Unanswered Questions and the Role of ctDNA Dynamics in Selecting Intensification Candidates in EGFR-Mutant NSCLC

In this final episode, Dr. Puri and Dr. Yu close the program with the most important unanswered questions after TOP. The overall survival (OS) data remain immature at roughly 30% maturity, and TOP did not compare osimertinib/chemotherapy head-to-head with amivantamab/lazertinib, so it cannot tell clinicians which intensification regimen is better for the TP53 subgroup. Dr. Yu identifies a predictive biomarker as the most pressing need: if a tumor's likely resistance mechanism could be predicted upfront, mitogen-activated protein kinase (MAPK)-driven or MET amplification–prone tumors might favor amivantamab/lazertinib, while tumors prone to dedifferentiation or plasticity might do better with chemotherapy-based intensification. She also wants better data to guide second-line selection between antibody–drug conjugates (ADCs) like datopotamab deruxtecan–based regimens and amivantamab-based options. Dr. Puri raises circulating tumor DNA (ctDNA) dynamics, noting that MARIPOSA showed patients who failed to clear ctDNA at cycle 3 had worse outcomes. Dr. Yu references an ongoing looking at treatment intensification based on ctDNA clearance at 3 weeks. She predicts the result will mirror TOP, with the high-risk group selected by ctDNA non-clearance benefiting from escalation. She adds that ctDNA clearance is being used more broadly, sometimes in the metastatic setting, but particularly in early-stage disease to inform adjuvant therapy duration, and is increasingly a relevant biomarker.

Thank you for watching this OncLive® NewsNetwork Presents discussion. Please subscribe to our e-newsletter for information on upcoming video series.