Background: Dacomitinib showed superior efficacy for patients with epidermal growth factor receptor (EGFR) sensitive mutations as compared to that of gefitinib, especially for those harboring exon 21 L858R mutation. However, the grade 3-4 treatment related adverse events were more common in patients receiving 45mg of dacomitinib as initial treatment. Hence, we did this study to explore efficacy and safety of low dose dacomitinib for first-line treatment of patients with EGFR exon 21 mutated non-small cell lung cancer (NSCLC). Methods: We retrospectively analyzed data of patients with EGFR exon 21 mutated advanced NSCLC treated with 15 mg dacomitinib as initial therapy between August 2019 and December 2020 at Affiliated Dongguan Hospital, Southern Medical University, China. EGFR mutation was identified using the scorpion amplification refractory mutation system method (ARMS) or next-generation sequencing technology (NGS). A total of 9 NSCLC patients with exon 21 mutation were included. All of these patients received dacomitinib (15 mg, once a day) until disease progression or unacceptable toxicity. Response was assessed according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Toxicities were recorded and classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. The last follow-up date is February 10, 2021. The primary end point was objective responsive rate (ORR). The secondary end points were disease control rate (DCR), median progression-free survival (PFS) and treatment related toxicity. Results: Among the 9 patients with EGFR exon 21 mutated NSCLC in this study, 8 patients harboring L858R mutation while one patients harboring L861Q mutation. The median age of treatment patients was 70 years (range, 39-87 years). There were 3 patients with brain brain metastases (33.3%) and had never received whole-brain radiation therapy (WBRT), surgery, radiosurgery or systemic treatment.They all received low dose of dacomitinib as initial treatment. The ORR was 77.8% and DCR was 100%. The median PFS data was not mature. None of these patients had a progression disease until the last follow-up date. Treatment related adverse events were generally mild. The most frequent toxicity was rash (44.4%), the remaining adverse events included rash, pruritus, diarrhea, abnormal hepatic function, anaemia and elevated creatinine, all of which occurred only once during the treatment period. None of the patients experienced grade 3 or higher toxicities. Conclusions: Our study showed that dacomitinib (15 mg, once a day) may be also effective for patients harboring EGFR exon 21 mutated NSCLC, with significantly reduced toxicities as compared to that of standard dose. Prospective or real-world studies are needed to further illuminate the effect of low dose of dacomitinib on EGFR exon 21 mutated patients.