Background: The 2-year mark has become a new milestone in pts with aNSCLC receiving immunotherapy. In pts who are progression free at that point, a subset experience ongoing disease control even after stopping active treatment. Some pts experience such impressive durability beyond 2 years, raising a question about potential cure. We queried a real-world (RW) clinico-genomic database (CGDB) to better understand these pts with durable benefit and their clinical and genomic features. Methods: Using the nationwide (̃280 US cancer clinics) de-identified EHR-derived Flatiron Health-Foundation Medicine aNSCLC CGDB linked to genomic data, pts treated with ICI (+/- chemotherapy) from 01/2011-06/2021 were selected. RW progression (rwP) was obtained via technology-enabled abstraction of EHR data. Durable benefit was classified as absence of rwP, death or treatment failure (indicated by switch to a new line of therapy) within 24 mos of beginning ICI therapy. Results: In a cohort of 4,030 evaluable aNSCLC pts, 184 (4.6%) were free of rwP or treatment failure at 24 mos. Of these 184 pts with durable benefit, 84% received ICI monotherapy and 16% received ICI with chemotherapy; ICI treatment was more often first line (1L, 43%) or 2L (38%). 59% with durable benefit were still on ICI at the 2-year mark, whereas 41% had stopped a median of 11.4 mos after therapy start. Of 109 pts remaining on ICI for 2-years, median time on ICI was 36.3 mos from therapy start. Overall, pts with durable benefit had a median rwPFS of 37.1 mos and median rwOS of 58.8 mos from start of ICI. Compared to pts with rwP on ICI before 24 mos, those with durable benefit were more likely to have history of smoking (94% vs 86%) and absence of liver, brain or bone metastases (all p < 0.001). High tumor mutational burden (TMB ≥10) was more common (62% vs 35%, p < 0.001) and STK11, CDKN2B, PIK3CA, and EGFR alterations were less common in pts with durable-benefit vs those with rwP on ICI before 24 mos. In a multivariate cox model of rwPFS beyond 24 mos in pts with durable benefit, TMB ≥20 was significantly associated with longer rwPFS (HR 0.45 95% CI 0.24-0.83, p = 0.01) while TMB ≥10 was marginally significant (HR 0.65 95% CI 0.40-1.03, p = 0.07); treatment with ICI with chemotherapy was significantly associated with worse rwPFS (HR 1.84 95% 1.093.12, p = 0.02). High PD-L1 > 50% was noted in 728 (19%) of those without durable benefit and 38 (21%) of those with durable benefit, though many in the data set had unknown PD-L1 status. Conclusions: Pts with durable benefit > 2 years after starting ICI therapy for aNSCLC represent a unique population of immune survivors with a median OS of almost 5 years; 41% of pts stopped ICI before the 2-year mark. Elevated TMB was associated with durable benefit on ICI as well as prolonged rwPFS after the 2-year mark and deserves further investigation as a biomarker for prolonged benefit to ICI in aNSCLC.