e21156 Background: The identification of driver mutations and development of targeted therapies have significantly improved outcomes of patients with advanced non-small cell lung cancer (aNSCLC). It has been shown in clinical trials that immunotherapy (IO) has limited effectiveness in patients with aNSCLC and driver mutations, but as there is a lag in the widespread use of targeted agents for newer driver oncogenes it is important to define the efficacy of non-targeted treatments. We sought to explore the real-world treatment patterns and outcomes of patients with aNSCLC and driver mutations treated with first-line (1L) chemotherapy (chemo) as compared to chemo +/- IO. Methods: This retrospective study utilized the COTA real-world database, a de-identified database derived from the electronic health records of healthcare providers in the United States. Patients included in the study had diagnosed aNSCLC and at least one positive test result for BRAF v600, HER2 mutation, EGFR, MET, RET or ROS1 prior to the initiation of 1L therapy. Additionally, patients must have received frontline chemotherapy, IO monotherapy, or IO+chemo combination in the advanced setting. Outcomes to first-line treatment (real-world progression-free survival (rwPFS) and real-world time to next treatment (rwTTNT)) were calculated using the Kaplan-Meier method. Results: A total of 170 qualified patients were identified as having at least one positive mutation and having received frontline chemotherapy (n=119), IO monotherapy (n=28), or chemo+IO combination (n=23). Mean age was 65 yrs and patients were predominantly white (71.2%), treated in the academic setting (74.1%), and denovo metastatic (67.1%). Outcomes to 1L treatment are reported in Table. Patients treated with 1L chemo+IO combination had longer rwPFS and rwTTNT as compared to patients treated with chemo alone or IO monotherapy, though outcomes did not reach statistical significance. Conclusions: Our study showed that in a real-world population of patients with aNSCLC and driver mutations, patients treated with chemo+IO combination had longer rwPFS and rwTTNT as compared to those treated with chemo alone or IO monotherapy. The overall short duration of benefit supports the model of using targeted treatment as optimal first line therapy, and the overall lack of benefit from IO. [Table: see text]