Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Christopoulos P

PROVIDER: S-EPMC10965206 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Christopoulos Petros P Harel Michal M McGregor Kimberly K Brody Yehuda Y Puzanov Igor I Bar Jair J Elon Yehonatan Y Sela Itamar I Yellin Ben B Lahav Coren C Raveh Shani S Reiner-Benaim Anat A Reinmuth Niels N Nechushtan Hovav H Farrugia David D Bustinza-Linares Ernesto E Lou Yanyan Y Leibowitz Raya R Kamer Iris I Zer Kuch Alona A Moskovitz Mor M Levy-Barda Adva A Koch Ina I Lotem Michal M Katzenelson Rivka R Agbarya Abed A Price Gillian G Cheley Helen H Abu-Amna Mahmoud M Geldart Tom T Gottfried Maya M Tepper Ella E Polychronis Andreas A Wolf Ido I Dicker Adam P AP Carbone David P DP Gandara David R DR

JCO precision oncology 20240301

<h4>Purpose</h4>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 a ...[more]

PMID: 38513170

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Project description:Background and objectiveFirst-line treatment options for patients with advanced non-small cell lung cancer (aNSCLC) whose tumors harbour anaplastic lymphoma kinase (ALK) gene rearrangements have rapidly evolved from chemotherapy, to the first in class ALK-targeted tyrosine kinase inhibitor (TKI) crizotinib in 2011, and now include no fewer than five Food and Drug Administration (FDA)-approved ALK inhibitors. However, while superiority to crizotinib has been established, head-to-head clinical trials comparing newer generation ALK inhibitors are lacking, and decisions on optimal first-line treatment must be based on analysis of the relevant trials, with attention to systemic and intracranial efficacy, toxicity profile as well as consideration of patient factors and preferences. Here we aim to synthesise findings from review of these trials and to describe options for optimal first-line treatment for ALK+ NSCLC.MethodsA literature review of relevant randomised clinical trials was undertaken using Embase database. There were no limitations to time frame or language applied.Key content and findingsCrizotinib was established as the standard of care first-line treatment for patients with ALK+ aNSCLC in 2011. Since this time, alectinib, brigatinib, ensartinib and lorlatinib have all demonstrated superiority as first-line treatments compared to crizotinib, based on progression free survival, intra-cranial efficacy, and side-effect profiles.ConclusionsOptions for optimal first-line treatment for ALK+ aNSCLC include alectinib, brigatinib and lorlatinib. This review serves as a resource summarizing data from key clinical trials with ALK inhibitors to aid in decision making when tailoring treatment for patients. Future research in the field includes real world analysis of efficacy and toxicity of next-generation ALK-inhibitors, identification of mechanisms of tumor persistence and acquired resistance, development of novel ALK inhibitors, and use of ALK-TKIs in earlier stage disease.

Project description:This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.

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Dataset Information

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

Purpose

Patients and methods

Results

Conclusion

Publications

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

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