A pragmatic, prospective phase II clinical trial protocol published in Frontiers in Oncology outlines plans to evaluate standard first-line immunotherapy-based regimens in advanced non-small cell lung cancer patients who present with borderline performance status. Developed by an investigative team from Wake Forest University School of Medicine, Wake Forest Baptist Medical Center, and Tulane University School of Medicine, the single-center pilot investigation is designed to compare therapeutic outcomes between patients categorized as Eastern Cooperative Oncology Group performance status 2 and those presenting with performance status 0 to 1.
According to the study protocol, approximately 20% to 40% of patients diagnosed with metastatic non-small cell lung cancer present with an Eastern Cooperative Oncology Group performance status of 2. Despite accounting for a substantial fraction of the clinical population, these patients have been systematically excluded from pivotal clinical trials evaluating immunotherapy regimens. Current clinical practice guidelines recommend similar first-line treatment regimens for performance status 0 to 1 and performance status 2 cohorts based primarily on extrapolated data, creating persistent clinical uncertainty for practicing oncologists.
To address this clinical evidence gap, the pragmatic pilot phase II study establishes a prospective comparative framework operating within routine oncology practice. Eligible participants with metastatic non-small cell lung cancer receive National Comprehensive Cancer Network preferred frontline immunotherapy-based regimens. Rather than assigning experimental treatment allocations, the protocol permits treating healthcare providers to select preferred regimens in accordance with routine standards of medical care.
The primary clinical outcome specified in the study design is 3-month progression-free survival, defined as the proportion of enrolled patients who remain without objective disease progression following four cycles of treatment. By evaluating disease status after four therapeutic cycles, the study aims to assess whether performance status 2 patients achieve early disease control comparable to that observed in patients with performance status 0 to 1.
Methodologically, the trial employs a formal non-inferiority statistical design to compare early disease control between the two cohorts. The statistical framework establishes a non-inferiority margin of a minus 0.20 absolute difference in the 3-month progression-free survival proportion, tested at an alpha significance level of 0.05 with 83% statistical power to detect whether selected performance status 2 patients meet the predefined non-inferiority threshold.
Beyond the primary progression-free survival measure, the protocol monitors secondary clinical outcomes including treatment-related adverse events and longitudinal patient-reported quality of life changes. By tracking adverse events and quality of life assessments across treatment courses, the trial intends to evaluate whether the toxicity burden and patient-reported well-being in the borderline performance status group remain acceptable during standard frontline therapy.
The authors hypothesize that selected performance status 2 patients will demonstrate non-inferior 3-month progression-free survival compared to performance status 0 to 1 patients under standard immunotherapy-based care, accompanied by acceptable toxicity and quality of life profiles. Because the publication details a planned study protocol rather than completed therapeutic results, definitive clinical efficacy and safety findings remain subject to prospective trial execution, registered on ClinicalTrials.gov under identifier NCT04253964.
A primary objective of the pragmatic pilot trial is to resolve whether performance status alone should preclude patients with metastatic non-small cell lung cancer from receiving standard frontline immunotherapy-based regimens. Because historical clinical trial exclusion has left oncologists reliant on extrapolated recommendations, generating prospective real-world evidence directly addresses a critical evidence gap. The resulting data are intended to supply substantive clinical information to guide shared decision-making discussions between treating oncologists and an underrepresented patient population facing first-line therapeutic choices.
The study protocol was authored by Yaffa Ali, Haley Westervelt, Sarah N. Price, Beverly Levine, David Soto-Pantoja, John Hunting, Stefan Grant, William Jeffrey Petty, and corresponding author Thomas Lycan Jr. This collaborative investigative group connects researchers across Wake Forest Baptist Medical Center and Wake Forest University School of Medicine in Winston-Salem with colleagues at Tulane University School of Medicine in New Orleans. Their shared research framework focuses specifically on chemo-immunotherapy and immunotherapy regimens administered within routine care settings.
Published in the Thoracic Oncology section of Frontiers in Oncology, the study protocol was officially received on July 6, 2026, and accepted on October 19, 2026. Because this publication represents a study protocol article rather than a report of completed clinical trials, it describes planned methodological criteria rather than observed therapeutic results. Any formal evaluation of treatment-related safety, patient-reported quality of life, or clinical non-inferiority must await the completion of patient treatment and outcome reporting under the registered trial.
Subject of Research: Phase II trial protocol evaluating first-line immunotherapy in borderline performance status metastatic lung cancer
Article Title: Treating beyond trial eligibility: a pragmatic, prospective phase II study of first-line immunotherapy regimens in advanced non–small cell lung cancer patients with borderline performance status
Article References: Ali, Y., Mabry, H. W., Price, S. N., Levine, B., Soto-Pantoja, D., Hunting, J., Grant, S., Petty, W. J., & Lycan, T. W., Jr. (2026). Treating beyond trial eligibility: a pragmatic, prospective phase II study of first-line immunotherapy regimens in advanced non–small cell lung cancer patients with borderline performance status. Frontiers in Oncology, 16, Article 1929978. https://doi.org/10.3389/fonc.2026.1929978
Image Credits: AI Generated
DOI: 10.3389/fonc.2026.1929978
Keywords: metastatic non-small cell lung cancer, non-small cell lung cancer, ECOG performance status 2, performance status, first-line immunotherapy, chemo-immunotherapy, phase II trial, pragmatic clinical trial, study protocol, progression-free survival, non-inferiority trial, patient-reported quality of life, treatment-related adverse events, NCCN-preferred regimens, NCT04253964, borderline performance status, early disease control, Frontiers in Oncology
News Source: Nathaniel Bowman. (November 14, 2026). Phase II Protocol Evaluates First-Line Immunotherapy for Borderline Performance Lung Cancer. Scienmag.
