The TOP trial: osimertinib + chemotherapy for EGFR-mutant advanced NSCLC with a TP53 co-mutation

The phase III TOP trial, presented at the European Lung Cancer Congress (ELCC) 2026 and discussed in this video by Prof Mariana Brandão (Institut Jules Bordet, Brussels) provides confirmatory evidence supporting treatment intensification in a high-risk subgroup of advanced EGFR-mutant non-small cell lung cancer (NSCLC). This randomized study enrolled 292 treatment-naïve patients with EGFR-mutant NSCLC harboring concurrent TP53 mutations, a population consistently associated with poorer prognosis and reduced durability of response to EGFR tyrosine kinase inhibitors (TKIs). Building on the rationale and findings of the FLAURA2 trial, TOP evaluated whether the addition of platinum–pemetrexed chemotherapy to osimertinib could specifically improve clinical outcomes in this molecularly defined subgroup.

The results demonstrated a clinically meaningful and statistically significant improvement in progression-free survival (PFS), the primary endpoint. Median PFS increased from 15.6 months with osimertinib monotherapy to 34 months with the combination, corresponding to a hazard ratio of 0.44. This substantial benefit was consistently observed across all predefined subgroups, including different EGFR mutation types (exon 19 deletions and L858R) and in patients with or without brain or liver metastases. Early overall survival (OS) data, although still immature, showed a favorable trend with the combination approach, with median OS extending from roughly 36.5 months to 48.5 months (hazard ratio of 0.57). The safety profile of the combination was consistent with prior studies, with no new safety signals identified.

In brief, the TOP trial confirms that upfront osimertinib plus chemotherapy provides substantial benefit in EGFR/TP53 co-mutated NSCLC. However, it does not resolve the critical question of whether a subset of patients might safely avoid chemotherapy and preserve quality of life with TKI monotherapy alone.