib in patients with pretreated HER2-mutant advanced NSCLC: Beamion LUNG-1. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT050.
2. Boehringer’s zongertinib receives Priority Review from U.S. FDA for the treatment of HER2 (ERBB2)-mutant advanced non-small cell lung cancer. Boehringer. February 19, 2025. Accessed May 1, 2025. https://www.boehringer-ingelheim.com/us/zongertinib-granted-priority-review-us-fda