A combination of sintilimab, anlotinib, and chemotherapy has shown promising efficacy in patients with relapsed small cell lung cancer (SCLC), according to a recent study. The trial, which included 25 patients, demonstrated a confirmed objective response rate (ORR) of 60% and a median overall survival (OS) of 13.4 months, offering a potential new treatment option for this aggressive cancer.
Efficacy and Outcomes
The study revealed that 15 out of 25 patients experienced a confirmed partial response (PR), while 4 patients had stable disease (SD). The confirmed ORR was 60% (95% CI: 38.7–78.9%), and the disease control rate (DCR) was 76% (95% CI: 54.9–90.6%). The median time to response was 1.9 months (95% CI: 1.57–NA), and the median duration of response (DOR) was 5.2 months (95% CI: 4.1–11.7). The median progression-free survival (mPFS) was 6.0 months (95% CI: 5.4–9.7), with a 6-month PFS rate of 49.2%. The median OS was 13.4 months (95% CI: 11.8–NR), and the 12-month OS rate was 62.2%.
Safety Profile
The combination therapy was generally well-tolerated. The most common treatment-related adverse events (TRAEs) of any grade were leukopenia (56.0%), anemia (52.0%), and elevated γ-glutamyltransferase (GGT) (48.0%). Grade 3 or 4 TRAEs occurred in 16% of patients, with elevated aspartate aminotransferase (AST) being the most common. Serious adverse events occurred in three patients, and TRAEs leading to drug discontinuation occurred in two patients. No treatment-related deaths were reported.
ctDNA Analysis and Biomarker Discovery
Exploratory analysis of circulating tumor DNA (ctDNA) revealed that the most frequently mutated genes included TP53 (88%), MUC16 (56%), RB1 (44%), DNMT3A (31%), and ZFHX4 (31%). Notably, the presence of KMT2D mutations showed a trend towards a negative impact on survival, with a hazard ratio (HR) of 4.103 (95% CI: 0.968–17.382, p = 0.055). Patients with KMT2D mutations experienced shorter PFS (Log-Rank p = 0.038), suggesting a potential role of KMT2D mutations in treatment resistance.
Further analysis showed that low on-treatment bTMB was correlated with improved outcomes, with an HR of 0.197 (95% CI: 0.037–1.037, p = 0.055). Patients exhibiting high on-treatment bTMB levels during treatment demonstrated markedly improved PFS (Log-rank P = 0.034) and OS (Log-rank P = 0.005), suggesting on-treatment bTMB as a predictive biomarker for therapeutic efficacy.
Functional and Epigenetic Consequences of KMT2D Mutations
Comparative analysis of KMT2D protein levels revealed a significant reduction in the mutant (MUT) group compared to the wild-type (WT) group (p < 0.01). Epigenetic changes associated with KMT2D mutations highlighted the regulatory impact of such mutations on gene expressions, particularly affecting histone methylation, chromatin disassembly, and protein–DNA complex disassembly. Enrichment analysis indicated that histone H3K9 trimethylation, a critical marker of gene silencing, was the most significantly impacted process (p < 0.01), underscoring the profound epigenetic influence exerted by KMT2D mutations in SCLC.
Modulation of Cellular and Immune Pathways by KMT2D Mutations
Significant pathway suppression was observed in KMT2D mutant cells, particularly in apoptotic signaling and immune response pathways. Comparative protein expression analysis demonstrated significant downregulation of key apoptosis-related proteins in the presence of KMT2D mutations, indicating a broad impact on cellular stress responses and apoptotic mechanisms. GSEA highlighted notable downregulation of antigen processing and presentation pathways, highlighting potential immune evasion by mutant cells.
The findings suggest that the combination of sintilimab, anlotinib, and chemotherapy may offer a valuable treatment option for patients with relapsed SCLC. Further research is needed to validate these results and to explore the potential of KMT2D mutations and bTMB as predictive biomarkers.
