Key Adverse Effects of Novel Antibody-Drug Conjugates in NSCLC
Key Points
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Three antibody-drug conjugates (ADCs) are approved for non-small cell lung cancer (NSCLC): trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), and telisotuzumab vedotin (Teliso-V).
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Like other cytotoxic therapies, ADCs are broadly associated with nausea, fatigue, gastrointestinal (GI) effects, and cytopenias.
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ADCs also have unique toxicities, such as interstitial lung disease (ILD), oral and eye inflammation, and peripheral neuropathy, that may require additional monitoring.
ADC Side Effect Management in NSCLC
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with Jacob Sands, MD, of Dana-Farber Cancer Institute, about managing adverse effects associated with ADCs used in the treatment of NSCLC.
ADCs use monoclonal antibodies to selectively deliver a linked cytotoxic payload to cancer cells. Its immunotherapy target and cytotoxic payload largely shapes each agent’s toxicity profile. Three ADCs are currently approved for NSCLC: T-DXd for HER2-mutated or HER2-positive NSCLC, Dato-DXd for EGFR-mutated NSCLC, and Teliso-V for NSCLC with MET protein overexpression.
T-DXd Toxicities and ILD Risk
T-DXd was initially approved for HER2-mutated NSCLC after prior systemic therapy. More recently, it received FDA approval for all unresectable or metastatic solid tumors with HER2 overexpression, as determined by immunohistochemistry (HER2 IHC 3+). T-DXd and other ADCs with a deruxtecan payload share common toxicities, including nausea, vomiting, cytopenias, alopecia, GI events, fatigue, transaminitis, and ILD.
ILD is the toxicity outlier, especially for T-DXd, as some trials reported grade 5 events. Oncologists should monitor all patients for ILD, and patients who develop severe shortness of breath should stop treatment and start high-dose steroids. However, distinguishing clinically meaningful grade 1 or grade 2 inflammatory findings and symptoms is challenging, particularly because they could be driven by something other than T-DXd. Dr. Sands advocated for partnering with pulmonology colleagues to assist with the differential diagnosis in patients with signs of ILD.
Oral and Ocular Side Effects With Dato-DXd
In June 2025, the FDA approved Dato-DXd for EGFR-mutated locally advanced or metastatic NSCLC after prior EGFR-targeted therapy and platinum-based chemotherapy. Similar to T-DXd, Dato-DXd is associated with nausea, cytopenias, fatigue, alopecia, and ILD. In addition, Dato-DXd exhibits distinct oral and ocular toxicities associated with TROP-2 inhibition. Patients should be referred to an ophthalmologist or optometrist when starting Dato-DXd. Most eye irritation is mild and can be managed with preservative-free lubricating eye drops. However, ophthalmological monitoring can help identify more problematic toxicities.
Stomatitis or mucositis occurs in most patients, although events are typically grade 1 and asymptomatic. For symptomatic grade 2 events, treatment delays may be required, with consideration of dose reduction if events persist. Ice chips and steroid mouth rinses are recommended to help manage oral toxicities, although their efficacy remains uncertain, Dr. Sands said.
Teliso-V Adverse Event Profile
Teliso-V is approved for NSCLC with MET overexpression after prior systemic therapy. In addition to some of the common toxicities associated with T-DXd and Dato-DXd, Teliso-V also has the risk of peripheral neuropathy and peripheral edema. Supportive interventions, such as duloxetine for peripheral neuropathy or compression socks for both peripheral neuropathy and edema, have been reported. But dose reduction remains the most reliable strategy for managing these adverse effects, Dr. Sands said.
Now that ADC research has refined the monoclonal antibody and linker components, the next step may be to experiment with different payloads. “Right now we’re talking about all of these cytotoxic toxicities because our payloads are chemotherapy, I think that’s going to evolve in the years ahead,” Dr. Sands said.