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

Author(s): Petros Christopoulos, MD, PhD1,2; Michal Harel, PhD3; Kimberly McGregor, MD3; Yehuda Brody, PhD3; Igor Puzanov, MD4,5; Jair Bar, MD, PhD6,7; Yehonatan Elon, PhD3; Itamar Sela, PhD3; Ben Yellin, PhD3; Coren Lahav, MSc3; Shani Raveh, PhD3; Anat Reiner-Benaim, PhD8; Niels Reinmuth, MD9,10; Hovav Nechushtan, MD11; David Farrugia, MD12; Ernesto Bustinza-Linares, MD13; Yanyan Lou, MD14; Raya Leibowitz, MD, PhD15; Iris Kamer, PhD6; Alona Zer Kuch, MD16; Mor Moskovitz, MD17; Adva Levy-Barda, PhD18; Ina Koch, PhD9; Michal Lotem, MD19; Rivka Katzenelson, MD20; Abed Agbarya, MD21; Gillian Price, MD22; Helen Cheley, RN23; Mahmoud Abu-Amna, MD24; Tom Geldart, MD25; Maya Gottfried, MD26; Ella Tepper, MD27; Andreas Polychronis, MD28; Ido Wolf, MD29; Adam P. Dicker, MD, PhD30; David P. Carbone, MD31; David R. Gandara, MD32

FCS medical oncologist and hematologist Ernesto Bustinza-Linares, MD has co-authored an abstract published in the American Society of Clinical Oncology Journal, JCO Precision Oncology, that uncovers a new testing method to determine personalized care options for patients with metastatic non-small cell lung cancer (NSCLC). The abstract’s authors address the limitations of existing guidelines that recommend checkpoint immunotherapy, sometimes in combination with chemotherapy, for treating NSCLC, which often discounts patient variability and immune factors. The findings from the study show that by incorporating additional plasma proteome-based testing, combined with the standard protein inhibitor testing, clear differences in patient outcomes were observed after applying targeted treatments based on the testing results.


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.


We conducted a multicenter observational trial ( 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.


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 (R2 = 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 (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424).


Plasma proteome–based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor–based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.

Author Affiliations

1Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, Germany; 2Translational Lung Research Center Heidelberg (TLRC-H), member of the German Center for Lung Research (DZL), Heidelberg, Germany; 3OncoHost Ltd, Binyamina, Israel; 4Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY; 5The Roswell Park Comprehensive Cancer Center Data Bank and BioRepository; 6Institute of Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel; 7Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv, Israel; 8Department of Epidemiology, Biostatistics and Community Health Sciences, School of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 9Asklepios Kliniken GmbH, Asklepios Fachkliniken Muenchen, Gauting, Germany; 10The German Center for Lung Research (DZL), Munich-Gauting, Germany; 11Oncology Laboratory, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 12Cheltenham General Hospital, Cheltenham, United Kingdom; 13University of Central Florida, FL; 14Division of Hematology and Oncology, Mayo Clinic School of Medicine, Jacksonville, FL; 15Shamir Medical Center, Oncology Institute, Zerifin, Israel; 16Department of Oncology, Rambam Medical Center, Haifa, Israel; 17Thoracic Cancer Service, Davidoff Cancer Center, Beilinson, Petah Tikva, Israel; 18Biobank, Department of Pathology, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel; 19Center for Melanoma and Cancer Immunotherapy, Hadassah Hebrew University Medical Center, Sharett Institute of Oncology, Jerusalem, Israel; 20Kaplan Medical Center, Rehovot, Israel; 21Institute of Oncology, Bnai Zion Medical Center, Haifa, Israel; 22Department of Medical Oncology, Aberdeen Royal Infirmary NHS Grampian, Aberdeen, United Kingdom; 23Swansea Bay UHB; 24Oncology & Hematology Division, Cancer Center, Emek Medical Center, Afula, Israel; 25Royal Bournemouth Hospital; 26Department of Oncology, Meir Medical Center, Kfar-Saba, Israel; 27Department of Oncology, Assuta Hospital, Tel Aviv, Israel; 28Mount Vernon Cancer Centre, Northwood, United Kingdom; 29Division of Oncology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; 30Thomas Jefferson University, Philadelphia, PA; 31Comprehensive Cancer Center, Ohio State University, Columbus, OH; 32Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA

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