Background: Chemotherapy is the current standard of care for pts with EGFR-mutant NSCLC whose tumor develops EGFR TKI resistance. We are conducting a real-world study to understand resistance mechanisms to EGFR TKI and outcomes with subsequent therapies (targeted and non-targeted). Here we report outcome results for standard of care given after resistance to a first-line (1L) EGFR TKI. Methods: This is a non-interventional descriptive cohort study using electronic medical record data and biomarker data from the United States TEMPUS database, which will continue until end of 2024 with new pts entering the study cohort over time. The study period for this reported analysis on real-world chemotherapy outcomes was any time until June 2022. Drug resistance was defined as disease progression on an EGFR TKI. Pts entering the study cohort were adult, with stage IIIB–IV NSCLC, had received an EGFR TKI either as a monotherapy or in combination with other systemic therapies, and had disease progression after EGFR TKI initiation. Pts were followed after tumor progression and from the initiation of a chemotherapy regimen, to describe treatment patterns and treatment outcomes (real-world progression-free survival [rw-PFS] and overall survival [OS]). Results: Of 21,425 pts with NSCLC, 1,087 patients were eligible for inclusion into the study cohort, with their stage IIIB–IV NSCLC diagnosis spanning from 1999 to 2021. A total of 588 pts (54.1%) received a 1L EGFR TKI and a subsequent second-line (2L) systemic therapy after disease progression. Of these, 100 pts received 2L chemotherapy regimens (platinum-based chemotherapy, n = 48; taxane monotherapy, n = 12; taxane + other chemotherapy, n = 3; pemetrexed, n = 28; other chemotherapy-only regimens, n = 9). Overall, these chemotherapy-treated pts had a median rw-PFS of 4.3 months (95% CI: 3.3, 5.1), and a median OS of 14.2 months (95% CI: 11.8, 22.2). Conclusions: Here, we show that after disease progression on a 1L EGFR TKI, patients had poor disease outcomes on 2L chemotherapy, indicating an unmet medical need as these pts likely developed EGFR TKI resistance. Treatment adaptation based on identified mechanism of resistance such as MET amplification, may improve outcomes for these patients.