TOP: A phase III, multicentre, randomized controlled study comparing osimertinib in combination with carboplatin and pemetrexed to osimertinib monotherapy for untreated patients with advanced non-squamous (Non-sq) non-small cell lung cancer (NSCLC) with concurrent EGFR and TP53 mutations.

TPS8662 Background: Osimertinib is the current standard first-line treatment for advanced non-sq NSCLC with sensitive EGFR mutations. However, previous studies demonstrated that patients with concurrent EGFR and TP53 mutations had suboptimal clinical benefit with EGFR-TKI monotherapy. FLAURA2 study showed that osimertinib plus pemetrexed and platinum-based chemotherapy significantly improved progression-free survival (PFS) compared with osimertinib monotherapy for EGFR-mutated advanced NSCLC patients. Further study is needed to better understand the benefits of the FLAURA2 model for patients with concurrent mutations. The objective of this study is to determine whether osimertinib plus chemotherapy could improve efficacy compared with osimertinib monotherapy in patients with concurrent EGFR and TP53 Mutations. Methods: This is a phase III, randomized, open-label trial in patients with advanced Non-sq NSCLC harboring EGFR mutations (exon 19 deletion or L858R) and TP53 mutations, with a performance status of 0 to 1, and planned to receive first-line therapy. Eligible patients will be randomized 1:1 to osimertinib monotherapy arm (osimertinib 80 mg orally per day) or combination therapy arm (osimertinib 80 mg orally per day plus pemetrexed 500 mg/m 2 and carboplatin area under curve 5 intravenously every 3 weeks for four cycles, followed by maintenance pemetrexed and osimertinib). Randomization will be stratified by PS score (0 vs. 1), brain metastases status (yes vs. no) and mutation type (exon 19 deletion vs. L858R). The primary end point is PFS per RECIST 1.1 assessed by investigator. Secondary end points include overall survival, objective response rate, duration of response, adverse events and quality of life. Exploratory endpoint is correlation between concurrent mutations other than TP53 and efficacy, and the resistance mechanisms to combination therapy revealed by dynamic ctDNA profiling. Approximately 170 PFS events will be required to detect hazard ratio of 0.65 with 80% power at a two-sided significance level of 0.05. 292 patients will be enrolled. Until February 1, 2024, 204 patients have been enrolled, the last patient is expected to be enrolled in June 2024. Clinical trial information: NCT04695925 .