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CC BY 4.0 · Indian J Med Paediatr Oncol
DOI: 10.1055/s-0046-1817162
Drug Review

Zongertinib and Sevabertinib for Her2-Mutant Non-Small Cell Lung Cancer

Authors

  • Goutham Sunny

    1   Department of Medical and Pediatric Oncology, Gujarat Cancer and Research Centre, Ahmedabad, Gujarat, India

  • Praloy Basu

    2   Department of Medical Oncology, Desun Hospital, Kolkata, West Bengal, India

  • Rajan Yadav

    1   Department of Medical and Pediatric Oncology, Gujarat Cancer and Research Centre, Ahmedabad, Gujarat, India
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Abstract

Alterations of exon 20 of the tyrosine kinase areas of HER2 characterize a particular molecular subgroup of non-small cell lung cancer (NSCLC), which is resistant to previously used epidermal growth factor receptor (EGFR)-target therapy and is less sensitive to standard chemotherapy. Despite the improvement in outcomes with antibody drug conjugates, its application is limited by intravenous delivery and clinically relevant toxicity. In this review, the next-generation oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib, are reviewed in terms of their development, pharmacology, clinical efficacy, and safety. The two agents were both rationally developed to overcome steric hindrance of exon 20 insertions with minimal wild-type EGFR inhibition. We contrast their mechanistic variations, critical clinical trial results, toxicity data, and new applications on treatment sequencing. Collectively, they constitute a promising treatment option for patients with HER2-mutant NSCLC.


Keywords

HER2-mutant NSCLC - HER2 exon 20 insertions - zongertinib - sevabertinib - tyrosine kinase inhibitors

Background and Rationale

Non-small cell lung cancer (NSCLC) with activating mutations of ERBB2 (HER2) exon 20 tyrosine kinase domain (TKD) is a biologically distinct category, which contributes to approximately 2 to 5% of all cases.[1] Such tumors portray intrinsic resistance to earlier generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and have had a poor response to cytotoxic chemotherapy in the past.[1] Whereas HER2-targeted antibody drug conjugates (ADCs), especially trastuzumab deruxtecan, have demonstrated a better outcome, they are constrained by intravenous delivery as well as by clinically significant toxicities, especially interstitial lung disease (ILD).

There is a significant unmet need for a mutation-selective, orally bioavailable HER2 TKIs in this space. Next-generation HER2 TKIs such as zongertinib and sevabertinib have the ability to overcome steric constraints of exon 20 insertions, with minimal inhibition of wild-type EGFR, which can enhance tolerability without compromising efficacy.[2] [3]


Discovery and Drug Development

Zongertinib (BI 1810631; HERNEXEOS)

The structure-guided medicinal chemistry approach of Boehringer Ingelheim in the development of zongertinib focused on achieving highly selective, irreversible target binding of mutant HER2. Preclinical development was aimed at reducing EGFR wild-type inhibition, which was a major limitation of previous pan-HER inhibitors.[2] [4] [5] [6] The compound showed high activity on the HER2 exon 20 insertion mutations; particularly the YVMA insertion variants with an interesting sparing of EGFR, making its rapid advancement into clinical development.[2] [7]


Sevabertinib (BAY 2927088; HYRNUO)

Bayer created sevabertinib as a reversible adenosine triphosphate-competitive kinase inhibitor of mutant HER2, as well as EGFR exon 20 insertions.[8] In contrast to zongertinib, its design strategy involved broader ErbB pathway inhibition, which is founded on the assumption that the HER2-mutant tumor could retain partial EGFR-dependent signaling.[2] [8] The reversible binding profile was also supposed to maintain activity in covalent inhibitor resistance mutations.[4] [8]


Poziotinib (HM781–36B; POZIOTISO)

The failure in the development of earlier TKI poziotinib by Spectrum Pharmaceuticals came mostly due to the fact that it had a nonselective pan-HER mode of action that led to the inhibition of wild-type EGFR to a considerable extent. This unselectivity resulted in frequent and serious EGFR-mediated toxicities, especially grade ≥ 3 rash, diarrhea, and stomatitis, causing dose reductions, treatment pauses, and the inability to maintain therapeutic levels of dosing.[9] [10] Thus, its minimal efficacy failed to measure up with the safety issues and it was not allowed by the regulators.

Conversely, zongertinib and sevabertinib were rationally designed to selectively suppress HER2-controlled oncogenic signaling and mostly spare wild-type EGFR. This enhanced selectivity made it possible to administer at biologically effective doses with significantly enhanced tolerability. The two agents showed differences in terms of increased objective response rates (ORRs), sustained clinical benefit, and manageable safety profiles that underpin positive benefit–risk evaluations and resulted in Food and Drug Administration (FDA) accelerated approval in HER2-mutant NSCLC.[4]



Mechanism of Action

Zongertinib

Zongertinib is an irreversible, covalent HER2 TKI that interacts with cysteine 805 of the HER2 kinase domain through an acrylamide group. The consequence of this irreversible covalent interaction is a long-lasting inhibition of HER2 signaling despite having a comparatively low plasma half-life.[6] [11] Zongertinib exhibited approximately 100-fold selectivity for mutant HER2 compared with wild-type EGFR in preclinical models and this translated to downstream suppression of MAPK and PI3K-AKT signaling with minimal epithelial toxicity. The irreversible binding is the mechanism that makes the drug vulnerable to resistance through C805S substitution.[2] [7]


Sevabertinib

Sevabertinib is a reversible and noncovalent inhibitor of mutant HER2 and EGFR. Notably, it retains activity even in the presence of the HER2 C805S mutation responsible for resistance to covalent inhibitors.[8] Downstream sevabertinib blocks ERK and AKT phosphorylation, but its extended ErbB inhibition is the reason behind the increased rate of EGFR-related adverse events identified in clinical practice.[12]



Pharmacology and Pharmacokinetics

Zongertinib

Zongertinib is given orally as a single daily dose; weight-based (< 90 kg: 120 mg; > 90 kg: 180 mg).[11] The oral bioavailability is approximately 76% with the effective half-life being approximately 12 hours.[13] The CYP3A4/5 are the major enzymes involved in the metabolism of the drug and strong CYP3A inducers reduce drug exposure to a large extent. Food does not interfere with absorption. Covalent target binding enables long-lasting HER2 inhibition despite moderate systemic exposure.[14]


Sevabertinib

Sevabertinib is administered orally; 20 mg twice a day but should be taken with food.[12] [15] The effective half-life is between 8 and 10 hours.[8] It is mainly metabolized through CYP3A, and strong inhibitors raise exposure two to three times and strong inducers lower exposure by approximately 80%, making appropriate dose modification challenging in daily clinical practice.[8]

[Table 1] outlines the pharmacologic properties and metabolic characteristics of zongertinib and sevabertinib.

Table 1

Pharmacokinetics and metabolic profile

Parameter

Zongertinib

Sevabertinib

Oral bioavailability

∼76%

Not specified

Effective half-life

∼12 hours

∼8 hours

Metabolism

CYP3A4/5 (major)

CYP3A (major)

Effect of CYP3A inhibitors

Not clinically significant

↑ AUC ∼2.3-fold

Effect of CYP3A inducers

↓ AUC ∼63%

↓ AUC ∼79%

Tablet handling

Swallow whole

Swallow whole

Considerations for dose adjustment

Strong CYP3A inducers

Strong CYP3A inhibitors/inducers

Abbreviation: AUC, area under the curve.




Clinical Testing and Efficacy

Zongertinib: Beamion LUNG-1 (Phase Ia/Ib)

Zongertinib showed significant clinical activity in previously treated HER2 TKD-mutant NSCLC. The confirmed ORR at the recommended dose of 120 mg daily was 71% in TKI-naive patients and the median progression-free survival (mPFS) and median duration of response (DOR) were 12.4 and 14.1 months, respectively.[5] [11] The trial also reported intracranial activity; the intracranial ORR was 41% in assessable patients with brain metastases. Response was maintained in patients who had been previously treated with HER2 ADCs with 48% ORR.[2] [7] [11]


Sevabertinib: SOHO-01 (Phase I/II)

In the SOHO-01 study, sevabertinib had an ORR of 64% in pretreated, TKI-naive patients and 71% in treatment-naive patients. The mPFS was between 8.3 months in those that were pretreated and 5.5 months in those that received ADC.[12] [15] Exploratory analysis of Cohort D demonstrated that patients harboring Y772_A775dupYVMA mutation had a much longer mPFS of 12.2 months.[12] The ORR in Cohort D was 59.3% and disease control rate was 84%. Most common toxicity was diarrhea, which was manageable and rarely led to treatment discontinuation. Clinically meaningful responses were seen, but numerically lower median DOR and PFS were seen than when zongertinib was used, acknowledging that cross-trial comparisons of results should be interpreted cautiously.

[Table 2] summarizes the pivotal clinical trials of both drugs along with their reported efficacy outcomes.

Table 2

Efficacy outcomes in pivotal clinical trial

Drug

Trial

Population

ORR (%)

Median PFS (mo)

Median DOR (mo)

Zongertinib

Beamion LUNG-1 (Phase Ia/Ib)

HER2 TKD mutant, TKI-naive, pretreated

71

12.4

14.1

Beamion LUNG-1

Prior HER2 ADC

48

Not reached

Not reported

Sevabertinib

SOHO-01 (Phase I/II)

Pretreated, TKI-naive

64

8.3

9.2

SOHO-01

Prior HER2 ADC

38

5.5

Not reported

SOHO-01

Treatment-naive

71

Not mature

Not mature

Abbreviations: ADC, antibody drug conjugate; DOR, duration of response; ORR, objective response rate; PFS, progression-free survival; TKD, tyrosine kinase domain; TKI, tyrosine kinase inhibitor.




Safety and Tolerability

Zongertinib had a good tolerability profile with grade ≥ 3 treatment-related adverse events found in approximately 17% of the patients. Diarrhea was frequent but mostly low grade, and grade ≥ 3 was found in approximately 1%. Notably, there was neither drug-related ILD nor pneumonitis.[11]

EGFR-related toxicity was reported more with sevabertinib. Up to 86 to 91% of patients developed diarrhea with grade ≥ 3 being observed in approximately 23% of the pretreated cohort. There were also increased instances of all grades of rash and transaminitis. There were no cases of drug-related ILD in the early studies, but further follow-up is still warranted.[12]

[Table 3] presents a comparative overview of treatment-related adverse events observed in the landmark trials.

Table 3

Selected treatment-related adverse events

Adverse event

Zongertinib (120 mg QD)

Sevabertinib (20 mg BID)

Grade ≥ 3 TRAEs

∼17%

∼38%

Diarrhea (any grade)

∼56%

86–91%

Diarrhea (grade ≥ 3)

∼1%

∼23%

Rash (any grade)

∼33% (all grade 1–2)

∼51%

Hepatotoxicity (ALT/AST ↑)

Reported; grade ≥ 3 uncommon

Reported; grade 3

Drug-related ILD/pneumonitis

Not reported

Not reported

Treatment discontinuation

∼3%

1–5%

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice a day; ILD, interstitial lung disease; QD, once daily; TRAE, treatment-related adverse event.



Regulatory Status

Accelerated FDA approval has been granted for both the agents in adult patients with unresectable or metastatic nonsquamous NSCLC who have activating HER2 TKD mutations following one prior line systemic therapy. Phase III investigations to evaluate for clinical benefit are underway to determine their role in earlier lines of treatment.[16] [17]

[Table 4] details the current regulatory approval status and approved clinical indications for each agent.

Table 4

Regulatory status and ongoing phase III trials

Drug

FDA status (2025)

Approved indication

Zongertinib

Accelerated approval

HER2 TKD-mutant metastatic NSCLC after prior therapy

Sevabertinib

Accelerated approval

HER2 TKD-mutant metastatic NSCLC after prior therapy

Abbreviations: FDA, Food and Drug Administration; NSCLC, non-small cell lung cancer; TKD, tyrosine kinase domain.



Comparative Perspective and Role in Therapy

The two unique design philosophies in the category of HER2-targeted kinase inhibition are represented by zongertinib and sevabertinib.[4] Zongertinib highlights mutant selectivity and sustained target interaction, which translates into reduced EGFR-mediated toxicity and extended observed PFS. Sevabertinib is more focused on wider coverage of the ErbB pathway and resistance mutations, but at the expense of higher gastrointestinal and dermatologic toxicity.[8] [11] [12]

These agents offer critical oral alternatives to ADCs, expand sequencing options after trastuzumab deruxtecan, and potentially redefine the first-line treatment pending phase III results.

[Table 5] contrasts the key therapeutic and pharmacologic attributes of zongertinib and sevabertinib.

Table 5

Key drug characteristics of zongertinib and sevabertinib

Parameter

Zongertinib (BI 1810631; HERNEXEOS)

Sevabertinib (BAY 2927088; HYRNUO)

Developer

Boehringer Ingelheim

Bayer

Drug class

HER2-selective tyrosine kinase inhibitor

HER2/EGFR tyrosine kinase inhibitor

Binding mechanism

Irreversible, covalent

Reversible, noncovalent

Target residue

Cysteine 805 (HER2 TKD)

ATP-binding site

Her2 exon 20 activity

High potency

High potency

Wild-type EGFR inhibition

Minimal

Low but clinically relevant

Activity against C805S mutation

No

Yes

Route of administration

Oral

Oral

Dosing schedule

Once daily (weight-based)

Twice daily (fixed dose)

Effect of food

None

Must be taken with food

Abbreviations: ATP, adenosine triphosphate; EGFR, epidermal growth factor receptor; TKD, tyrosine kinase domain.



Indian Perspective: Strengths, Limitations, and Future of Research

From an Indian perspective, zongertinib and sevabertinib have great potential with important strengths being oral and mutation-specific HER2 TKIs that may potentially eliminate dependence on expensive intravenous ADCs and extended hospital stays. Their good toxicity profiles are beneficial to patients who have limited access to supportive care. Some of the key limitations, though, are that the drugs are expensive, regulatory approvals are delayed in India, and that access to full next-generation sequencing is limited, which results in fewer number of HER2 exon 20 mutations being diagnosed. The lack of Indian real-world efficacy, safety, and pharmacogenomic data also restricts confident adoption. Future research must focus on Indian cohort studies, cost-effectiveness analyses, expanded molecular testing, and inclusion of Indian centers in global HER2-mutant NSCLC clinical trials.


Conclusion

Zongertinib and sevabertinib mark a significant advancement in the treatment of HER2-mutant NSCLC where the mutation-selective oral kinase inhibition becomes the new paradigm. Their different pharmacologic and mechanistic specifics provide complementary therapeutic approaches in an ever more molecularly stratified treatment landscape, and current trials are set to elucidate the most efficient sequencing, combinations, and long-term results.



Conflict of Interest

None declared.

Authors' Contributions

G.S. and P.B. contributed to the concept of the study, while the design was carried out by G.S. and R.Y. All authors contributed to the definition of intellectual content. G.S. conducted the literature search. Data acquisition was performed by G.S. and P.B. Manuscript preparation was undertaken by G.S. and P.B., and all authors were involved in manuscript editing and review. Clinical and experimental studies, data analysis, and statistical analysis were not applicable.



Address for correspondence

Goutham Sunny, MD, DM
Department of Medical and Pediatric Oncology, Gujarat Cancer and Research Institute
BJ Medical College, Asarwa, Ahmedabad 380016, Gujarat
India   

Publication History

Article published online:
25 February 2026

© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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