An exploratory biomarker analysis of the Phase 1/2 SOHO-01 trial (NCT05099172) has identified secondary HER2 T862A substitution as the predominant genomic mechanism of acquired resistance to sevabertinib, a potent and selective HER2 tyrosine kinase inhibitor (TKI), in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC). The findings, presented at the IASLC 2026 World Conference on Lung Cancer, provide the first systematic characterization of the molecular resistance landscape for this agent and highlight the likely importance of nongenetic mechanisms in a majority of progressing patients.

Clinical Takeaway

In patients with HER2-mutant NSCLC progressing on sevabertinib, secondary HER2 T862A was the most frequently emerging genomic resistance alteration, identified in 16.4% of evaluable patients. Importantly, the majority of patients who progressed (~70%) had no identifiable genomic resistance driver, pointing to nongenetic or adaptive resistance as a critical unresolved challenge. Preclinical work is underway to define the structural and functional impact of T862A on sevabertinib binding.

Drug Profile & Mechanism

  • Drug: Sevabertinib, a selective HER2 tyrosine kinase inhibitor (TKI)
  • Target: HER2 (Human Epidermal Growth Factor Receptor 2), a driver oncogene mutated in approximately 2–4% of NSCLC cases and associated with poor clinical outcomes
  • Clinical context: Sevabertinib has demonstrated durable and clinically meaningful activity across both treatment-naïve (Group F) and pretreated patients (Groups D and E) with advanced HER2-mutant NSCLC in SOHO-01
  • Resistance gap: Before this analysis, the molecular mechanisms underlying acquired resistance to HER2 TKIs in NSCLC remained poorly defined

Target Population

  • Adults with advanced HER2-mutant NSCLC
  • Enrolled across Groups D, E (pretreated) and Group F (treatment-naïve) of the SOHO-01 trial
  • Biomarker subset: 73 patients with HER2 mutations detected in baseline ctDNA and paired or unpaired progression plasma samples available for next-generation sequencing

Study Design

  • Trial: SOHO-01 (NCT05099172), Phase 1/2, multi-group, open-label study of sevabertinib in HER2-mutant NSCLC
  • Analysis type: Exploratory biomarker analysis focused on acquired resistance mechanisms
  • Sample collection: Plasma samples collected at baseline (BL), during treatment, and at treatment discontinuation
  • Progression sample criteria: Plasma obtained up to 4 weeks before radiographic progression (PD), at PD, or after PD, paired with baseline samples where available
  • ctDNA profiling platforms:
  • Analytical approach: Paired BL–PD and PD-only samples interrogated for emergent genomic alterations, classified as:
    • Secondary HER2 alterations (mutations or amplification)
    • Bypass and downstream pathway events
  • Evaluable resistance cohort: 85 patients with successful NGS of paired BL and PD plasma; 73 (85.9%) had HER2 mutations in baseline ctDNA and formed the primary resistance analysis subset

Key Biomarker Findings

  • Overall mutational landscape: Most patients exhibited a relatively stable mutational profile over time; HER2 and TP53 were the most frequently altered genes at both baseline and progression
  • Putative resistance events identified: 22 of 73 patients (30.1%) had identifiable genomic resistance-associated alterations at progression
  • Secondary HER2 T862A substitution:
    • Most common emergent resistance alteration: 12 of 73 patients (16.4%)
    • Consistent findings observed in unpaired PD-only samples without matched baseline specimens
    • Patients with secondary HER2 T862A showed comparable duration of response and time to progression versus those without this alteration
  • HER2 amplification: Emergent in 2 of 73 patients (2.7%)
  • HER2 C805S mutations: Not detected in any progression plasma samples, a notable absence given the relevance of this gatekeeper-region mutation for other HER2 inhibitors
  • Bypass/downstream pathway alterations:
  • Patients without identifiable genomic resistance driver: ~70% of patients who progressed lacked a detectable genomic mechanism, suggesting a major role for nongenetic or adaptive resistance mechanisms

Key Clinical Implications

✔ HER2 T862A is the dominant on-target resistance mutation to sevabertinib, emerging in approximately 1 in 6 evaluable patients at progression; clinicians and researchers should prioritize characterizing its structural impact on drug binding to guide next-generation inhibitor design.

✔ HER2 C805S was not detected at progression, which may differentiate sevabertinib’s resistance profile from that of other HER2-targeted agents and has implications for sequencing strategies and cross-resistance considerations.

✔ The absence of identifiable genomic drivers in ~70% of progressing patients underscores the critical need for research into nongenetic, epigenetic, and adaptive mechanisms of resistance to HER2 TKIs in NSCLC.

✔ Liquid biopsy–based ctDNA profiling at progression is a feasible and informative strategy for characterizing resistance in HER2-mutant NSCLC and should be incorporated into future trial designs and, where possible, clinical practice.

✔ PIK3CA/PTEN and MAPK pathway alterations represent actionable bypass resistance mechanisms in a subset of patients, potentially offering combinatorial therapeutic opportunities worthy of prospective investigation.

✔ The comparable outcomes observed in patients with vs. without HER2 T862A suggest this alteration may not uniformly abrogate clinical benefit, but its role and the optimal post-progression strategy remain to be defined through ongoing preclinical and structural modeling studies.

Bottom Line

This exploratory biomarker analysis from SOHO-01 represents the most comprehensive genomic characterization of acquired resistance to a HER2-selective TKI in HER2-mutant NSCLC to date. Secondary HER2 T862A emerges as the predominant on-target resistance mechanism, identified in 16.4% of patients, while bypass pathway alterations involving PIK3CA/PTEN and MAPK genes account for an additional 12.3%. The notable absence of HER2 C805S may reflect a distinct resistance profile for sevabertinib relative to other agents in this class. No genomic resistance driver was detectable in approximately 70% of progressing patients, underscoring the urgency of investigating nongenetic resistance mechanisms. Preclinical and structural studies are actively underway to elucidate the biology of T862A and inform the rational development of next-generation strategies to overcome sevabertinib resistance.

Sources:

  • Le X, et al. (2026). Molecular Landscape of Acquired Resistance to Sevabertinib in HER2-mutant NSCLC: Exploratory Biomarker Analysis of SOHO-01. Presented at IASLC 2026 World Conference on Lung Cancer. Abstract MO12.04.