FDA Approval of Zongertinib in HER2-Mutated NSCLC
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Key Points
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Zongertinib is the first oral tyrosine kinase inhibitor (TKI) to be approved for patients with HER2-mutated, non-squamous, non-small cell lung cancer (NSCLC).
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HER2 mutation occurs in about 2% to 4% of patients with NSCLC, and is identified via presence of ERBB2 mutation on next-generation sequencing (NGS).
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Zongertinib showed a 71% response rate in patients who were not previously treated with HER2-directed antibody-drug conjugates (ADCs) and a 45% overall response rate if they were previously treated with a HER2-directed ADC.
Granted FDA Accelerated Approval
As part of the Oncology Brothers podcast’s series covering recent approvals in cancer therapies, Joshua Sabari, MD, of Perlmutter Cancer Center, discussed the approval of zongertinib for advanced NSCLC with HER2 tyrosine kinase domain (TKD) mutations. Zongertinib is the first oral TKI approved for non-squamous NSCLC with HER2 mutations. The FDA granted accelerated approval to zongertinib based on the primary analysis of the Beamion LUNG-1 study.
Before discussing the results of the study, Dr. Sabari distinguished three HER2 alteration subtypes: HER2 mutation identified on broad-panel NGS, HER2 overexpression identified on immunohistochemistry (IHC), and HER2 amplification identified on fluorescence in situ hybridization or NGS.
Beamion LUNG-1 Cohort Breakdown
The Beamion LUNG-1 study was a phase 1a/1b trial that investigated zongertinib in patients with advanced or metastatic HER2-mutated NSCLC. After the study’s interim analyses, all patients were treated at a dose of 120 mg once daily.
The primary analysis, presented at the American Association for Cancer Research Annual Meeting 2025, covered three cohorts of previously treated patients with NSCLC:
- 75 patients with HER2 TKD mutations (cohort 1)
- 20 patients with non-TKD mutations (cohort 3)
- 31 patients with HER2 TKD mutations that had also previously received a HER2-directed ADC (cohort 5)
In addition, the study included two ongoing cohorts of treatment naive patients (cohort 2) and those with active central nervous system (CNS) metastases (cohort 4).
Strong Beamion LUNG-1 Outcomes
By the data cutoff of November 29, 2024, cohort 1 had an objective response rate (ORR) of 71% (95% CI, 60-80; P < .001), a median duration of response of 14.1 months (95% CI, 6.9-not evaluable [NE]), and a median progression-free survival (PFS) of 12.4 months (95% CI, 8.2-NE). Comparatively, cohorts 3 and 5 had ORRs of 30% (95% CI, 15-52) and 48% (95% CI, 32-65), respectively.
The data suggest “true targeted therapy response rates” with zongertinib for this NSCLC population, Dr. Sabari said. “I think what’s most important for me with this therapy is it’s truly targeted and we don’t really see off-target toxicity—so very low rates of gastrointestinal or skin toxicity,” he said.
Zongertinib Side Effect Management
About half of patients treated with zongertinib report grade 1 or 2 diarrhea, with about 1% reporting grade 3 or clinically significant diarrhea, according to Dr. Sabari. Diarrhea can be effectively managed with imodium, he explained. For cutaneous side effects, Dr. Sabari recommended topical emollients. He cited that rates of paronychia were extremely low and no interstitial lung disease were reported with zongertinib.
Zongertinib Versus T-DXd in HER2-Positive NSCLC
The doctors also discussed the appropriate sequencing of zongertinib and the other approved HER2-directed agent in NSCLC, trastuzumab deruxtecan (T-DXd). Given Beamion LUNG-1 showed previous anti-HER2 therapy exposure negatively impacted the response rate of zongertinib, Dr. Sabari said he would be sequencing zongertinib prior to T-DXd in his practice.
Moreover, because T-DXd contains a topoisomerase 1 inhibitor payload, patients can experience chemotherapy-like side effects including fatigue, nausea, hair loss, hematologic events, and pneumonitis. Zongertinib is more targeted, less toxic, and doesn’t inhibit EGFR, explained Dr. Sabari, who added that it would be his standard of care choice in the second-line setting.
Notably, the approval of zongertinib is currently specific to NSCLC with HER2 TKD or non-TKD mutations. The data are not clear if zongertinib is active in HER2 overexpression, so T-DXd is still recommended for patients with IHC 3-positive. Because the data for T-DXd in IHC 2-positive are not as strong, Dr. Sabari said the choice of treatment may be trickier.
For cases where there is CNS involvement, more data are needed to determine treatment selection or sequencing, Dr. Sabari said. In particular, for patients with treatment-naive CNS involvement. Currently, Dr. Sabari radiates CNS metastases prior to starting any systemic therapy.
“Hopefully, with next-generation HER2 inhibitors, we continue to move the needle forward for our patients,” Dr. Sabari said.