“Off-Label” Use of Checkpoint Inhibitors in Patients With Negative or Unknown PD-L1 Status in Advanced Head and Neck Cancer
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Background: The KEYNOTE-048 study established the checkpoint inhibitor (CPI) pembrolizumab, with/without chemotherapy, as frontline treatment for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, pembrolizumab monotherapy has limited efficacy in PD-L1–negative disease. Clinical practice patterns regarding PD-L1 combined positive score (CPS) testing and PD-L1–guided treatment selection remain unknown. Patients and Methods: This retrospective analysis included patients who initiated treatment for R/M HNSCC from 2011 to 2023 in a nationwide electronic health record–derived deidentified database. Frontline therapy was categorized as CPI monotherapy, CPI with chemotherapy, or chemotherapy ± cetuximab without CPI. A subset of patients treated in 2019 and beyond (2019+ cohort) were analyzed to investigate PD-L1 testing rates, treatment patterns following FDA approval of pembrolizumab, and the proportion receiving “off-label” CPI monotherapy (single-agent use in patients with metastatic HNSCC and negative/unknown PD-L1 status). Factors associated with “off-label” use were identified using multivariable logistic regression. Results: The total cohort included 7,657 patients with a median age of 65 years (IQR, 58–72); 67% were White, 78% had a history of smoking, 66% had an ECOG performance status (PS) of 0–1, and 31% were HPV-positive. The 2019+ subset included 3,395 patients, of whom nearly half (47%) did not have a known PD-L1 CPS prior to systemic treatment initiation. The most common frontline treatment in the total cohort was CPI monotherapy (43%). CPI monotherapy use was even higher in patients aged ≥75 years (54%) and those with ECOG PS ≥2 (52%). Among the 2019+ subgroup with PD-L1 CPS negative/unknown tumors (n=1,926), 536 (28%) received CPI monotherapy “off-label.” Factors associated with “off-label” use on multivariable regression included age ≥75 years (odds ratio [OR], 1.4), community practice setting (OR, 1.5), and earlier year of treatment (OR, 1.3 per year) (all P<.05). Conclusions: Most US patients with R/M HNSCC are now receiving CPI-based therapy in the frontline setting; however, PD-L1 testing remains underutilized. “Off-label” use of CPI monotherapy in PD-L1–negative/unknown HNSCC is common, particularly among elderly patients.
Submitted June 21, 2024; final revision received October 28, 2024; accepted for publication October 29, 2024. Published online February 11, 2025.
M. Stalker and K. Qu contributed equally.
Author contributions: Conceptualization: Sun. Proposal submission: Stalker. Data analysis: Stalker. Statistical analysis: Qu, Hwang, Sun. Resources: Qu. Supervision: Mamtani, Sun. Writing—original draft: Stalker. Writing—review & editing: Stalker, Qu, Cohen, Mamtani, Sun.
Disclosures: Dr. Mamtani has disclosed serving as consultant for Seagen, Astellas Pharma, Merck, and Bristol Myers Squibb; and receiving institutional grant/research support from Merck and Astellas Pharma. Dr. Sun has disclosed receiving institutional grant/research support from Blueprint, Seagen, IO Biotech, Erasca, Immunocore, and AbbVie; and receiving honoraria from and serving as a scientific advisor for Genmab, Seagen, Bayer, and Medscape. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.
Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2024.7085. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.
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