102P - Dynamic profiling of ctDNA in HER2-alterated advanced NSCLC treated with pyrotinib and apatinib: Exploratory biomarker analysis from a phase II trial

Background

The PATHER2 trial demonstrated the promising antitumor activity of pyrotinib plus apatinib in HER2-mutated or HER2-amplified advanced non-small cell lung cancer (NSCLC). This study aims to characterize the association between circulating tumor DNA (ctDNA) and treatment responses, as well as explore potential resistance mechanisms.

Methods

Among 27 HER2-alterated advanced NSCLC patients (pts) in PATHER2 cohort, 58 ctDNA samples were collected at various time points (baseline (n=27), after first treatment cycle (C1, n=13), after disease progression (n=18)). ctDNA was extracted with HiPure Circulating DNA Kit, and targeted sequencing was performed on 556 cancer-relevant genes.

Results

Analysis of 27 pts (25 HER2-mutated and 2 HER2-amplified) revealed a median progression-free survival (PFS) of 6.93 months. Baseline ctDNA analysis showed that mutations in TP53 (P=0.01), DNMT3A (P=0.02), ARID1B (P=0.04) were associated with shorter PFS. The presence or higher variant allele frequency (VAF) of HER2 mutations were not associated with PFS. Among the clinical and pathological characteristics analyzed (including age, gender, TNM staging, smoking history, number of organ metastases number, and lines of treatment), number of organ metastases was significantly associated with shorter PFS (P=0.001). A Cox regression model incorporating the significant clinical and mutational features for PFS was constructed, with TP53 and DNMT3A mutations remaining significant. Analysis of C1 ctDNA showed that clearance of HER2 mutations was associated with improved patient prognosis (PFS: 7.53 mo vs 4.43 mo, P=0.021). Analysis of post-progression samples revealed novel mutations in HER2, including A775_G776insSV, G776C, G776V, T772_A775dup. Additionally, 35 genes with novel mutations were enriched in chromatin remodeling pathways (n=14), including SMARCA4, ARID1B, and CREBBP.

Conclusions

Dynamic ctDNA characterization showed baseline TP53 wild type, DNMT3A wild type, HER2 clearance after C1 were associated with better efficacy of pyrotinib plus apatinib in HER2-alterated advanced NSCLC pts. Chromatin remodeling emerges as a potential mechanism for resistance to pyrotinib plus apatinib.

Clinical trial identification

PATHER2 trial: ChiCTR1900021684.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Peking Union Medical College.

Disclosure

All authors have declared no conflicts of interest.