Four-year follow-up and re-treatment of mesothelioma patients with combined tremelimumab and durvalumab: the NIBIT-MESO-1 study

Background: The NIBIT-MESO-1 study demonstrated the activity and safety of tremelimumab combined with durvalumab in unresectable mesothelioma (Calabrò L et al. Lancet Resp Med 2018; 6:451-460). We report four-year survival and retreatment outcomes from this study, and the role of tumor mutational burden (TMB) in identifying patients with a better outcome to combined therapy. Methods: Patients with disease progression following initial clinical benefit were eligible for retreatment and received intravenous tremelimumab (1 mg/kg) and durvalumab (20 mg/kg) every four weeks (Q4W) for 4 doses, then maintenance durvalumab (20 mg/kg) Q4W for nine doses. Tumour response per immune-related (ir)-modified RECIST criteria, overall survival, safety, and immuno-biologic correlates of clinical activity were evaluated. This study is registered with ClinicalTrials.gov, number NCT0258813. Findings: At a median follow-up of 52 months (IQR: 49-53), median overall survival of the 40 patients enrolled in the study was 16·5 months (IQR: 9·4-29·3); 3- and 4-year survival rates were 20% and 14·6%, respectively. Seventeen (42·5%) patients were re-treated; 7/17 (41·2%) achieved ir-stable disease. At a median follow-up of 24 months (IQR: 22-25), median overall survival was 12·5 months (IQR: 5·8-20·5), and 2-year survival was 23·5%. There were no grade 3-4 ir-AEs. Patients with a TMB above the median value of 8·3 mutations/Mb had the highest median overall survival. Interpretation: Tremelimumab combined with durvalumab induced long-term survival in mesothelioma patients. Retreatment was clinically meaningful and safe, and merits further investigation. TMB at baseline identified patients with more favourable outcome to therapy.