LAUSR

Background: Different metastatic sites have distinct response rates to immune checkpoint inhibitors (ICI), suggesting that anatomical locations play a role in treatment response and survival. This project investigated the impact that sites of metastases present at baseline - ie. before starting treatment - have on the anatomical patterns of progression and their association with survival in patients (pts) exposed to ICI and BRAF/MEK inhibitors (BRAF/MEKi) as first line treatment. Methods: We curated the progression history of distant metastases of 568 stage IV pts; 352 pts had first line treatment with antiPD1 +/- antiCTLA4, and 216 pts had first line BRAF/MEKi. We sought to investigate the association between sites of metastases at baseline and (a) sites of progression in pts who failed first line anti-PD1 vs first line BRAF/MEKi, (b) sites of progression in pts who failed first line anti-PD1 with innate vs acquired resistance, and (c) survival of all pts, from time of first line treatment to last follow-up. Results: Using a sophisticated mathematical graph representation of anatomical disease progression, we unveiled sites of metastases at baseline that impacted where new sites of metastases developed on treatment failure. In pts with brain metastasis at baseline, pts who failed anti-PD1 had higher progression in the brain compared to BRAF/MEKi progressors (68.1% in anti-PD1 progressors vs 62.5% in BRAF/MEKi progressors). In contrast, the opposite trend was observed in the progression to the brain in pts with no brain metastasis at baseline, which was lower in anti-PD1 progressors compared to BRAF/MEKi progressors (20.6% in anti-PD1 progressors vs 32.6% in BRAF/MEKi progressors).Within pts who failed anti-PD1, pts with innate resistance (n=95) had a higher rate of progression in the brain (42.1%) compared to pts with acquired (n=36) resistance (25%). Among pts with innate resistance who had brain metastasis at baseline (n=36), 80.6% progressed in the brain. In contrast, among pts with innate resistance without brain metastasis at baseline (n=59), only 18.6% progressed to the brain.Sites of metastases at baseline also had an impact on the survival of pts. In BRAF/MEKi pts, brain metastasis at baseline was not associated with survival (log-rank p-value=0.6). In contrast, anti-PD1 pts with brain metastasis at baseline had worst survival (2-yr survival 56%) compared to pts without brain metastasis at baseline (2-yr survival 73%, log-rank p-value=0.005). Utilisation of this graph representation for the development of a time-dependent predictor of brain metastases will be presented. Further associations of metastatic sites of disease at baseline with progression and survival will be discussed. Conclusions: Different sites of metastases at baseline have a distinct effect on the progression patterns and survival of pts who received BRAF/MEKi or anti-PD1 as first line treatment. Citation Format: Ismael A. Vergara, Serigne N. Lo, Isabel Li, Alexander M. Menzies, Matteo S. Carlino, Richard A. Scolyer, Georgina V. Long, Ines Pires da Silva. Sites of metastases prior to systemic treatment influence progression patterns and survival in stage IV melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6747.