BACKGROUND: To evaluate the efficacy and safety of aumolertinib combined with pemetrexed and carboplatin as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation (exon 19 deletion or exon 21 L858R). METHODS: In phase II trial (NCT04646824), patients received aumolertinib 110 mg once daily plus pemetrexed (500 mg/m2) and carboplatin (area under curve = 5) once every 3 weeks for 4 cycles, followed by maintenance aumolertinib (110 mg once daily) and pemetrexed (500 mg/m2 once every 4 weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: From November 2020 to October 2021, 34 patients were included for analysis. The median PFS was 28.0 months (95% CI, 18.7-36.9). The ORR was 91.2% (31/34), and the DCR was 100%. The median OS was not reached. Of 28 patients with circulating tumor DNA (ctDNA) testing, 22 (78.6%) showed clearance of EGFR mutation after 2 or 4 cycles. The median PFS was 31 months in patients with EGFR mutation clearance in ctDNA, and the ORR of them was higher than those without EGFR mutation clearance in ctDNA (90.9% vs 33.3%). The most common grade ≥ 3 treatment-related adverse event was decreased neutrophil count (22 [64.7%]). CONCLUSION: Aumolertinib plus chemotherapy shows potential as first-line treatment for patients with EGFR-mutant advanced NSCLC, which deserves to be investigated in randomized controlled trials. CtDNA clearance may be a prognostic marker.