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Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial
IMPORTANCE: Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Medical Association
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10654930/ https://www.ncbi.nlm.nih.gov/pubmed/37971722 http://dx.doi.org/10.1001/jamaoncol.2023.4853 |
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author | Hanna, Glenn J. Villa, Alessandro Nandi, Shuvro P. Shi, Ruichao ONeill, Anne Liu, Mofei Quinn, Charles T. Treister, Nathaniel S. Sroussi, Herve Y. Vacharotayangul, Piamkamon Goguen, Laura A. Annino, Donald J. Rettig, Eleni M. Jo, Vickie Y. Wong, Kristine S. Lizotte, Patrick Paweletz, Cloud P. Uppaluri, Ravindra Haddad, Robert I. Cohen, Ezra E. W. Alexandrov, Ludmil B. William, William N. Lippman, Scott M. Woo, Sook-bin |
author_facet | Hanna, Glenn J. Villa, Alessandro Nandi, Shuvro P. Shi, Ruichao ONeill, Anne Liu, Mofei Quinn, Charles T. Treister, Nathaniel S. Sroussi, Herve Y. Vacharotayangul, Piamkamon Goguen, Laura A. Annino, Donald J. Rettig, Eleni M. Jo, Vickie Y. Wong, Kristine S. Lizotte, Patrick Paweletz, Cloud P. Uppaluri, Ravindra Haddad, Robert I. Cohen, Ezra E. W. Alexandrov, Ludmil B. William, William N. Lippman, Scott M. Woo, Sook-bin |
author_sort | Hanna, Glenn J. |
collection | PubMed |
description | IMPORTANCE: Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell–rich microenvironment, providing strong rationale to investigate immune checkpoint therapy. OBJECTIVE: To determine the safety and clinical activity of anti–programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL. DESIGN, SETTING, AND PARTICIPANTS: This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia). INTERVENTION: Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit. MAIN OUTCOMES AND MEASURES: The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response. RESULTS: A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss. CONCLUSIONS AND RELEVANCE: This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03692325 |
format | Online Article Text |
id | pubmed-10654930 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Medical Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-106549302023-11-16 Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial Hanna, Glenn J. Villa, Alessandro Nandi, Shuvro P. Shi, Ruichao ONeill, Anne Liu, Mofei Quinn, Charles T. Treister, Nathaniel S. Sroussi, Herve Y. Vacharotayangul, Piamkamon Goguen, Laura A. Annino, Donald J. Rettig, Eleni M. Jo, Vickie Y. Wong, Kristine S. Lizotte, Patrick Paweletz, Cloud P. Uppaluri, Ravindra Haddad, Robert I. Cohen, Ezra E. W. Alexandrov, Ludmil B. William, William N. Lippman, Scott M. Woo, Sook-bin JAMA Oncol Original Investigation IMPORTANCE: Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell–rich microenvironment, providing strong rationale to investigate immune checkpoint therapy. OBJECTIVE: To determine the safety and clinical activity of anti–programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL. DESIGN, SETTING, AND PARTICIPANTS: This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia). INTERVENTION: Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit. MAIN OUTCOMES AND MEASURES: The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response. RESULTS: A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss. CONCLUSIONS AND RELEVANCE: This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03692325 American Medical Association 2023-11-16 /pmc/articles/PMC10654930/ /pubmed/37971722 http://dx.doi.org/10.1001/jamaoncol.2023.4853 Text en Copyright 2023 Hanna GJ et al. JAMA Oncology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the CC-BY-NC-ND License. |
spellingShingle | Original Investigation Hanna, Glenn J. Villa, Alessandro Nandi, Shuvro P. Shi, Ruichao ONeill, Anne Liu, Mofei Quinn, Charles T. Treister, Nathaniel S. Sroussi, Herve Y. Vacharotayangul, Piamkamon Goguen, Laura A. Annino, Donald J. Rettig, Eleni M. Jo, Vickie Y. Wong, Kristine S. Lizotte, Patrick Paweletz, Cloud P. Uppaluri, Ravindra Haddad, Robert I. Cohen, Ezra E. W. Alexandrov, Ludmil B. William, William N. Lippman, Scott M. Woo, Sook-bin Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial |
title | Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial |
title_full | Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial |
title_fullStr | Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial |
title_full_unstemmed | Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial |
title_short | Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial |
title_sort | nivolumab for patients with high-risk oral leukoplakia: a nonrandomized controlled trial |
topic | Original Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10654930/ https://www.ncbi.nlm.nih.gov/pubmed/37971722 http://dx.doi.org/10.1001/jamaoncol.2023.4853 |
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