Progression-free survival (PFS) doubled in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) who also carry TP53 mutations and received osimertinib plus chemotherapy vs those who received osimertinib alone.

The findings, which were presented at the European Lung Cancer Congress (ELCC) 2026 in Copenhagen, Denmark, could fill a treatment gap for the group included in the study. These patients often go on to develop resistance to TKIs such as osimertinib, said study author and presenter Yunpeng Yang, MD, of Sun Yat-sen University Cancer Center, Guangzhou, China.

Median PFS was 34.0 months vs 15.8 months (P < .001) with osimertinib plus platinum-based chemotherapy vs osimertinib alone in patients. This PFS benefit was seen consistently across all prespecified subgroups.

While overall survival data were not yet mature at interim analysis, there was a trend for benefit with combination therapy (hazard ratio, 0.57) over treatment with osimertinib alone.

While no patients in either group achieved a complete response, the overall response rate was higher for those receiving combination therapy (82.9%) than for those receiving osimertinib alone (71.6%); the median duration of response was 32.7 and 15.3 months, respectively.

“The findings provide key evidence to support a molecular risk-guided, individualized treatment strategy for EGFR-mutated advanced NSCLC,” said Yang.

The results come from the TOP phase 3 trial, which randomly assigned 294 patients with stage IV or recurrent non-squamous NSCLC harboring EGFR-sensitizing mutations and concurrent TP53 mutations to receive osimertinib plus chemotherapy (n = 146) or osimertinib alone (n = 148). The median age was 57 years, and just over half of participants were female in each group. Chemotherapy included pemetrexed and carboplatin.

In the combination group, patients received a median of 17 cycles of pemetrexed, and 84.4% completed at least four cycles of carboplatin-based chemotherapy. The median duration of osimertinib exposure was 20.3 months vs 15.4 months in the combination vs monotherapy groups.

TKIs, such as osimertinib, have shown superior efficacy over cytotoxic chemotherapy in patients with EGFR-mutant NSCLC, Yang said during the session. However, patients treated with TKIs eventually experience disease progression caused by unique submolecular characteristics. TP53 mutations are the most common co-alterations detected in patients with EGFR-mutated NSCLC with an estimated prevalence of 54.6%–68.8%. Patients with TP53 co-mutations have low response rates and poor prognosis when treated with TKI therapy, Yang said.

While osimertinib remains a standard first-line treatment, studies such as the FLAURA2 study showed that osimertinib plus pemetrexed and platinum-based chemotherapy significantly improved PFS over osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC. The TOP study limited patients to those with TP53 co-mutations only — patients with known poor prognosis.

Yang called treatment-related adverse events (TRAEs) comparable to those seen in the FLAURA2 trial. In the TOP study, TRAEs occurred in nearly all patients in each group. Grade 3 and greater TRAEs were much more common among patients receiving combination therapy (62.4%) than among those receiving osimertinib alone (14.9%) in TOP. Treatment-related serious adverse events were also more common in the combination group — 10.6% vs 1.4%, respectively.

The most common TRAEs were hematologic for those in the combination group, and most non-hematologic TRAEs were grade 1 or 2. The most common TRAEs in the monotherapy group were lymphocyte count decrease and diarrhea.

The invited discussant, Yi-Long Wu, MD, noted that while the study demonstrates benefit with combination therapy in TP53-mutant disease, it does not establish TP53 as a predictive biomarker to guide which patients require treatment intensification.

Wu added that given that TOP enrolled only patients with TP53 mutations, it cannot determine whether these patients derive greater benefit from the addition of chemotherapy than those without the mutation.

Additional work is needed to establish a predictive benefit with combination therapy in these patients, he said.

Wu is an oncologist at Guangdong Lung Cancer Institute at the Guangdong Provincial People’s Hospital in Guangzhou, China.

The TOP study was funded by AstraZeneca. The authors and Wu reported having no relevant financial relationships.