Interpreting TOP Alongside FLAURA2 and MARIPOSA

In this episode, Dr. Yu and Dr. Puri compare the TOP results against FLAURA2 and MARIPOSA. TOP delivered a roughly 18-month median progression-free survival (PFS) improvement (hazard ratio [HR], 0.44) and an early overall survival (OS) signal (HR, 0.57) at 30% maturity. Dr. Puri says TOP has become her strongest evidence base specifically for the TP53-mutant subgroup and now anchors her recommendation for osimertinib plus chemotherapy in those patients. Outside that subgroup, she treats osimertinib/chemotherapy and amivantamab/lazertinib as equivalent regimens, because cross-trial subgroup comparisons cannot reliably separate them. Decisions then come down to patient preference, efficacy expectations, and side-effect tolerance. Dr. Puri identifies two situations where she favors amivantamab/lazertinib: upfront MET co-mutation, and leptomeningeal disease (LMD), where prospective LMD response data exist. Dr. Yu agrees, noting that baseline MET amplification is rare (3–5%) but biologically rationalizes a MET-directed regimen. Both discuss MET immunohistochemistry (IHC) at diagnosis: it would be useful upfront, but tissue limitations and the current telisotuzumab vedotin approval restricted to later lines mean it is rarely available when first-line decisions are being made.

In the next episode, “Subgroup Consistency in TOP: CNS, Liver, and Mutation Type,” Dr. Yu and Dr. Puri unpack the prespecified subgroup signals.