Extended interval dosing in patients with cancer receiving immune checkpoint inhibitors: Safety analysis from the EDICI study.
Authors: Cantini Luca , Paoloni Francesco , Pecci Federica , Spagnolo Francesco , Aerts Sophie , Indini Alice , Fancelli Sara , Citarella Fabrizio , Garutti Mattia , Sergi Maria Chiara , Giusti Raffaele , Di Giacomo Anna Maria , Veccia Antonello , Cortinovis Diego Luigi , Leporati Rita , Scaglione Ilaria Mariangela , Atzori Francesco , Festino Lucia , Aerts Joachim , Berardi Rossana 
Published: June 2022

2595

Background: Healthcare costs and need of frequent patients' (pts) access to oncology departments led to an increasing interest in alternative immune check-point inhibitors (ICIs) administration schedules able to offer longer dose intervals. The extended interval dosing (ED) of nivolumab and pembrolizumab was approved based on pharmacokinetic data, the relationship of exposure to efficacy, and the relationship of exposure to safety. We aimed to investigate real-life immune-related adverse events (irAEs) incidence in pts treated with ED-ICIs. Methods: Clinicopathological and treatment characteristics of all consecutive solid cancer pts treated with ICIs (pembrolizumab, nivolumab) monotherapy who received at least one cycle of the ED (pembrolizumab 400 every 6 weeks or nivolumab 480 mg every 4 weeks) were identified from patient electronic records of 37 oncology departments across Europe and entered into a prospectively maintained database. Results: Among 756 pts enrolled in the EDICI study, 733 pts (229 treated with pembrolizumab, and 504 with nivolumab) were included in the final safety analysis (median follow up time: 24.7 months). 476 pts were males, with melanoma (441, 60%) and non-small cell lung cancer (151, 20%) being the prevalent tumor types. Median age was 67 years old, and 589 (80%) pts received ICIs in the advanced setting. 501 (68%) of the enrolled pts started ICIs with canonical interval dosing (CD, median number of cycles administered: 13) and subsequently switched to ED after a median time interval of 210 days. During CD-ICI, 197 pts (39%) developed irAEs of any grade and 14 patients (3%) G3/G4 events; after switching to ED-ICI treatment, which was administered for a median of 7 cycles and 336 days, irAEs of any grade and G3/G4 events were experienced by 155 (36%) and 20 (5%) pts, respectively; 73 (47%) cases of any grade-toxicity and 12 (60%) of G3/G4-toxicity were de novo. 33 (7%) pts switched back to CD, in 45% of the cases due to toxicity. Pts who started upfront with ED (n = 232, 32%) were exposed to the drug for a median of 7 cycles; 56 of them (25%) developed irAEs of any grade and 9 (6%) G3/G4 irAEs. Skin (12% of patients), endocrine (11%), rheumatic (10%) and gastrointestinal (9%) were the most common irAEs during ED; 42% were “multiple-site” irAEs, showing no difference with CD (p = 0.21). Lower creatinine values before switch to ED (adjusted odds ratio [aOR], 1.24; 95%CI, 1.03-1.48; P = 0.02) and previous toxicity during CD (aOR, 1.20; 95%CI, 1.08-1.33; P < 0.01) were independent risk factors for development of irAEs during ED. Conclusions: Despite similar exposure time, the safety profile of ED treatment did not differ from CD, confirming that ED-ICI administration is a safe and feasible option also in cancer pts outside of clinical trials. Future investigations are needed to explore efficacy data and economic impact of this strategy.