Access to innovative therapies outside clinical trials in pediatric oncology: a national real-world analysis of off-label and compassionate use of targeted therapies and immunotherapies

Background Targeted therapies and immunotherapies are increasingly used in pediatric oncology; however, many innovative agents are prescribed off-label or through compassionate use programs due to limited pediatric approvals and restricted access to clinical trials. Real-world data on these access pathways remain limited. Methods This retrospective multicenter observational study was promoted by the Italian Association of Pediatric Hematology and Oncology (AIEOP) Working Group on New Drugs. Prescriptions made between 2018 and 2023 for patients aged ≤25 years receiving targeted therapies or immunotherapies through off-label or compassionate use were collected from 19 AIEOP pediatric oncology centers, covering approximately 80% of national pediatric cancer cases. Variables included diagnosis, indication, access modality, regulatory status, molecular rationale, treatment duration, discontinuation. Results A total of 562 prescriptions involving 70 drugs were collected. Off-label prescriptions accounted for 77% (n=431) and compassionate use for 23% (n=131). Treatments were mainly for relapsed (46%) or refractory (35%) disease. The most frequent diagnoses were acute lymphoblastic leukemia (n=119, 21%) and gliomas (n=76, 14%). Molecular alterations supporting treatment selection were reported in a subset, including FLT3 , BCR::ABL1 , BRAF , and MAPK alterations. Median treatment duration was 133 days (interquartile range (IQR), 42–399). Discontinuation was mainly due to disease progression (n=216, 47%), completion of planned therapy (n=175, 38%), or toxicity (n=33, 7%). Lack of clinical trials was the main driver for access (n=438, 78%). Median authorization time was 9.5 days (IQR, 5–15)., with bureaucratic complexity as the main barrier. Conclusions Off-label and compassionate use represented a common access pathway for innovative therapies in Italian pediatric oncology, particularly in relapsed or refractory disease. These findings highlight persistent challenges in pediatric drug development, clinical trial availability, and regulatory pathways.