Multicenter phase 3 trial of osimertinib with or without chemotherapy for advanced EGFR-mutated NSCLC with concurrent TP53 mutations

A phase 3 trial at 17 centers in China evaluated addition of chemotherapy to first-line osimertinib in adult patients with nonsquamous advanced non-small cell lung cancer (aNSCLC) with EGFR mutations and concurrent TP53 mutations. Patients were randomized 1:1 to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n=146) orosimertinib monotherapy (n=148). The primary endpoint was investigator-assessed progression-free survival (PFS). At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median PFS was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 versus 15.6 months; HR 0.44; p<0.001). This benefit was consistent across prespecified subgroups, including those with brain metastases en L858R mutations. The overall survival data remained immature, with a trend of overall survival benefit with combination therapy. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified. The authors conclude that addition of chemotherapy to first-line osimertinib significantly increased PFS among patients with EGFR-mutated aNSCLC harboring concurrent TP53 mutations.