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Helena Yu, MD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, told Targeted Oncology that antibody-drug conjugates have established a defined role for patients with EGFR-mutant non-small-cell lung cancer who have exhausted EGFR-targeted inhibitors and standard chemotherapy. Datopotamab deruxtecan (Dato-DXd, Datroway), a TROP2-directed ADC approved within the past year, is the new second-line option for this population.
The sequence begins with progression. A re-biopsy identifies a new targetable mutation, such as MET amplification or a secondary EGFR alteration, in approximately 25% of patients, which allows targeted therapy to continue along a different axis. For the remaining 75%, no clear genomic target is found, and these patients require a biomarker-agnostic approach. Datopotamab deruxtecan addresses that gap.
Two harder scenarios sit alongside the resistance question. Histologic transformation occurs in roughly 15% of patients, in which the tumor shifts from adenocarcinoma to squamous or small-cell lung cancer and requires an entirely different chemotherapy paradigm. Current research focuses on preventing the transformation before it occurs. Central nervous system disease is the second, with nearly two-thirds of EGFR-mutant patients developing brain metastases or leptomeningeal disease over the course of their illness. Treatment selection in this group is shaped by CNS penetration of available agents and continued access to clinical trials.
Yu noted that while the easy targets in EGFR-mutant lung cancer have been addressed, complex resistance patterns and access to clinical trials for patients with advanced CNS involvement now define the next frontier of care. Re-biopsy at progression remains the gating step, since it determines whether a patient continues on targeted therapy or moves to the ADC-based pathway.
