Abstract / Summary
Olorofim, the first orotomide antifungal, is active against Aspergillus spp., Lomentospora prolificans, Scedosporium spp. and Coccidioides spp. We reviewed published clinical reports of olorofim in invasive fungal disease (IFD) with limited or no treatment options. PubMed/MEDLINE, Europe PMC, Crossref, ClinicalTrials.gov and web sources were searched up to 1 September 2026 (PRISMA 2020; OSF registration). Trials, cohorts, case series and case reports of olorofim-treated patients were eligible; quality was appraised with JBI checklists and comparable safety and mortality data from the trial and the cohort studies were pooled (random-effects models), with case reports confined to narrative synthesis. Twenty-one reports were included: a single-arm phase 2b trial (202 evaluable patients) with three secondary reports, two cohorts (17 and 5 treated patients), a 3-patient series and 14 case reports. In the trial, adjudicated global response was 28.7% at day 42 and 27.2% at day 84 (75.2% and 63.4% including stable disease), with day-42 response of 42.3% in Lomentospora and 36.4% in Scedosporium infection; all-cause mortality was 11.9% and 16.3%; olorofim-attributed liver enzyme elevation occurred in 9.9%. Clinical success in disseminated coccidioidomycosis was 75.6% at day 42, with no deaths. Among 17 individually reported patients, infection was controlled in 10 and treatment failed in 5. Pooled olorofim-attributed liver enzyme elevation across non-overlapping trial and cohort groups was 10.8% (95% CI 4.0 to 26.3; I2 = 75%) and pooled early mortality was 19.5% (11.0 to 32.1; I2 = 44%). Adverse events were not addressed in 6 of the 14 case reports. In heavily pretreated patients, oral olorofim achieved strict global response in about one quarter, disease control in most and low early mortality; hepatotoxicity is the main safety signal, although safety reporting in the case literature is incomplete. Evidence is uncontrolled; randomised data are needed.