9106 Background: Previous evidence has revealed the potential efficacy of dacomitinib in patients with advanced non-small cell lung cancer (NSCLC) carrying uncommon epidermal growth factor receptor ( EGFR) mutations, but it remains unknown whether there are differences in its efficacy for different combination patterns of these uncommon mutations. Methods: The AFANDA cohort, an ambispective cohort including 121 NSCLC patients with uncommon EGFR mutations admitted from two tertiary hospitals in China, was employed for exploration. Meanwhile, a cohort of 63 patients with common mutations was included for comparison. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed between groups. Results: A total of 133 patients with advanced or recurrent NSCLC that received dacomitinib were eligible for analysis. Baseline characteristics were balanced between subgroups. A significant difference was observed between patients with common mutations (C group, n = 63), common mutation plus uncommon mutations (C+U group, n = 24), and uncommon mutations (U group, n = 46) regarding to PFS (mPFS: 7.07, 8.17, and 11.97 months; p = 0.026). Moreover, the highest ORR and DCR of the U group were observed among subgroups, although the differences were not statistically significant (ORR, 40.4%, 40.9%, and 61.4%; p = 0.085; DCR, 78.9%, 72.7%, 90.9%; p = 0.134). Furthermore, the multivariate analysis revealed that the mutation pattern was an independent prognostic indicator of PFS ( p = 0.049), with the C+U group having the highest risk of progression (HR [hazard ratio]: 1.438, 95% CI [confidence interval]: 0.818-2.528) while the U group having the lowest one (HR: 0.666, 95% CI: 0.409-1.084). For toxicity analysis, no significant difference was observed regarding grade 3-4 AEs among subgroups (12.7%, 8.3%, 13.0%; p = 0.827). The drug resistance analysis did not reveal a significant difference concerning the secondary T790M mutation rate (26.3%, 0%, 13.3%; p = 0.331). Conclusions: Dacomitinib demonstrated different therapeutic efficacy for patients with NSCLC harboring different combination patterns of uncommon EGFR mutation, which should be considered in clinical trials' design and clinical application. [Table: see text]