BACKGROUND: Diffuse pleural mesothelioma (dPM) is an aggressive malignancy, primarily treated with palliative systemic therapy. Since 2022, nivolumab-ipilimumab (nivo/ipi) has replaced chemotherapy as the standard first-line treatment for dPM in the Netherlands. Chemotherapy remains a rational second-line treatment. The real-world effectiveness of second-line treatment after doublet immunotherapy remains unknown. The FLORA study aimed to provide an overview of treatment patterns in patients with dPM after first-line nivo/ipi and evaluate the effectiveness of second-line chemotherapy based on real-world data. PATIENTS AND METHODS: FLORA was a Dutch multicenter retrospective cohort study. Clinical data were collected from the medical records. The primary endpoints were treatment patterns after nivo/ipi and median overall survival (mOS) of patients receiving second-line chemotherapy. The secondary endpoints were objective response rate (ORR), median progression-free survival (mPFS) of second-line chemotherapy, and subgroup analyses (Eastern Cooperative Oncology Group performance status and histological subtype). The study also updated the mOS for first-line nivo/ipi patients. RESULTS: Between May 2021 and July 2023, 277 patients with dPM receiving first-line nivo/ipi therapy were included. Sixty-eight percent of the patients were male, with a median age of 72 years (interquartile range 67-77 years). The histological subtypes were epithelioid (62%), sarcomatoid (22%), biphasic (13%), and unknown (3%). One hundred and two (47%) of the 218 patients with disease progression received second-line treatment, of whom 83 received second-line platinum-pemetrexed chemotherapy. The mOS and mPFS for second-line chemotherapy were 8.2 months ([95% confidence interval (CI) 7.4-9.1 months] and 5.6 months (95% CI 4.9-6.3 months), respectively, with an ORR of 37%. Poor performance score was the main reason for not receiving second-line treatment. CONCLUSION: This study provides the first real-world data on subsequent treatment of patients with dPM with disease progression on nivo/ipi, resulting in an mOS of 8.2 months after second-line chemotherapy.