Objectives: Treatment optimization studies (TOS) are clinical trials that address research questions which fall outside of a commercial and regulatory scope despite their inherent value to health technology assessment and reimbursement-related decision-making. Examples include comparative effectiveness, dose de-escalation and combination therapy studies. Historically, such trials have mainly been undertaken by academic groups and independent not-for-profit organizations such as the EORTC. The objective of this study was to characterize the TOS performed by the EORTC in the past and determine their scientific impact so as to guide the setup of future TOS. Methods: We searched the EORTC clinical trials database for studies fitting the definition of TOS within the areas of breast, lung and colorectal cancer. In total, 110 trials conducted between the 1980s and 2010s were selected. Subsequently, we analyzed both publicly available sources of information (e.g. journal publications and ClinicalTrials.gov records) and internal documents (e.g. trial protocols and statistical reports) to further analyze these studies based on a number of predefined criteria. Results: Of the included TOS, the majority employed a phase III (71.8%), randomized (91.8%), open-label (92.7%) design and featured an active comparator treatment consisting of the standard of care (74.5%). They enrolled 332 patients and were carried out across 35 sites and 9 countries (median values). Results of completed studies (positive or negative) were published in 95.9% of cases, mostly (87.2%) in journals with an impact factor of 6 or higher, and the associated articles received a median of 75 citations. Additional analyses of the endpoints and selection criteria used are currently being performed. Conclusions: The breast, lung and colorectal cancer TOS conducted by the EORTC over the past four decades were typically large, multicenter, international trials with a randomized open-label design and an active comparator treatment representing the standard of care. Their scientific impact was substantial.