Background: Initial treatment with immunotherapy (IO) and/or platinum-based chemotherapy (PBC) is SOC for patients (pts) with mNSCLC without AGAs (woAGA). SOC for pts with AGAs (wAGA) is targeted therapy, typically followed by PBC. There are limited treatment options and little real-world evidence on outcomes for pts who have experienced progression following SOC. This study characterized treatment patterns and clinical outcomes among pts with mNSCLC woAGA and wAGA after discontinuation of SOC therapies in the US. Methods: This retrospective observational study included pts with mNSCLC (≥18 years at diagnosis) from the ConcertAI Patient360 NSCLC EMR database (01/2015–09/2022). Pts were classified into 2 cohorts (wAGA and woAGA) based on positive or negative results from genetic testing for an AGA (ALK, BRAF, EGFR, MET, NTRK, RET, KRAS, HER2 and/or ROS1). All pts were required to initiate a subsequent line of treatment (index LOT) after discontinuation of prior SOC therapies. Kaplan-Meier analysis was used to estimate median time to discontinuation (TTD), time to next treatment (TTNT), real-world progression free survival (PFS), and real-world overall survival (OS) for the index LOT. Results: The study included 1,386 pts woAGA and 349 pts wAGA. In the study cohort (woAGA vs wAGA), median age at index date was 67 vs 66 years, the median number of prior LOTs was 2 vs 3, 42.4% vs 63.6% were female, 74.5% vs 59.6% were treated in a community setting, 21.5% vs 34.2% had documentation of brain mets, and 92.3% vs 68% had ECOG ≤1. Among pts wAGA, 72% had an EGFR mutation. Median follow-up from index LOT initiation to end of study was 7 months for both groups. The most common index regimens among pts woAGA were non-PBC (44.8%), IO-based therapy (42.1%), and PBC (12%). Among pts wAGA, targeted therapies (35%), non-PBC (24.4%), and IO-based therapy (17.5%) were most often received in the index LOT. Docetaxel with or without ramucirumab was the most used index agent in both cohorts [pts woAGA (25.4%) and wAGA (10.6%)]. Median rwOS, rwPFS, TTD, and TTNT for index LOT are reported in Table 1. Conclusions: Following progression on SOC, pts with mNSCLC have limited treatment options and are predominantly treated with non-PBC (such as docetaxel ± ramucirumab) or rechallenged on previously used therapies. Observed treatment duration, PFS, and OS in this real-world setting were short and comparable to prior phase 3 trials, emphasizing the need for more effective treatment options among mNSCLC pts woAGA and wAGA post SOC therapies.