Patient-reported outcomes for identification of distinct tolerance phenotypes with differential survival impact under osimertinib in EGFR-mutated NSCLC.

Abstract

e24178 Background: In advanced EGFR-mutated NSCLC, osimertinib is administered over prolonged periods, making patient-reported symptom burden a key determinant of quality of life and treatment sustainability. Clinician-reported safety assessments incompletely capture low-grade, cumulative, and patient-relevant toxicities. We hypothesized that longitudinal patient-reported outcomes (PROs) could identify clinically meaningful tolerance phenotypes with prognostic implications. Methods: Structured longitudinal PRO data from 94 patients treated with osimertinib were analyzed, covering 89 symptom domains with severity and timing. PROs were collected using a validated, web-based tool (Cureety), with high compliance and systematic weekly reporting throughout treatment. Symptoms were assessed based on prevalence, temporal relationship to drug exposure, and biological plausibility. Unsupervised hierarchical clustering identified tolerance phenotypes. Associations with dose modification and exploratory survival outcomes were evaluated. Results: Patients reported a substantial symptom burden, with a median of 8 symptoms per patient (range 0–32). Three distinct and clinically interpretable tolerance phenotypes were identified. The Early On-Target Toxicity Phenotype (≈33%) was characterized by early dermatologic and gastrointestinal toxicities (rash, diarrhea, mucositis) and the highest rate of dose modification (≈25–30%). Median progression free survival (PFS) and overall survival (OS) in this group were 12.5 months and 22.1 months, respectively. The Cumulative Burden Phenotype (≈30%) was dominated by persistent constitutional and neurocognitive symptoms (fatigue, anorexia, dizziness, cognitive complaints) emerging with prolonged exposure, and showed an unfavorable survival trend (median PFS 9.1 months, OS 16.8 months). The Clinically Silent Exposure Phenotype (≈37%) was characterized by minimal persistent symptoms and low rates of dose modification ( < 10%) and were associated with longer survival (median PFS 18.4 months, OS 34.6 months). Conclusions: PRO-based monitoring reveals distinct tolerance phenotypes under osimertinib with differential survival outcomes. These symptoms may reflect adequate systemic drug exposure rather than toxicity-driven treatment compromise. These findings support integrating longitudinal PRO monitoring into routine care and future trials to individualize dose management and follow-up strategies. Key patient-reported tolerance profiles and outcomes. Phenotype / Symptom Proportion (%) Median PFS (mo) Median OS (mo) Early on-target toxicity phenotype ~33 12.5 22.1 Cumulative burden phenotype ~30 9.1 16.8 Clinically silent exposure phenotype ~37 18.4 34.6