A New Drug for HER2-Mutant Lung Cancer: Sevabertinib Takes the Stage at ESMO 2025

Why Does It Matter?

HER2 mutations occur in approximately 2–4% of NSCLC cases, and standard treatments are often inadequate for this subtype. Although antibody–drug conjugates (ADCs) are available, an oral selective tyrosine kinase inhibitor (TKI) needs high efficacy + good tolerability . Bayer's sevabertinib could fill this gap through relative sparing of wild-type EGFR and strong activity against HER2 mutations.

Study Design (SOHO-01, Phase 1–2)

• Open-label, multicenter phase 1–2 study; 20 mg orally 2 times daily was established as the recommended dose.
• Primary endpoint: Objective response rate (ORR); secondary endpoints: duration of response (DoR) and progression-free survival (PFS).
• Results from 3 arms were presented at ESMO 2025:
  • Cohort D: Previously treated, without prior HER2-targeted therapy (n=81).
  • Cohort E: Previously received a HER2-directed ADC (n=55).
  • Cohort F: Treatment-naive (n=73).
• Data cut-off: June 27, 2025.

📊 Main Findings (KPI)

Responses

Mechanism of Action (MOA)

Biomarker Clues

• HER2 Y772_A775dupYVMA and other TKD alterations were associated with higher responses and longer PFS .
• TP53 co-alterations may be associated with shorter PFS.
• ctDNA clearance/negativity (weeks 2–6) appears associated with longer PFS.

Safety (Drug-Related AEs)

• Any-grade AEs: 96–100%; Grade ≥3: approximately 23–38%.
• Diarrhea: 84–91%; Grade ≥3: 5–23%; No Grade 4. No discontinuations due to diarrhea were reported.
• Skin rash: ~47–51%; Paronychia: ~22–29%.
• ILD/pneumonitis: reported as unrelated to the drug .
• Dose changes: reductions 25–35%; discontinuations 1–5%.

DROZDOGAN Academy Commentary

Sevabertinibstands out in HER2-mutant NSCLC as an oral option after ADCs . Particularly, 71% ORR and 11-month median response duration in the first-line (1L) cohort suggest potential for earlier use.

The drug's wild-type EGFR-sparing selectivity —strong HER2 targeting with reduced conventional EGFR toxicities—could, when applied clinically, open the way to better-tolerated long-term treatment strategies.

These data suggest a substantial role in HER2-mutant lung cancer for ADCs and oral small-molecule TKIs. The ongoing SOHO-02 phase 3 trial will be decisive for sevabertinib's move into first-line treatment .

Our view: If phase 3 confirms this trend, sevabertinib could open a new chapter in HER2-mutant NSCLC treatment . ADCs and TKIs could then become complementary pillars of a treatment-sequencing strategy.

A Few Notes:

• Dose: 20 mg, twice daily (BID).
• Brain Metastases: There is an efficacy signal; clinical examples highlight intracranial activity .
• Monitoring: Diarrhea/skin management, dose reduction when needed.

Sources

• Le X, Kim TM, et al. Sevabertinib in Advanced HER2-Mutant NSCLC. N Engl J Med. 2025. (SOHO-01)