Background <p>Datopotamab deruxtecan (Dato-DXd) is an investigational antibody–drug conjugate that has shown promising results in phase III clinical trials of lung and breast cancers. Stomatitis is a common adverse event associated with Dato-DXd in these trials, and there are currently no formalized guidelines for its prevention and management. An expert consensus was needed to establish these guidelines.</p> Methods <p>Fifteen experts participated in a modified three-round Delphi to achieve consensus on the prevention and management of Dato-DXd-related stomatitis in lung and breast cancer patients. Fourteen experts had managed Dato-DXd-induced stomatitis and served as investigators in the TROPION-Lung01, TROPION-Lung05, and TROPION-Breast01 phase III clinical trials. The first two rounds consisted of anonymized surveys with a mixture of open- and closed-ended questions, and the third round consisted of a consensus group meeting and 1:1 follow-up meetings.</p> Findings <p>Experts recognized stomatitis as an important adverse event associated with several anticancer treatments and its impact on patients’ quality of life. Lung and breast cancer specialists noted similar manifestations of stomatitis with Dato-DXd, with breast cancer experts referencing similarities to everolimus-induced conditions and lung cancer experts reporting ulcerative lesions. There was consensus on the need for standardized guidelines to improve outcomes and reduce treatment disruptions. Agreed preventive measures emphasized patient education, oral hygiene, and prophylactic mouthwashes. Management strategies focused on patient-centered care, monitoring of symptoms, and timely interventions, such as the use of a steroid-containing mouthwash to maintain treatment schedules and quality of life.</p> Interpretation <p>We used the expert consensus to provide guidelines for the prevention and management of stomatitis in patients treated with Dato-DXd.</p> Putting research into context Evidence before this study <p>Dato-DXd has shown promising results in clinical trials for lung and breast cancers. However, many patients in these trials developed stomatitis, an adverse event that may impact quality of life and disrupt treatment regimens. The lack of standardized guidelines for dealing with stomatitis in this context necessitated the establishment of best practices via expert consensus.</p> Added value of this study <p>This study provides peer-reviewed guidance for the prevention and management of stomatitis secondary to Dato-DXd. Most experts selected for this study had experience using this therapy and preventing and managing stomatitis associated with Dato-DXd and other anticancer treatments. Thus, the study has collected the perspectives of well-placed, expert clinicians and derived best practices pending the completion of clinical trials.</p> Implications of all the available evidence <p>The development and implementation of this guidance and the education therein will lead to improved quality of life, greater treatment compliance, and better clinical outcomes.</p>