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Clinical Trials: Immunotherapy

Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial

Ravindra Uppaluri, Katie M. Campbell, Ann Marie Egloff, Paul Zolkind, Zachary L. Skidmore, Brian Nussenbaum, Randal C. Paniello, Jason T. Rich, Ryan Jackson, Patrik Pipkorn, Loren S. Michel, Jessica Ley, Peter Oppelt, Gavin P. Dunn, Erica K. Barnell, Nicholas C. Spies, Tianxiang Lin, Tiantian Li, David T. Mulder, Youstina Hanna, Iulia Cirlan, Trevor J. Pugh, Tenny Mudianto, Rachel Riley, Liye Zhou, Vickie Y. Jo, Matthew D. Stachler, Glenn J. Hanna, Jason Kass, Robert Haddad, Jonathan D. Schoenfeld, Evisa Gjini, Ana Lako, Wade Thorstad, Hiram A. Gay, Mackenzie Daly, Scott J. Rodig, Ian S. Hagemann, Dorina Kallogjeri, Jay F. Piccirillo, Rebecca D. Chernock, Malachi Griffith, Obi L. Griffith and Douglas R. Adkins
Ravindra Uppaluri
1Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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  • For correspondence: Ravindra_Uppaluri@DFCI.Harvard.edu
Katie M. Campbell
3Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
4McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
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  • ORCID record for Katie M. Campbell
Ann Marie Egloff
1Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
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Paul Zolkind
5Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
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Zachary L. Skidmore
4McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
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  • ORCID record for Zachary L. Skidmore
Brian Nussenbaum
5Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
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  • ORCID record for Brian Nussenbaum
Randal C. Paniello
5Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
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  • ORCID record for Randal C. Paniello
Jason T. Rich
5Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
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Ryan Jackson
5Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
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Patrik Pipkorn
5Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
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  • ORCID record for Patrik Pipkorn
Loren S. Michel
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
7Department of Medicine/Medical Oncology, Washington University School of Medicine, St. Louis, Missouri.
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Jessica Ley
7Department of Medicine/Medical Oncology, Washington University School of Medicine, St. Louis, Missouri.
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Peter Oppelt
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
7Department of Medicine/Medical Oncology, Washington University School of Medicine, St. Louis, Missouri.
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Gavin P. Dunn
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
8Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri.
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Erica K. Barnell
3Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
4McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
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Nicholas C. Spies
4McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
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Tianxiang Lin
5Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
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Tiantian Li
9Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
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David T. Mulder
9Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
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Youstina Hanna
9Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
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Iulia Cirlan
9Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
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Trevor J. Pugh
9Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
10Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
11Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
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Tenny Mudianto
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Rachel Riley
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Liye Zhou
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Vickie Y. Jo
1Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
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Matthew D. Stachler
12Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
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Glenn J. Hanna
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Jason Kass
1Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Robert Haddad
1Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Jonathan D. Schoenfeld
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
13Department of Radiation-Oncology, Brigham and Women's Hospital, Boston, Massachusetts.
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Evisa Gjini
12Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
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Ana Lako
12Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
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Wade Thorstad
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
14Department of Radiation-Oncology, Washington University School of Medicine, St. Louis, Massachusetts.
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Hiram A. Gay
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
14Department of Radiation-Oncology, Washington University School of Medicine, St. Louis, Massachusetts.
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Mackenzie Daly
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
14Department of Radiation-Oncology, Washington University School of Medicine, St. Louis, Massachusetts.
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Scott J. Rodig
12Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
15Center for Immuno-Oncology, Brigham and Women's Hospital, Boston, Massachusetts.
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Ian S. Hagemann
16Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
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Dorina Kallogjeri
5Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
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Jay F. Piccirillo
5Department of Otolaryngology, Washington University School of Medicine, St. Louis, Missouri.
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
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Rebecca D. Chernock
16Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
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Malachi Griffith
3Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
4McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
7Department of Medicine/Medical Oncology, Washington University School of Medicine, St. Louis, Missouri.
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Obi L. Griffith
3Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
4McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
7Department of Medicine/Medical Oncology, Washington University School of Medicine, St. Louis, Missouri.
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Douglas R. Adkins
6Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
7Department of Medicine/Medical Oncology, Washington University School of Medicine, St. Louis, Missouri.
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DOI: 10.1158/1078-0432.CCR-20-1695 Published October 2020
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This article has a correction. Please see:

  • Correction: Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–unrelated Head and Neck Cancer: A Multicenter, Phase II Trial - January 4, 2021

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Abstract

Purpose: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)–unrelated HNSCC.

Patients and Methods: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%–49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684).

Results: Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3–4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%–41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients.

Conclusions: Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:5140–52

  • Received May 3, 2020.
  • Revision received June 8, 2020.
  • Accepted July 8, 2020.
  • Published first July 14, 2020.
  • Corrected online November 25, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (19)
October 2020
Volume 26, Issue 19
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Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial
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Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial
Ravindra Uppaluri, Katie M. Campbell, Ann Marie Egloff, Paul Zolkind, Zachary L. Skidmore, Brian Nussenbaum, Randal C. Paniello, Jason T. Rich, Ryan Jackson, Patrik Pipkorn, Loren S. Michel, Jessica Ley, Peter Oppelt, Gavin P. Dunn, Erica K. Barnell, Nicholas C. Spies, Tianxiang Lin, Tiantian Li, David T. Mulder, Youstina Hanna, Iulia Cirlan, Trevor J. Pugh, Tenny Mudianto, Rachel Riley, Liye Zhou, Vickie Y. Jo, Matthew D. Stachler, Glenn J. Hanna, Jason Kass, Robert Haddad, Jonathan D. Schoenfeld, Evisa Gjini, Ana Lako, Wade Thorstad, Hiram A. Gay, Mackenzie Daly, Scott J. Rodig, Ian S. Hagemann, Dorina Kallogjeri, Jay F. Piccirillo, Rebecca D. Chernock, Malachi Griffith, Obi L. Griffith and Douglas R. Adkins
Clin Cancer Res October 1 2020 (26) (19) 5140-5152; DOI: 10.1158/1078-0432.CCR-20-1695

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Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial
Ravindra Uppaluri, Katie M. Campbell, Ann Marie Egloff, Paul Zolkind, Zachary L. Skidmore, Brian Nussenbaum, Randal C. Paniello, Jason T. Rich, Ryan Jackson, Patrik Pipkorn, Loren S. Michel, Jessica Ley, Peter Oppelt, Gavin P. Dunn, Erica K. Barnell, Nicholas C. Spies, Tianxiang Lin, Tiantian Li, David T. Mulder, Youstina Hanna, Iulia Cirlan, Trevor J. Pugh, Tenny Mudianto, Rachel Riley, Liye Zhou, Vickie Y. Jo, Matthew D. Stachler, Glenn J. Hanna, Jason Kass, Robert Haddad, Jonathan D. Schoenfeld, Evisa Gjini, Ana Lako, Wade Thorstad, Hiram A. Gay, Mackenzie Daly, Scott J. Rodig, Ian S. Hagemann, Dorina Kallogjeri, Jay F. Piccirillo, Rebecca D. Chernock, Malachi Griffith, Obi L. Griffith and Douglas R. Adkins
Clin Cancer Res October 1 2020 (26) (19) 5140-5152; DOI: 10.1158/1078-0432.CCR-20-1695
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