Active symptom control with or without oral vinorelbine in patients with relapsed malignant pleural mesothelioma (VIM): A randomised, phase 2 trial.

Background: Currently, there is no US Food and Drug Administration approved therapy for patients with pleural mesothelioma who have relapsed following platinum-doublet based chemotherapy. Vinorelbine has demonstrated useful clinical activity in mesothelioma, however its efficacy has not been formally evaluated in a randomised setting. BRCA1 expression is required for vinorelbine induced apoptosis in preclinical models. Loss of expression may therefore correlate with vinorelbine resistance.
Methods: In this randomised, phase 2 trial, patients were eligible if they met the following criteria: age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, histologically confirmed pleural mesothelioma, post platinum-based chemotherapy, and radiological evidence of disease progression. Consented patients were randomised 2:1 to either active symptom control with oral vinorelbine versus active symptom control (ASC) every 3 weeks until disease progression, unacceptable toxicity or withdrawal at an initial dose of 60 mg/m ² increasing to 80 mg/m ² post-cycle 1. Randomisation was stratified by histological subtype, white cell count, gender, ECOG performance status and best response during first-line therapy. The study was open label. The primary endpoint was progression-free survival (PFS), measured from randomisation to time of event (or censoring). Analyses were carried out according to intention-to-treat (ITT) principles. Recruitment and trial follow-up are complete. This trial is registered with ClinicalTrials.gov, number NCT02139904.
Findings: Between June 1, 2016 and Oct 31, 2018, we performed a randomised phase 2 trial in 14 hospitals in the United Kingdom. 225 patients were screened for eligibility, of whom 154 were randomly assigned to receive either ASC + vinorelbine ( n  = 98) or ASC ( n  = 56). PFS was significantly longer for ASC+vinorelbine compared with ASC alone; 4.2 months (interquartile range (IQR) 2.2-8.0) versus 2.8 months (IQR 1.4-4.1) for ASC, giving an unadjusted hazard ratio (HR) of 0·60 (80% CI upper limit 0.7, one-sided unadjusted log rank test p  = 0.002); adjusted HR 0.6 (80% CI upper limit 0.7, one-sided adjusted log rank test p  < 0.001). BRCA1 did not predict resistance to ASC+vinorelbine. Neutropenia was the most common grades 3, 4 adverse events in the ASC +vinorelbine arm.
Interpretation: Vinorelbine plus ASC confers clinical benefit to patients with relapsed pleural mesothelioma who have progressed following platinum-based doublet chemotherapy.
Funding: This study was funded by Cancer Research UK (grant CRUK A15569).
Competing Interests: Prof Fennell reports grants from Astex Therapeutics, Boehringer Ingelheim, MSD, and Bayer; personal fees from Aldeyra, Inventiva, and Paredox; non-financial support from Clovis, Eli Lilly, and BMS; and personal fees and non-financial support from Roche, during the conduct of the study. Prof Griffiths reports grants from Jannsen-cilag, grants and personal fees from AZ, grants from Novartis, grants from Astex, grants from Roche, grants from Heartflow, personal fees from Celldex, grants from BMS, grants from BioNtech, outside the submitted work. All other authors declare no competing interests.
(© 2022 The Authors.)