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
Source: https://doi.org/10.1200/PO.23.00555
Professional photo of Ernesto Bustinza, MD
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.

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 (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).

CONCLUSION

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

Leave a Comment

Your email address will not be published. Required fields are marked *

Related Articles

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Read More »

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.

Read More »

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

The phase 3 MARIPOSA trial compared amivantamab–lazertinib (Ami-Laz) to osimertinib (Osi) in untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC), showing a significant overall survival (OS) benefit for Ami-Laz (3-yr OS was 60% vs 51%). Median OS was not reached for Ami-Laz vs 36.7 months for Osi, with a projected >12-month median OS advantage. Ami-Laz also improved time to symptomatic progression (43.6 vs 29.3 months) and showed durable intracranial control, though grade ≥3 adverse events (AEs) were higher (80% vs 52%), notably skin, venous thromboembolism (VTE), and infusion reactions. In short, Ami-Laz is emerging as a new standard for first-line EGFRm NSCLC, but we’ll need to be proactive about managing its toxicity profile in clinic and whether this is superior or equivalent to Osi + chemo is currently unclear.

Read More »

Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial

Adagrasib demonstrated a median progression-free survival (PFS) of 5.5 months compared to 3.8 months with docetaxel in patients with KRAS G12C-mutated tumors. Treatment-related adverse events occurred in 47% of patients receiving Adagrasib and 46% in the docetaxel group. In my experience, Adagrasib is also more tolerable, making it a favorable option for this patient population.

Read More »