Background: Although non-small cell lung cancer (NSCLC) patients with tumor harboring classical Epidermal Growth Factor Receptor (EGFR) mutations have numerous therapeutic choices, uncommon EGFR mutation NSCLC patients have limited treatment options. Sutetinib is a selective tyrosine kinase inhibitor (TKI) targeting uncommon EGFR mutations. Methods: In this multicenter, open-label phase 2a study, treatment-naïve adults with NSCLC harboring uncommon EGFR mutations (G719X, S768I, L861Q) received oral sutetinib monotherapy at 80 or 64 mg/day (Chinese trial register CTR20190681). The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DoR), overall survival (OS), safety and tolerability. Adverse events (AEs) were graded according to the CTCAE v5.0. Results: Sutetinib was administered to 30 NSCLC patients at 80 (n = 15) or 64 (n = 15) mg/day. Median age was 60 years old (range 47-74 years). Twenty patients (66.7%) were females, 10 patients (33.3%) had a history of smoking. Patients had an ECOG PS of 0 (10.0%) or 1 (90.0%). Tumors had a G719X (36.7%), L861Q (30.0%), or S768I (20.0%) EGFR mutation, or a combination of these uncommon EGFR mutations (13.3%). None had EGFR T790M, L858R, exon 19 deletions, or exon 20 insertions. The ORR was 71.4% (20/28), including 92.9% (13/14) and 50.0% (7/14) in the 80 and 64 mg/day cohorts, respectively. The disease control rate (DCR) was 96.4%, including 100.0% (14/14) and 92.8% (13/14) in the 80 and 64 mg/day cohorts, respectively. All responses were partial responses. The median DoR was 12.5 months (20.3 and 9.2 months in the 80 and 64 mg/day cohorts, respectively). One-year OS was 84.7% (92.9% and 75.0% in the 80 and 64 mg/day cohorts, respectively). As of 15 January 2022 (database lock), 11 (36.7%) patients were still receiving sutetinib treatment. Grade ≥3 treatment emerged AEs were similar in the 80 mg/day (80.0%, 12/15) and 64 mg/day (73.3%, 11/15) cohorts. The most frequently reported grade ≥3 Treatment-related AEs (TRAEs) were diarrhea (36.7%), abnormal liver function (13.3%), and rash (10.0%). One grade 4 TRAE was observed: hypokalemia in the 64 mg/day cohort. Conclusions: Sutetinib demonstrated a high response rate with durable antitumor activity in patients with NSCLC harboring uncommon EGFR mutations. The toxicities are expected and comparable to other EGFR TKIs. A multi-center phase 2b study is ongoing in the United States and China to further evaluate Sutetinib in uncommon EGFR mutation NSCLC. Clinical trial information: CTR20190681.