Subgroup Consistency in TOP — CNS, Liver, and Mutation Type

In this episode, Dr. Puri and Dr. Yu walk through the prespecified subgroup analyses from TOP, where progression-free survival (PFS) benefit was consistent across all subgroups. Roughly 49% of patients had baseline brain metastases, and the central nervous system (CNS) subgroup hazard ratio (HR) was 0.39 — particularly notable given the historically limited CNS penetration of platinum/pemetrexed. Dr. Yu views the CNS signal as one more additive risk factor and a strong reason to escalate, mirroring CNS subgroup signals seen in FLAURA2 and MARIPOSA. The liver metastases subgroup, though small (n=53), showed the most striking forest plot benefit, with an HR of 0.31 and median PFS of 27.7 versus 11.5 months. Dr. Yu agrees that visceral disease, particularly liver involvement, signals more biologically aggressive disease and reinforces the case for upfront intensification, while acknowledging the small sample limits independent decision-making. The conversation then turns to L858R versus exon 19 deletion. Dr. Puri notes that osimertinib monotherapy has historically underperformed in L858R, making it a clear candidate for intensification, particularly when paired with TP53 co-mutation. Both agree that risk factors are additive and that TOP, while not changing their default of combination therapy, strengthens the rationale for it across these higher-risk subgroups.

In the next episode, “Safety, Tolerability, and Patient Counseling in Combination Therapy,” Dr. Yu and Dr. Puri walk through the risk-benefit conversation with patients.