Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer

PURPOSE: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB (R(2) = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (

• Christopoulos, P.
• Harel, M.
• McGregor, K.
• Brody, Y.
• Puzanov, I.
• Bar, J.
• Elon, Y.
• Sela, I.
• Yellin, B.
• Lahav, C.
• Raveh, S.
• Reiner-Benaim, A.
• Reinmuth, N.
• Nechushtan, H.
• Farrugia, D.
• Bustinza-Linares, E.
• Lou, Y.
• Leibowitz, R.
• Kamer, I.
• Zer Kuch, A.
• Moskovitz, M.
• Levy-Barda, A.
• Koch, I.
• Lotem, M.
• Katzenelson, R.
• Agbarya, A.
• Price, G.
• Cheley, H.
• Abu-Amna, M.
• Geldart, T.
• Gottfried, M.
• Tepper, E.
• Polychronis, A.
• Wolf, I.
• Dicker, A. P.
• Carbone, D. P.
• Gandara, D. R.