The ocular toxicity seen with the folate-targeted ADC mirvetuximab is not due to folate receptors in the eye. It is theorized to be caused by micropinocytosis, an alternative mechanism where the drug is non-specifically taken up by normal corneal cells, representing an off-target, off-tumor toxicity.
An ADC may show better response rates than chemotherapy, but its true benefit is compromised if toxicities lead to treatment discontinuation. As seen with failed PARP/IO combinations, if patients cannot tolerate a drug long enough, the regimen's overall effectiveness can become inferior to standard therapy.
Clinicians should avoid directly comparing the toxicity profiles of new ADCs, as the data often comes from different trial stages. A drug in a Phase 1 expansion cohort may appear more toxic than one with mature Phase 2 randomized data, making definitive safety assessments premature.
The traditional six-month timeframe for defining platinum sensitivity is being challenged. A growing theory suggests that tumors progressing while on a PARP inhibitor have a distinct biology that responds poorly to subsequent platinum, indicating a potential need to move directly to therapies like ADCs.
The discovery of low-grade, asymptomatic interstitial lung disease (ILD) on scans for patients on certain ADCs does not mandate permanent discontinuation. By holding the drug, initiating steroids, and involving pulmonology, the inflammation can resolve, often allowing the patient to safely resume a highly effective therapy.
While not yet validated, ctDNA is being used by clinical experts as a de-escalation tool to provide confidence when stopping long-term maintenance therapies like PARP inhibitors. This novel application focuses on reducing treatment burden rather than solely detecting disease progression.
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.
Patients whose ovarian cancer progresses on the folate-targeted ADC mirvetuximab may still respond to a subsequent folate-targeted ADC with a different cytotoxic payload. This suggests that the folate receptor alpha target remains viable and that resistance may be payload-specific, opening new sequencing strategies.
Unlike in breast cancer, where HER2 IHC 2+ requires FISH confirmation, in gynecologic cancers an IHC 2+ result is often considered directly actionable for prescribing HER2-targeted ADCs like T-DXD. This reflects a different, less stringent clinical standard for biomarker-guided therapy in this setting.