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Patient Selection and the New Frontier in EGFR-Mutant NSCLC: Post-ELCC Insights From the TOP Study

2 experts are featured in this series.

EP. 1: Initial Reactions to TOP — Confirming TP53 as a High-Risk Subgroup

ByHelena A. Yu, MD,Sonam Puri, MD

In this episode, Dr. Yu and Dr. Puri share their initial reactions to the phase 3 TOP study, the first prospective trial to specifically test treatment intensification in EGFR-mutant non–small cell lung cancer (NSCLC) patients selected by concurrent TP53 mutation. Dr. Yu reviews the headline data: median progression-free survival (PFS) of 34.0 versus 15.6 months (hazard ratio [HR], 0.44), overall response rate (ORR) of 83% versus 72%, median duration of response (DoR) of 32.7 versus 15.3 months, and an interim overall survival (OS) hazard ratio of 0.57 at roughly 30% maturity. Dr. Puri notes that the positivity of the result was not surprising given prior signals from FLAURA2 and MARIPOSA, but the magnitude of benefit was striking. She underscores that TP53 had previously been examined only post-hoc or as a secondary endpoint, never as the primary selection criterion. Dr. Yu frames the contribution of TOP as confirming that TP53 is not only prognostic but also predictive of benefit from intensification, with TP53-altered patients potentially deriving as much or more benefit than lower-risk groups. Both agree that TOP definitively answers the question of whether the TP53 co-mutated subgroup needs intensification, while acknowledging that OS data remain immature. In the next episode, “Operationalizing First-Line Intensification: TP53 and the Borderline Patient,” Dr. Yu and Dr. Puri discuss how they translate TP53 status into upfront treatment decisions.

2 experts are featured in this series.

EP. 2: Operationalizing First-Line Intensification — TP53 and the Borderline Patient

ByHelena A. Yu, MD,Sonam Puri, MD

In this episode, Dr. Puri and Dr. Yu discuss how TP53 status informs first-line intensification in clinic. Both have moved to an opt-out approach: combination therapy is the default, and monotherapy is reserved for patients whose performance status, comorbidities, or preferences make combination unsuitable. Dr. Yu notes she had been intensifying selectively based on progression-free survival (PFS) data from FLAURA2 and MARIPOSA, but the overall survival (OS) readouts shifted her to upfront combination for nearly all patients. Dr. Puri agrees, noting the discussion in her clinic now starts with combination and works backward. They address the borderline patient — exon 19 deletion, low burden, no central nervous system (CNS) disease, but TP53 co-mutation — and conclude that risk factors are additive and even a single high-risk feature like TP53 generally tips the decision toward intensification. Roughly 60% of EGFR-mutant cases harbor TP53 alterations, so this is not a niche subgroup. On TP53 mutation type, Dr. Yu treats it as binary in practice while acknowledging truncating mutations confer worse prognosis than missense mutations. Dr. Puri notes that at Moffitt, paired tissue and liquid next-generation sequencing (NGS) often deliver TP53 results in time for first-line decisions, but she emphasizes that even without it, the opt-out strategy holds. In the next episode, “Interpreting TOP Alongside FLAURA2 and MARIPOSA,” Dr. Yu and Dr. Puri compare the strength of evidence across the three intensification trials.