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Background: Osimertinib is broadly used for advanced EGFR-mutant NSCLC patients. However, the activity of osimertinib is not fully characterized in tumors harboring uncommon EGFR mutations, which represents about 10% of EGFR-mutated NSCLC cases. Hence, we conducted a systematic review and meta-analysis to assess the efficacy and safety of osimertinib in patients with NSCLC and uncommon tumoral EGFR mutations. Methods: PubMed, Embase, and the Cochrane Library were searched for eligible studies. Uncommon EGFR mutations were defined as any mutation other than the exon 19 deletion, L858R and T790M mutations, and exon 20 insertion, except when in compound. Efficacy was assessed by objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Heterogeneity was examined with I² statistics and random-effect model was used for a meta-analysis. Results: Nine studies comprising 331 patients were included. Median follow-up ranged from 12.6 to 22.0 months (mos). Median age in each study ranged from 51 to 72 years old (table). Overall, 62% (205/331) of patients were female and 77% (256/331) of patients had an ECOG PS ≤1. About 78% (258/331) of patients received Osimertinib in a 1^st line setting. Uncommon tumoral EGFR mutations included G719X in 40% (131/331) of patients, L861X in 27% (91/331), and S768I in 15% (49/331). Pooled analysis showed an overall ORR of 49.5% (95% CI, 42.2 – 56.9), a DCR of 90.2% (95% CI, 86.2 – 94.3), a median OS of 24.5 mos (95% CI, 11.9 – 24.5), a median PFS of 9.5 mos (95% CI, 8.2 – 11.0), and a median DOR of 17.4 mos (95% CI, 7.9 – 22.7). Intracranial (i) efficacy had an iORR of 50.3% (95% CI, 30.3 – 70.3), an iDCR of 92.8% (95% CI, 76.2 – 100), and a median iPFS of 6.1 mos (95% CI, 4.5 – 6.6). In a subgroup analysis according to EGFR mutation, overall ORR was significantly different in patients with tumoral G719X, S768I and L861 mutations (ORRs of 28.8%, 33.3%, and 67.7%, respectively, p for subgroup differences < 0.01). Overall, osimertinib was well tolerated with a frequency of all-grade AEs of 86.2% (95% CI, 61.2 – 100) and ≥ G3 of 18.0% (95% CI, 1.2 – 34.7). Conclusions: This systematic review and meta-analysis suggests that patients with NSCLC with uncommon tumoral EGFR mutations may benefit from osimertinib treatment. Patients harboring tumoral L861 mutation achieved a significantly higher ORR compared to the modest ORR in G719X, S768I cases.

N: number.

^†Median. y: year. CNS: central nervous system. NA: not available.