Toxicity Management for Dato-DXd: Stomatitis, Eye Issues, and ILD

In an interview with Targeted Oncology, Jacob Sands, MD, medical oncologist at Dana-Farber Cancer Center, discusses toxicities associated with datopotamab deruxtecan (Dato-DXd; Datroway) and their management.

For patients undergoing treatment with Dato-DXd, there are several distinct toxicities to monitor, though these are not exclusive to Dato-DXd and have been observed with other regimens. These include stomatitis/mucositis, eye surface toxicity, and interstitial lung disease (ILD).

Stomatitis/Mucositis

Stomatitis and mucositis were commonly observed, affecting over 50% of patients. While a significant portion of these cases were grade 1, meaning they were asymptomatic and detected only on examination without impacting the patient's quality of life or eating habits, grade 2 and higher toxicities present more challenges. Grade 2 stomatitis involves noticeable symptoms that can significantly affect a patient's daily life and comfort, especially if persistent. More severe cases, classified as grade 3, are certainly more debilitating.

Management strategies for stomatitis/mucositis include:

• Steroid mouth rinses: These are a primary recommendation, and in some cases, prophylactic use may be considered. While initial trials like Tropion-Lung01 and Tropion-Lung05 did not fully reflect the benefits of early steroid mouth rinse intervention due to their late incorporation into the protocols, subsequent breast cancer trials with Dato-DXd showed a reduction in mucositis rates when steroid mouth rinses were introduced earlier. It is still being investigated whether this reduction is solely due to the rinses or other population differences.
• Ice chips: Using ice chips during infusion may help reduce drug exposure to mucous membranes by causing vasoconstriction, thereby limiting blood flow to these areas. Ice chips can also provide symptomatic relief for patients experiencing discomfort from stomatitis.
• Oral hygiene: Maintaining good oral hygiene is a crucial first step. This includes using a soft toothbrush and avoiding irritants like spicy foods and alcohol, which can exacerbate symptoms.

If a patient experiences persistent grade 2 or higher stomatitis that impacts their well-being, resolution is necessary before the next dose. This may lead to dose delays or, in prolonged cases, dose reductions. While dose reduction may slightly impact efficacy compared to the standard 6 mg/kg starting dose, it generally leads to a significant improvement in symptoms and maintains a degree of therapeutic benefit.

Eye Surface Toxicity

Eye surface toxicity is another observed side effect, though it is less problematic than stomatitis. The exact mechanism is not fully understood, but clinically, it often manifests similarly to dry eye. The recommended treatment is typically preservative-free lubricating eye drops, which have proven effective for the vast majority of patients.

While the product label recommends a baseline ophthalmologic exam, obtaining a prompt appointment with an ophthalmologist can be challenging. Therefore, treatment should not be delayed for this unless there are specific, compelling circumstances. If patients develop symptoms such as eye irritation or watering after starting Dato-DXd, initiating preservative-free lubricating eye drops is recommended, and a subsequent ophthalmology consultation within a month is generally sufficient. More severe symptoms like vision changes or "beefy red eyes" (as described by ophthalmologists) warrant an emergent ophthalmology visit, though such severe presentations have not been commonly observed with Dato-DXd.

Interstitial Lung Disease (ILD)

ILD is a more serious, though less frequent, toxicity, observed in approximately 4% of patients in combined EGFR cohorts from TROPION-Lung01 and TROPION-Lung05. While most cases were grade 1 or 2, grade 5 (fatal) events have been reported in larger cohorts across various studies involving deruxtecan-payload drugs (eg, patritumab deruxtecan, trastuzumab deruxtecan, and ifinatumab deruxtecan). This highlights the need for vigilance.

Diagnosing drug-related ILD can be challenging, as grade 1 ILD may present as asymptomatic inflammatory findings on scans that can wax and wane. Grade 2 ILD involves symptoms, ranging from mild shortness of breath during exertion to more significant respiratory distress at rest, accompanied by inflammatory findings on scans.

Key considerations for ILD include:

• Careful monitoring: Clinicians should actively look for signs and symptoms of ILD.
• Differential diagnosis: When ILD is suspected, it is crucial to rule out other possible etiologies before attributing it solely to the drug, given the non-specific nature of some findings.
• Severity awareness: Although rare, the potential for severe, even fatal, outcomes underscores the importance of prompt recognition and management.

While the incidence of ILD is low, it is a significant concern that requires close attention during treatment with Dato-DXd.