The Future of Dato-DXd in Lung Cancer and Beyond

In an interview, Jacob Sands, MD, medical oncologist at Dana-Farber Cancer Center, discusses the benefits of the arrival of datopotamab deruxtecan (Dato-DXd; Datroway) into the EGFR-positive non–small cell lung cancer (NSCLC) treatment landscape and the next steps in research for this agent.

This new treatment option is particularly promising, offering a potentially superior alternative to traditional chemotherapy agents like docetaxel, especially for patients with a specific type of NSCLC. Initial studies have shown that Dato-DXd appears to outperform docetaxel in certain patient populations. While TROPION-Lung01 included both squamous and nonsquamous NSCLC, the greatest benefit of Dato-DXd was observed in the nonsquamous subset, especially within the EGFR-positive cohort. The drug's toxicity profile is generally manageable and compares favorably to docetaxel, though there are specific side effects that require careful monitoring.

Oncologists and other medical professionals are becoming more familiar with managing these adverse effects. Stomatitis and mucositis, for example, are toxicities that many oncologists are already experienced in treating with other regimens, making their management with Dato-DXd relatively straightforward. The drug can also cause ocular surface toxicity, the mechanism of which is currently unknown. This necessitates close collaboration with ophthalmology to ensure proper management.

Additionally, while rare, there is a risk of interstitial lung disease, a serious side effect that requires vigilance and early intervention. As more experience with Dato-DXd is gained, the management of these toxicities is expected to become more refined and predictable. Future research may also help delineate the specific etiologies of these side effects, leading to more targeted treatment strategies, such as the potential use of steroid mouthwashes for stomatitis.

Looking ahead, Dato-DXd is being investigated in a variety of clinical trials that could expand its use to earlier lines of therapy. The ORCHARD trial, for instance, is exploring Dato-DXd in combination with osimertinib for patients who have progressed on osimertinib (Tagrisso) alone. A second-line randomized trial is also underway, comparing osimertinib plus Dato-DXd, Dato-DXd alone, and standard chemotherapy after osimertinib progression. Furthermore, a 3-arm trial is evaluating Dato-DXd as a potential first-line treatment, both alone and in combination with osimertinib. These trials suggest that Dato-DXd may eventually move earlier in the treatment paradigm, potentially offering a new first-line option. For now, however, it represents a valuable new option for patients who have progressed after treatment with both osimertinib and chemotherapy.