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Purpose: Prior data suggest driver-mutated NSCLC, especially EGFR and ALK tumors, poorly respond to immunotherapy. However, little research using real-world cohorts have been performed, nor is it clear whether PD-L1 and smoking history are predictive of outcomes in such tumors. This study assessed rwPFS in a large cohort with driver-mutated advanced NSCLC treated with single-agent PD-1/PDL-1 inhibitors. Methods: Real-world data from 1746 patients were analyzed and rwPFS with immunotherapy was determined for EGFR, ALK, BRAF, and KRAS tumors. Kaplan–Meier curves characterized rwPFS and correlated with PD-L1 and smoking history. Comparisons were tested using log-rank. Results: Median rwPFS and the percent progression-free at 12 months were greater among KRAS (3.3 months, 21.1%) and BRAF (3.6 months, 20.6%) as compared to EGFR (2.5 months, 8.1%) and ALK tumors (2.3 months, 11.2%). KRAS tumors with PD-L1 ≥ 1% had longer rwPFS than PD-L1 < 1% tumors (4.1 versus 3.2 months, p = 0.001). PD-L1 positivity did not predict rwPFS in EGFR, ALK, or BRAF tumors. However, a smoking history was associated with longer rwPFS in EGFR (2.6 versus 2.3 months, p = 0.048) and ALK tumors (3.0 versus 2.1 months, p = 0.049) as compared to no smoking history. Conclusion: Real-world PFS with immunotherapy was greater in KRAS and BRAF as compared to EGFR and ALK tumors. PD-L1 positivity was predictive in KRAS and not associated with rwPFS in other mutation types. While median rwPFS was short for EGFR and ALK tumors, small subsets were progression-free at 12 months. Better characterizing these subsets that benefit, along with developing strategies to overcome immunotherapy resistance in EGFR/ALK tumors are needed. [ABSTRACT FROM AUTHOR]