SYS6010 is an antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). We report the results of a phase 1 trial (ChiCTR2300072141) of SYS6010 in patients with non-small cell lung cancer (NSCLC). A total of 236 patients were treated. One dose-limiting toxicity occurred at 6.4 mg/kg; therefore, 4.2, 4.5, and 4.8 mg/kg were selected for cohort expansion. Treatment-related adverse events (TRAEs; any/grade ≥ 3) occurred in 99.6%/57.2% of patients. Common grade ≥3 TRAEs included neutropenia (30.9%), leukopenia (25.0%), and thrombocytopenia (17.4%). Objective response rate was 34.7% in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum chemotherapy, 45.7% in EGFR-mutant NSCLC treated with EGFR TKIs, 20.0% in EGFR wild-type squamous NSCLC, and 35.7% in EGFR wild-type non-squamous NSCLC. Median progression-free survival and overall survival were 7.6 and 19.4 months, respectively, in EGFR-mutant NSCLC treated with EGFR TKIs and platinum chemotherapy. Overall, SYS6010 shows a manageable safety profile and encouraging antitumor activity in previously treated, advanced NSCLC.
Zi-Ming Li, Zhen Zhou, Zhi-Yong He et al.· Cancer Cell· 0 citations
Neoadjuvant chemoimmunotherapy has reshaped the treatment landscape for non-small cell lung cancer (NSCLC), yet critical gaps remain in real-time monitoring and personalized adaptation.
In this observational study, patients were evaluated via imaging and multidisciplinary review for subsequent surgery or radiotherapy after neoadjuvant chemoimmunotherapy. Serial plasma samples for circulating tumor DNA (ctDNA) dynamics and mutational analyses were collected. The endpoint was event-free survival (EFS). A pognostic mutational signature was developed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression.
Among the 138 patients, 46.4% and 52.2% underwent surgery and radiotherapy, respectively. Compared to patients with persistently positive ctDNA, the ctDNA non-shedder exhibited a numerically longer EFS (hazard ratio [HR] 0.26, 95% CI: 0.06–1.25,
p
= 0.062), and the clearance group exhibited a statistically longer EFS (HR 0.33, 95% CI: 0.11–0.97,
p
= 0.040). Patients with positive ctDNA before surgery/radiotherapy showed a shorter EFS (HR 3.38, 95% CI: 1.26–9.08,
p
= 0.010), and positive ctDNA was correlated with a numerically shorter EFS (HR 9.72, 95% CI: 0.98–95.96,
p
= 0.051) in patients assessed as stable disease (SD) of high heterogeneity in the exploratory subgroup analysis. For patients with post-C1 negative ctDNA, no EFS difference was observed between those receiving 3–4 versus 2 cycles of chemoimmunotherapy (HR 1.54, 95% CI: 0.56–4.26,
p
= 0.41). For patients with post-C1 positive ctDNA, the post-C1 quantity was associated with clearance (AUC = 0.72, 95% CI: 0.55–0.89,
p
= 0.019). After balancing clinical characteristics, LASSO-Cox regression selected four genes (SLX4, IRF4, TP53, and SOX2) to construct a prognostic signature for EFS. The AUC at 36 months was 0.75, 0.71, 0.74 in the training, validation and full cohort. The high-risk group demonstrated a shorter EFS (
p
= 0.0002).
Longitudinal ctDNA assessment identified high-risk subgroups in neoadjuvant NSCLC, particularly by refining prognosis in heterogeneous SD populations. An exploratory gene-based mutational signature provided potential molecular risk stratification.
Wenxin Jiang, Siyu Lei, Sijie Liu et al.· Respiratory Research· 0 citations
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