ESMO 2025 Targeted agents show first-line potential in advanced HER2-mutant NSCLC

medwireNews: Findings presented at the ESMO Congress 2025 point to the benefit of two different HER2 tyrosine kinase inhibitors (TKIs) for treatment-naïve, advanced HER2-mutant non-small-cell lung cancer (NSCLC).

Xiuning Le (The University of Texas MD Anderson Cancer Center, Houston, USA) reported results in Berlin, Germany, from the SOHO-01 trial of sevabertinib, an oral reversible TKI, while Sanjay Popat (The Royal Marsden Hospital, London, UK) spoke about the Beamion LUNG-1 trial of zongertinib, an irreversible TKI.

Durable response to sevabertinib in first-line and pretreated settings

Le explained that the dose escalation part of the phase 1/2 study established 20 mg twice daily as the recommended dose for further evaluation in the expansion and extension sections. She reported on three cohorts of patients with advanced NSCLC harboring HER2 mutations, who were categorized as below:

• previously treated but naïve to HER2-targeted therapies (cohort D; n=81);
• previously treated with HER2-targeted antibody–drug conjugates (cohort E; n=55); or
• no prior systemic therapy for advanced disease (cohort F; n=73).

The median duration of follow-up in the D, E, and F cohorts was 13.8, 11.6, and 9.9 months, respectively, and at this point, the primary endpoint of objective response rate (ORR) as assessed by blinded review was a respective 64%, 38%, and 71%.

Responses lasted for a median of 9.2, 8.5, and 11.0 months, respectively, and the corresponding median progression-free survival (PFS) times were 8.3 months, 5.5 months, and unreached.

The presenter highlighted that responses were observed both in patients with and without brain metastases at baseline. For instance, in previously untreated patients, the ORR was 78% for the nine patients with brain metastases and 70% among the 64 without.

Treatment-related adverse events (TRAEs) of at least grade 3 occurred in 36%, 31%, and 21% of participants in cohorts D, E, and F, respectively.

The most common AE with sevabertinib was diarrhea, with grade 3 events in 23%, 11%, and 5%, respectively, but Le pointed out that there were no grade 4 events, and no patients discontinued due to diarrhea. There were also no cases of interstitial lung disease or pneumonitis in any of the cohorts.

She concluded that “[t]hese data support sevabertinib as a potential new targeted therapy for patients with HER2-mutant NSCLC,” and added that the drug is currently being evaluated in the first-line setting in the ongoing phase 3 trial, SOHO-02.

The SOHO-01 trial results were simultaneously published in The New England Journal of Medicine.

Zongertinib beneficial for previously untreated patients

Popat reported on cohort 2 of the phase 1b study which included 74 patients with treatment-naïve disease positive for a HER2 tyrosine kinase domain mutation. He noted that findings from other cohorts of Beamion LUNG-1 comprising patients who had received prior treatment for advanced disease have already been presented.

In cohort 2, treatment with zongertinib 120 mg/day led to an ORR, as evaluated by blinded review, of 77% and a disease control rate of 96%.

The presenter pointed out that responses were “rapid”, occurring after a median 1.4 months, and durable, with 47% of responding patients remaining on treatment at data cutoff.

At a median follow-up of 11 months, median PFS had not been reached and the 6-month PFS rate was 79%.

“The pattern of adverse events observed in this treatment-naïve population was consistent with that reported in previously treated patients,” and the incidence of TRAEs of grade 3 or worse was “notably low,” said Popat.

Indeed, there were no grade 4 or 5 TRAEs at all in this cohort, and grade 3 events occurred in 18% of patients. Diarrhea was the most frequent AE of any grade, observed in just over half (54%) of the cohort.

A total of 9% of participants discontinued zongertinib due to AEs, and there were two cases of interstitial lung disease/pneumonitis, both of grade 2.

“Zongertinib given as first-line therapy demonstrated significant and clinically meaningful benefit” in this patient population and the phase 3 Beamion LUNG-2 trial, which aims to compare zongertinib with first-line standard of care for unresectable, locally advanced or metastatic HER2-mutant NSCLC, is ongoing, concluded the investigator.

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ESMO Congress 2025; Berlin, Germany: 17–21 October (LBA75)
ESMO Congress 2025; Berlin, Germany: 17–21 October (LBA74)
N Engl J Med 2025; doi:10.1056/NEJMoa2511065