Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions

Abstract

Purpose: The clinical relevance of different time-to-deterioration (TTD) definitions for patient-reported outcomes were explored.

Methods: TTD definitions differing by reference score and deterioration event were used to analyse data from the phase 3 FLAURA trial of first-line osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small cell lung cancer. Pre-specified key symptoms were fatigue, appetite loss, cough, chest pain and dyspnoea, scored using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 questionnaires (≥ 10-point difference = clinically relevant).

Results: No significant treatment differences in TTD (distributions) were observed using definitions based on transient or definitive deterioration alone. TTD definitions based on definitive, sustained deterioration, with death not included as an event, yielded a significant treatment difference for dyspnoea (hazard ratio [HR] 0.71; P = 0.034) when baseline was the reference, and for cough (HR 0.70; P = 0.009) and dyspnoea (HR 0.71; P = 0.004) when best previous score was the reference. With death included as an event, treatment differences were significant for dyspnoea (HR 0.70; P = 0.025) when baseline was the reference, and for cough (HR 0.70; P = 0.011), dyspnoea (HR 0.71; P = 0.003) and chest pain (HR 0.71; P = 0.038) when best previous score was the reference. Irrespective of definition, TTD for appetite loss and fatigue did not differ significantly between arms.

Conclusion: This exploratory work showed that different TTD definitions yield different magnitudes of treatment difference, highlighting the importance of pre-specifying TTD definitions upfront in clinical trials.

Clinical trial registration: ClinicalTrials.gov NCT02296125.

Keywords: Disease progression; Non-small cell lung cancer; Patient-reported outcomes.

Conflict of interest statement

AW and AR are employees of AstraZeneca and hold AstraZeneca shares. KS and MC are employed by IQVIA, which received funds from AstraZeneca to conduct the time-to-deterioration analysis of the study data.

© 2022. The Author(s).

Figures

Fig. 1

TTD analysis of pre-specified key symptoms for six different TTD definitions assessed using Kaplan–Meier estimates, with death not counted as an event. HRs with 95% CIs were calculated using a stratified Cox regression model with the stratification variables mutation type and race, and the covariates treatment, baseline score and baseline central nervous system metastasis status. aOsimertinib (n = 279)/gefitinib or erlotinib (n = 277)

Fig. 2

Linear-time MMRM (left panels) and observed means (right panels) for PROs before radiographically progressed disease or death in patients who had radiographic disease progression or who died