The 22nd National Report on Clinical Trials of Medicinal Products published by the Italian Medicines Agency (AIFA) in July 2026 highlights contrasting trends in Italian clinical research. In 2024, 669 prospective clinical trials were authorized, the highest number recorded in the last three years. Oncology and hemato-oncology remained the leading therapeutic area, accounting for 248 (37%) authorized trials and showing the largest absolute increase compared with 2023. Despite a stable overall number of authorized clinical trials, the composition of Italian clinical research is changing, with a progressive shift towards industry-sponsored and international studies and a decline in the relative contribution of non-commercial investigator-initiated trials (IITs). This decline is particularly relevant to oncology, a field historically supported by academic cooperative groups and independent research networks, especially in rare cancers and areas where IIT research has traditionally complemented commercially sponsored drug development. Several factors, including increasing regulatory, administrative, technological and organizational complexity, may contribute to the observed decline by disproportionately affecting academic sponsors. Strengthening Clinical Trial Units and investing in dedicated research professionals should therefore become a strategic priority. The future competitiveness of Italian oncology research should be measured not only by its ability to attract industry-sponsored trials, but also by its capacity to generate independent research addressing unmet clinical questions and needs.

The increasing complexity of precision medicine has highlighted the limitations of traditional randomized clinical trials (RCTs) when applied to highly stratified populations and biologically heterogeneous diseases. In this context, master protocols represent an evolution towards integrated experimental infrastructures, capable of simultaneously evaluating multiple interventions or molecular subgroups within a single methodological framework.These designs redefine the role of randomization in complex settings. Conventional RCTs remain indispensable as confirmatory studies, thanks to their methodological rigor and the robustness of the evidence they generate.Future developments will depend on the capacity to ensure statistical rigor, transparent governance, data protection and equitable access to experimental infrastructures and advanced molecular screening. In this evolving landscape, master protocols emerge not as a methodological trend, but as one of the most convincing tools for making evidence generation faster, more flexible, and more sustainable without giving up the scientific standards required by contemporary clinical research.

Few innovative treatments were developed for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in the past decades. The paper describes the OCTOPUS project (Optimising Combination Therapy fOr Paediatric, adolescent and yoUng adult patients with non-rhabdomyosarcoma soft tissue Sarcomas), a master protocol and includes an adaptive platform trial comprising different sub-trials, a real-world data registry, translational studies, and overarching study questions assessing local therapy issues and patient reported outcome measures (PROMs). The OCTOPUS consortium will provide an operational framework including a legal consortium structure, a network of national coordinating centres (NCCs) and sites within the EpSSG (European paediatric Soft tissue sarcoma Study Group) and ITCC (Innovative Therapies for Children and adolescents with Cancer) network. The overarching aim of the platform is to improve outcome and quality of life for patients with NRSTS by providing access to innovative treatments. Every sub-trial will have a unique design, tailored to the needs of the patients, the characteristics of the disease, and the stage of development of the experimental compound(s). Depending on the medical need in a specific patient population and the expected activity of a compound (or a combination), the innovative treatment(s) will be offered to patients with relapsed/refractory disease or placed in frontline treatment when appropriate.

Background and aimThere is limited data on the safety of switching between CDK4/6i to address toxicity-related permanent discontinuation in patients with HR+/HER2- advanced breast cancer (ABC).To overcome this issue, this international observational study included consecutive HR+/HER2- ABC patients treated with CDK4/6i at two cancer centers, who switched the CDK4/6i for toxicity. The study aimed to evaluate the safety, feasibility, and clinical impact of this approach.ResultsAmong 1413 patients, 67 (4.5%) switched CDK4/6i due to toxicity. The median time to switch was three months. Adverse events leading to switch were mainly hematologic and hepatic. Recurrence of the same toxicity occurred in 30% of patients, but with lower severity for neutropenia (p=0.047) and hepatotoxicity (p=0.005). Notably, among the 67 patients who switched CDK4/6i, only seven (10%) ultimately required permanent discontinuation of the second CDK4/6i for toxicity, primarily for abemaciclib-induced diarrhea, suggesting that switching may represent a promising strategy to avoid treatment interruption. Median progression-free survival from the start of the first CDK4/6i was 16.8 monthsConclusionIn conclusion, switching CDK4/6i appears to be a safe and pragmatic strategy to address toxicity-related permanent discontinuation of CDK4/6i.