e20541 Background: The non-random distribution of metastases (mets) to distant organ sites, known as organotropism, has been observed in patients with non-small cell lung cancer (NSCLC). Most patients will develop mets in two or more organ sites, with select sites and high met burden having prognostic and predictive significance. However, mechanisms driving site-specific and widespread metastatic potential are not well understood, and real-world overall survival (rwOS) remains poor. We used a database containing real-world clinical and genomic information to characterize and evaluate the prognostic value of temporal patterns of metastatic progression on rwOS in patients with NSCLC receiving systemic therapy (ST). Methods: This retrospective study utilized the Flatiron Health-Foundation Medicine Clinico-Genomic Database of patients with metastatic NSCLC treated with first-line (1L) ST. Patient, tumor, and treatment variables were summarized descriptively and compared with chi-squared tests. rwOS was estimated via Kaplan Meier method and compared with logrank test. Bernoulli mixture models were used to cluster patients by met sites at time of metastatic diagnosis, 1L therapy start, and last follow-up. Results: Data from 18 met sites was evaluated for 11,527 patients. Common sites at diagnosis were bone (22.7%), lung (17.4%), pleura (16.6%), and brain (13.0%). 72.9% of patients developed mets in two or more organ sites, and certain initial sites were associated with the non-random distribution of secondary mets. For example, patients with initial adrenal mets were more likely to develop a secondary brain met (OR 1.43, p < 0.001) compared to another site. Two phenotypes of patients with high met burden (HMB, ≥3 sites with frequency ≥0.5) at last follow-up were identified. HMB 1 (n = 1,556, median 4 sites) had frequent brain, bone, lung, and liver mets, whereas HMB 2 (n = 545, median 5 sites) had bone, distant lymph node, adrenal, soft tissue, and liver mets. HMB 1 patients more frequently had bone or liver avid disease at 1L start, whereas HMB 2 patients often had already developed HMB by this time. HMB 1 patients had better median rwOS (11.8 months) than HMB 2 patients (10.2 months), as well as compared to patients that had a lower met burden with bone (11.6 months) or liver avid disease (9.8 months, p < 0.05). Mutations in select genes that regulate interferon-gamma response and cytoplasm organization (KIF5B, CD74, ETV6, NCOA4) were associated with HMB 1, but not HMB 2 or site-specific disease. Conclusions: Definable patterns of metastasis are associated with rwOS in NSCLC. This study is the most comprehensive evaluation of the impact of longitudinal patterns of organ-specific spread and drivers of overall metastatic potential on survival outcomes in patients with NSCLC to date. This novel framework could serve as a crucial counseling and clinical management tool when caring for patients with advanced NSCLC.
Esnaola et al. (Thu,) studied this question.