TDXD is highly emetogenic. Adding low-dose olanzapine to the standard three-drug antiemetic prophylaxis regimen is a transformative strategy that significantly reduces both acute and delayed nausea, making the potent therapy much more tolerable for patients.

Due to fedratinib's significant GI side effect profile and the logistical difficulty of measuring thiamine levels, clinicians should proactively provide patients with thiamine supplements, anti-emetics, and anti-diarrheal therapies. Instructing patients to take the drug with food can also help mitigate GI toxicity.

Drawing lessons from T-DXD, experts treat newer exatecan-payload ADCs like RDXD as highly emetogenic from the first dose. Instead of a 'wait and see' approach, they recommend aggressive premedication with a triple-drug antiemetic regimen to prevent nausea and maintain quality of life.

Clinicians are finding that forgoing the standard 800mg loading dose of zolbituximab and starting directly with the 600mg maintenance dose appears to mitigate acute gastrointestinal toxicity, particularly gastritis. This practical adjustment is being formally studied but is already used in practice to improve patient experience.

The Phase 2 TRAIT study suggests starting adjuvant abemaciclib at a lower dose and escalating over several weeks significantly reduces early discontinuations due to side effects like diarrhea. This strategy helps more patients get through the initial high-toxicity period and remain on the effective dose for the full two-year course.

For managing nausea from ADCs like TDXD, a three-drug prophylactic regimen (steroid, 5-HT3 antagonist, NK1 inhibitor) is recommended. For delayed nausea, continuing the 5-HT3 antagonist on days two and three is often effective before needing to add agents like olanzapine.

Contrary to initial fears, both clinical trial and real-world data show that patients experiencing asymptomatic, grade 1 interstitial lung disease (ILD) from TDXD can be safely retreated. This allows patients to continue benefiting from a highly effective therapy without undue risk.

In the DESTINY-CRC02 trial, the lower 5.4 mg/kg dose of trastuzumab deruxtecan (TDXD) resulted in a higher response rate in colorectal cancer compared to the 6.4 mg/kg dose used in gastric cancer. This counter-intuitive finding suggests better tolerability led to longer treatment duration and superior outcomes.

The ADC Dato-DXD causes high rates of stomatitis and dry eye that are difficult to treat once they appear. Effective management requires aggressive, proactive prevention from the start of therapy using steroid mouthwash and lubricating eye drops, demanding significant patient engagement and vigilance.