A risk stratification schema for patients with non–small cell lung cancer with multiple organ metastases.

11138 Background: The majority of patients with non-small cell lung cancer (NSCLC) will have multiple organ sites of metastasis and poor overall survival (rwOS). Specific organ involvement influences patient outcomes, but the impact of overarching patterns of metastasis on rwOS and response to systemic therapy (ST) is poorly understood. Prior studies have been limited in their scale, availability of detailed data on sites of metastasis, and inclusion of patients receiving immunotherapy (IO) or targeted therapy (TT). We leveraged a large-scale, real-world database to characterize and assess the prognostic value of patterns of metastasis on rwOS and time to next therapy (rwTTNT) in patients with metastatic NSCLC receiving ST. Methods: This retrospective study utilized the Flatiron Health Research Database of patients with NSCLC treated with first-line (1L) ST (n = 327,044). Patient, tumor, and treatment variables were summarized descriptively and compared across patterns of metastasis. rwOS and rwTTNT from 1L start were estimated via Kaplan Meier method and compared with logrank test. Bernoulli mixture models were used to cluster patients by metastatic sites at 1L start. Results: Sites of disease were evaluated for 75,304 patients. Data from 5 metastatic sites revealed 6 clusters reflective of real-world patterns of metastasis: bone (n = 33,882), pleural (n = 12,123), liver (n = 6,133), brain (n = 11,441), adrenal avid (n = 6,975), and high metastatic burden (HMB, ≥3 sites with frequency ≥0.5, n = 4,750). While HMB (7.2 months median rwOS, 4.8 months median rwTTNT) and liver avid disease (9.4, 5.2 months) had poor outcomes as expected, we also found that bone (11.0, 5.9 months) and adrenal (11.8, 6.0 months) avid clusters had worse median rwOS and shorter rwTTNT compared to pleural (15.7, 7.6 months) and brain (15.3, 7.4 months, p < 0.001). Outcomes associated with a specific site of metastasis varied based on patient cluster assignment. Compared to the cluster equivalent (e.g., brain avid), individual metastatic site (e.g., brain) as a prognostic factor was associated with worse median rwOS by 1.0-2.9 months and shorter median rwTTNT by 0.1-0.9 months. Compared to individual sites and site-avid clusters, HMB more often had EGFR mutations (20.7% vs 13.6% overall). IO was associated with greater median rwOS over TT in the adrenal cluster (17.7 vs 15.6 months), and IO + CTX had better rwOS vs IO alone in pleural (15.7 vs 12.9 months) and liver clusters (10.7 vs 9.4 months, p < 0.001). Conclusions: The survival outcomes and treatment response associated with defined clusters of metastases are distinct from those associated with individual organ sites or widespread disease alone. A risk-stratification framework that uses “risk phenotypes” representative of real-world patterns of metastasis may have better prognostic and predictive significance in patients with multiple sites or higher burden of disease.