Durvalumab in frail and elder patients with stage four NSCLC: The DURATION trial

Abstract

Background: Elderly patients represent a major population of non-small cell lung cancer (NSCLC) patients in routine clinical practice, yet are underrepresented in clinical trials. In particular, data regarding efficacy and safety in frail or elderly patients with respect to immunotherapy is lacking. Importantly, immunosenescence in elderly patients can result in altered activities of immune-modulating drugs such as PD-1/PDL1 inhibitors. Thus, there is an urgent need to assess safety and efficiency of such inhibitors in this group. Trial design: In this prospective, open label, treatment stratified, and randomized phase II study, 200 patients with stage IV NSCLC, >70 years old and/or “frail” (Charlson Comorbidity Index >1) or restricted performance score (ECOG >1), who are amenable for at least chemotherapy with gemcitabine or vinorelbine, will be included. Patients are stratified after a modified CARG Score (a predicting chemotherapy toxicity score): “Fit” patients are treated with doublet chemotherapy (carboplatin/ nab-paclitaxel), while “unfit” patients receive monochemotherapy (gemcitabine or vinorelbine). Patients are then 1:1 randomized and receive either 4 cycles of chemotherapy+ follow-up every 8 weeks (Arm A/D) or 2 cycles of chemotherapy followed by 2 cycles of durvalumab and subsequent maintenance durvalumab every 4 weeks (Arm B/ C). The primary endpoint is the rate of treatment related grade III/IV adverse events (CTCAE V4.03). As secondary endpoints progression-free survival according to RECIST 1.1, overall survival, descriptive subgroup analyses according to PD-L1 expression, and quality of life will be addressed. Geriatric screening assessments and functional tests will be performed to complete the description of a potential “frail” and “elderly” patient cohort (G8-questionnaire, Timed up & go test, 6MWT). Further, a biomarker profiling program will analyse immune-related effects and potentially identify novel response predictors. The DURATION trial will prospectively investigate the safety and tolerability of PD-L1 treatment with durvalumab after chemotherapy in elderly and frail patients and thereby provide new insights into the effect of PD-L1 blockade and the impact of immunosenescence in this important cohort.