Osimertinib-Chemotherapy Combo Shows Major Benefit in High-Risk EGFR/TP53 NSCLC
The phase III TOP study shows osimertinib plus chemotherapy more than doubles progression-free survival to 34 months versus 15.6 months with osimertinib alone in EGFR/TP53 mutant NSCLC. The combination achieved an 82.9% response rate and represents a new strategy for this high-risk subgroup. Research continues into resistance mechanisms, including cancer-associated fibroblasts' role in promoting osimertinib resistance.
A phase III clinical trial has demonstrated that adding chemotherapy to osimertinib significantly improves outcomes for patients with a high-risk form of non-small cell lung cancer characterized by EGFR and TP53 mutations. The TOP study, presented at the European Lung Cancer Congress 2026, showed the combination regimen more than doubled progression-free survival compared to osimertinib alone in this aggressive disease subgroup.
Median progression-free survival was 34.0 months in the combination arm compared to 15.6 months with osimertinib alone, corresponding to a hazard ratio of 0.44 and representing a 56% reduction in the risk of disease progression or death. The objective response rate also improved, reaching 82.9% with combination therapy versus 72.0% with monotherapy, and responses were more durable with a median duration of response of 32.7 months versus 15.3 months.
The TOP study enrolled 294 patients with previously untreated advanced non-squamous NSCLC harboring sensitizing EGFR mutations and confirmed TP53 alterations. Patients were randomized to receive either standard osimertinib monotherapy or osimertinib plus platinum-based chemotherapy with pemetrexed for four cycles, followed by maintenance osimertinib and pemetrexed. The benefit of combination therapy was consistent across all prespecified subgroups, including patients with central nervous system metastases, which were present in nearly 50% of patients at baseline.
Although overall survival data remain immature, early signals suggest a potential survival advantage with a hazard ratio of 0.57. As expected, the addition of chemotherapy resulted in increased toxicity, with grade 3 or higher treatment-related adverse events reported in 62.4% of patients receiving the combination versus 14.9% in the monotherapy arm, though no new safety signals were identified.
These findings address a significant clinical challenge, as EGFR/TP53 mutant NSCLC represents a biologically aggressive subgroup associated with shorter progression-free survival and reduced responsiveness to EGFR-TKI monotherapy. The results support the use of upfront combination therapy as a strategy to overcome intrinsic resistance mechanisms associated with TP53 alterations.
Meanwhile, research continues into the mechanisms of resistance to targeted therapies like osimertinib. A separate study has found that cancer-associated fibroblasts promote osimertinib resistance in NSCLC cells via elevating RNA m7G modification. Methyltransferase 1 in NSCLC cells mediated CAFs' effect on m7G modification, and reducing m7G modification by METTL1 knockdown significantly attenuated CAFs' stimulatory effect on osimertinib resistance both in vitro and in vivo.
The treatment landscape for NSCLC continues to evolve, with immunotherapy forming part of first-line therapy for many patients lacking targetable mutations, though overcoming resistance remains a challenge. Recent phase III studies presented at the same congress showed mixed results for immunotherapy combinations in patients who had progressed on prior treatments, highlighting the need for better understanding of resistance mechanisms at the molecular level.