Feasibility of half-dose dual-targeted therapy in advanced solid tumors with NGS-proven actionable targets: A comparative analysis with OMCT.

Abstract

e14659 Background: Inspired by the efficacy of low-dose combination therapies in overcoming resistance in EGFR inhibitor-resistant NSCLC (Nature Communications), this study explores a similar strategy in advanced solid tumors. Standard-dose targeted therapies often face toxicity-related limitations in combinatory use. While metronomic chemotherapy (OMCT) reduces toxicity, it may not fully leverage molecular vulnerabilities .This feasibility study evaluates a novel approach using half-dose dual-targeted therapies, combining monoclonal antibodies (mAbs) or tyrosine kinase inhibitors (TKIs), to balance efficacy with reduced adverse effects. Methods: A multicentric, retrospective analysis was conducted on 48 patients with advanced solid tumors beyond the fourth line of therapy, all harboring at least two actionable targets via NGS. Patients were assigned to two arms: Intervention Arm: Half-dose dual-targeted therapy (n=24). Control Arm: Standard OMCT regimen (n=24). Results: NGS identified 376 non-silent mutations across 48 samples, with common mutations in CDK (46%), PIK3 (38%), RET (35%), EGFR (30%), and AR (25%). Most mutations were missense (84.3%). Efficacy: Median overall survival (OS) was longer in the intervention arm (11.4 ± 6.7 months) than the control arm (9.6 ± 3.8 months, p=0.02). Complete response (CR) was observed only in the intervention arm (n=2). Partial response (PR) was more frequent in the intervention arm (n=15 vs. 11, p=0.40), while stable disease (SD) was higher in the control arm (n=11 vs. 4, p=0.028). Safety: Grade III/IV adverse events (AEs) were more in interventional arm (n=3 vs. 11, p=0.001). Grade I/II AEs were comparable between arms (n=17 vs. 19, p=0.3). Quality of Life (QOL): QOL improvements were higher in the intervention arm (mean score 11.8 ± 3.6 vs. 7.6 ± 2.5, p=0.03). Time Without Symptoms or Toxicity (TWISTT): The intervention arm showed longer TWISTT durations (182 ± 51 days vs. 148 ± 36 days, p=0.01). Conclusions: This study highlights that half-dose dual-targeted therapy, leveraging mAbs and TKIs, offers a viable alternative to OMCT in advanced solid tumors with actionable targets. Targeting key mutations such as CDK , PIK3 , RET , EGFR , and AR showed promising results in improving efficacy, safety, and patient quality of life. Further prospective studies are needed to validate these . Demographic data. Characteristic Overall n=48 Doubket MAB/ TKI n=24 OMCT n=24 P-value Female : Male 7:5 7:5 1 Grade III/IV Adverse Events 14 11 3 0.001 Grade I/II Adverse Events 36 17 19 0.3 Complete response (CR) 2 2 0 0.317311 Partial Response (PR) 26 15 11 0.405381 Stable Disease (SD) 15 4 11 0.02846 Progressive Disease (PD) 5 3 2 1 Median OS (months) Mean+SD 11.4+6.7 9.6+3.8 0.02 QOL- improvement on scale of 50 (mean+SD) 7.6+2.5 11.8+3.6 0.03 TWISTT score- days (Mean+SD) 148+36 182+51 0.01