Prophylaxis, clinical management, and monitoring of datopotamab deruxtecan-associated oral mucositis/stomatitis

Abstract

Oral mucositis/stomatitis (hereafter stomatitis) is a common dose-limiting toxicity seen with various classes of cancer treatment. Symptoms associated with stomatitis, primarily oral pain, may impact patient quality of life and may lead to dose delay and reduction or treatment discontinuation. Datopotamab deruxtecan (Dato-DXd) is a novel trophoblast cell surface antigen 2-directed antibody-drug conjugate undergoing clinical investigation in multiple solid tumor types. Stomatitis is among the most reported adverse events associated with Dato-DXd, with most cases being grades 1-2. This article reviews the incidence of stomatitis seen with Dato-DXd, including in the phase III pivotal studies TROPION-Lung01 and TROPION-Breast01 (in patients with non-small cell lung cancer and hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, respectively), both studies met a dual primary endpoint of statistically significant improvement in progression-free survival compared to standard-of-care chemotherapies. Developing new cancer therapies requires evidence-based strategies to successfully prevent, monitor, and manage adverse events. Accordingly, a thorough evaluation of potential underlying mechanisms, risk factors, available clinical data, and adequacy of preventive and management recommendations for stomatitis is presented here. Prophylaxis recommendations for a daily oral care plan include oral hygiene education and the use of a prophylactic steroid-containing mouthwash. Ongoing studies continue to collect data on Dato-DXd-associated stomatitis to further characterize clinical features and possible mechanisms of this toxicity. Appropriate management may reduce the incidence, duration, and severity of events, improve quality of life, and support patient adherence to treatment.

Keywords: antibody-drug conjugate; management; oral mucositis; prophylaxis; stomatitis.

Figure 1.

Five-stage model for mucositis in patients treated with chemotherapy and radiotherapy. This model represents the pathogenesis of stomatitis induced by chemotherapy and radiotherapy. 0-2 days: Initiation phase and primary injury response. Radio- and chemotherapy-induced damages lead to DNA double-strand breaks and oxidative stress and, consequently, generates ROS. The injury to epithelial, submucosal, and endothelial cells provokes the release of endogenous DAMPs. 2-3 days: ROS, innate immune response, and binding of endogenous DAMPs (CRAMPs) to receptors further propagates and activates several transcriptional pathways, including NF-κB. This leads to the production of inflammatory cytokines, such as TNF-α and IL-6. 2-10 days: Amplification of the injury signal. The effectors produced during the previous phase result in an amplification of the injury signal. The released TNF-α initiates the activation of MAPK that sustains NF-κB activity. During this stage, the primary damage signaling is amplified through positive-feedback loop mechanisms. 10-15 days: Ulceration. Breaks in the submucosa allow microorganisms to invade this tissue district leading to mononuclear-infiltrating cell-mediated inflammation response. 15-21 days: Tissue re-epithelialization. Stimuli from the submucosa extracellular matrix and mesenchyme promote the healing process. Abbreviations: CRAMP, chemoradiation-associated pattern molecule; DAMP, damage-associated pattern molecule; IL, interleukin; MAPK, mitogen-activated protein kinase; MMP, metalloproteinase; NF-κB, nuclear factor kappa B; ROS, reactive oxygen species; TNF, tumor necrosis factor. Reprinted from Cancers (Basel), Vol 11, Basile D, et al. Mucosal injury during anti-cancer treatment: from pathobiology to bedside, pg 857, 2019, with permission from MDPI. https://creativecommons.org/licenses/by/4.0/.

Figure 2.

Stomatitis management recommendations. These guidelines reflect those that were in place in the clinical development program from December 5, 2022, and are continually being updated with the emergence of new safety data. ^aFor example, Dexamethasone 0.1 mg/mL oral solution (10 mL, 4 times per day, swish for 1-2 minutes then spit out). Similar mouthwash regimens using an alternative steroid can be used as advocated by institutional/local guidelines. Oral nystatin suspension or other topical antifungal agents can be used ≤15 minutes after the steroid-containing mouthwash as advocated by institutional/local guidelines. ^bIn the absence of a steroid-containing mouthwash, daily use of an inert, bland mouthwash is acceptable. For example, non-alcoholic and/or bicarbonate-containing mouthwash (4-6 times per day). ^cDoxepin 0.5%, viscous lidocaine 2%. Abbreviations: Dato-DXd, datopotamab deruxtecan. Reprinted from Cancer Treatment Reviews, Vol 125, Heist R, et al., Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan, pg 102720, 2024, with permission from Elsevier.