OBJECTIVES: There is limited data on the unmet needs of advanced non-small cell lung cancer (aNSCLC) patients with epidermal growth factor receptor exon 20 insertion mutations (EGFR exon20ins) in China. The single-arm CHRYSALIS study (NCT02609776) demonstrated durable responses of amivantamab monotherapy among aNSCLC patients with EGFR exon20ins after platinum-based chemotherapy. We aimed to leverage real-world data to describe the unmet needs of these patients and explore the clinical benefits of amivantamab monotherapy through indirect comparison to an external control (EC) from China. MATERIALS AND METHODS: Eligible patients with any systemic anti-cancer therapy (SACT) after the aNSCLC diagnosis were identified from the electronic medical records of three tertiary medical institutions. Clinical outcomes and treatment patterns were compared between patients with exon20ins and common EGFR (cEGFR) mutations. Effectiveness comparison, including real-world progression-free survival (rwPFS), real-world time to next therapy (rwTTNT) and real-world objective response rate (rwORR) was conducted between CHRYSALIS patients and the EC. Propensity score weighting was used to adjust the baseline characteristics between two cohorts. Real-world outcomes were compared between two cohorts using weighted Cox proportional hazards regression models. RESULTS: EGFR exon20ins patients (n = 60) under SACT had significantly shorter median rwPFS (9.36 vs. 12.42 months) and rwTTNT (9.82 vs. 16.49 months) compared to cEGFR patients (n = 753). The majority of first-line treatment for exon20ins patients was platinum-based regimens (n = 52, 86.7%). Patients from CHRYSALIS and EC cohort were included in the analysis at each qualifying line of therapy (n = 114 and n = 87). Amivantamab-treated patients had significantly improved median rwPFS (6.93 vs. 5.62 months; P = 0.0133), rwTTNT (12.16 vs. 6.01 months; P = 0.0024), and significantly higher rwORR (36.8% vs. 1.0%; P < 0.0001) than EC cohort. Real-world overall survival was numerically longer in amivantamab-treated patients (23.13 vs. 11.63 months; P = 0.1911). CONCLUSION: Chinese patients with EGFR exon20ins under SACT had poor clinical outcomes comparing to those with common EGFR mutations in the study. The clinical benefit of amivantamab monotherapy for exon20ins patients was demonstrated through comparing to a real-world EC under standard of care. Amivantamab monotherapy may be considered as a potential effective treatment option for the Chinese patients harboring exon20ins.