HER2-TKI in HER2-mutant, advanced NSCLC: Beamion-LUNG 1 and SOHO-01

The Swiss Cancer Institute’s Young Oncology Academy (YOA) is a support and mentorship program for young oncologists. Academy participants are supervised by a renowned faculty member for almost a year and are required to write a review paper on a topic of interest. Today we present Dr. med. Julia Jägerʼs paper, a comparative review of two studies. Dr. med. Jäger was a YOA participant in 2025 with the speciality medical oncology and was mentored by Prof. Dr. med. et Dr. phil. nat. Sacha Rothschild.

HER2 belongs to the ERBB receptor family. HER2-mutated non-small cell lung cancer (NSCLC) accounts for approximately 2–4% of all cases and represents a distinct molecular subgroup with an unfavorable prognosis. Most alterations are activating mutations, particularly exon 20 insertions fundamentally differing from HER2 overexpression or amplification in breast or gastric cancer.^1–3 These biological differences explain the historically limited responses to conventional HER2-directed therapies and highlight the need for mutation-specific treatment approaches.

The current standard of care in the first line setting for advanced HER2-mutant NSCLC is pembrolizumab plus pemetrexed and platinum-based chemotherapy (KEYNOTE-189).⁴ After disease progression, the HER2-directed antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) is available in Switzerland.⁵ Data from DESTINY-Lung01 and DESTINY-Lung02 demonstrated robust activity in pretreated HER2-mutant NSCLC, with objective response rates (ORR) around 55–57%, a median progression-free survival (PFS) of roughly 8.2 months, and a median duration of response of approximately 9 months. Interstitial lung disease (ILD)/pneumonitis remains an important toxicity requiring close monitoring. Despite these challenges, T-DXd has become a key therapeutic option in the second-line setting.

Two next-generation, highly selective, covalent HER2 tyrosine kinase inhibitors (TKIs) – sevabertinib and zongertinib – are now being evaluated and may shift treatment paradigms in the future. BEAMION-Lung1 and SOHO-01 are the respective trials that showed promising ORR. Both studies had multiple cohorts representing different treatment situations: untreated or pretreated, either with HER2-targeting ADC or with chemoimmunotherapy.

Beamion-LUNG 1

Beamion-LUNG 1 is a phase Ia/Ib study investigating the irreversible, selective HER2-TKI zongertinib. Primary endpoint was ORR. At the ESMO annual meeting the results of cohort 2 including treatment-naïve patients were presented. ORR was 77% with a rapid median time to response of 1.4 months (range: 1.1–6.9 months). Although PFS data remain immature yet, the 6-months PFS rate was 79%. The 6 months DOR was 80% with a median follow-up of 9.7 months. Responses were observed across different HER2 mutation types.⁶

SOHO-01

SOHO-01 is a phase I/II study of sevabertinib in advanced HER2-mutated NSCLC with ORR as a primary endpoint. Sevabertinib showed promising response rates in all cohorts, ranging from 38% in the HER2-ADC pretreated patients to 71% in untreated patients. In untreated patients PFS was not mature yet (with a median follow-up time of 9.9 months), the 12 months PFS was 55%. The median DOR was 11 months. In the cohort with pretreated patients who were naïve to an HER2-ADC, an exploratory biomarker analysis was performed as it was the largest cohort with the longest follow-up. This analysis indicated that patients with HER2-TKD mutations, especially YVMA exon 20 insertions, had higher response rates.⁷

Adverse events

Both TKIs were associated with manageable toxicities. Diarrhea and rash were common adverse events (AEs). In both studies patients needed to have dose reductions to complete treatment (15% with zongertinib, 28% with sevabertinib). Diarrhea grade ≥2 occurred more frequently with sevabertinib (34% grade 2, 6.7% grade 3), as well as paronychia. This is probably due to a greater inhibition of EGFR wildtype. With dose reductions and treatment interruptions, the toxicities were manageable with supportive care in both studies.

Conclusion

Both trials underline that HER2-TKIs have the potential to transform the management of HER2-mutant NSCLC. Ongoing phase III studies (Beamion-LUNG 2, SOHO-02, DESTINY-Lung 04) are expected to clarify optimal sequencing strategies – such as whether TKI- or ADC-based therapy should be used first – and help to define which approach offers the greatest survival benefit.