TY - JOUR
T1 - Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus–Unrelated Head and Neck Cancer
T2 - A Multicenter, Phase II Trial
AU - Uppaluri, Ravindra
AU - Campbell, Katie M.
AU - Egloff, Ann Marie
AU - Zolkind, Paul
AU - Skidmore, Zachary L.
AU - Nussenbaum, Brian
AU - Paniello, Randal C.
AU - Rich, Jason T.
AU - Jackson, Ryan
AU - Pipkorn, Patrik
AU - Michel, Loren S.
AU - Ley, Jessica
AU - Oppelt, Peter
AU - Dunn, Gavin P.
AU - Barnell, Erica K.
AU - Spies, Nicholas C.
AU - Lin, Tianxiang
AU - Li, Tiantian
AU - Mulder, David T.
AU - Hanna, Youstina
AU - Cirlan, Iulia
AU - Pugh, Trevor J.
AU - Mudianto, Tenny
AU - Riley, Rachel
AU - Zhou, Liye
AU - Jo, Vickie Y.
AU - Stachler, Matthew D.
AU - Hanna, Glenn J.
AU - Kass, Jason
AU - Haddad, Robert
AU - Schoenfeld, Jonathan D.
AU - Gjini, Evisa
AU - Lako, Ana
AU - Thorstad, Wade
AU - Gay, Hiram A.
AU - Daly, Mackenzie
AU - Rodig, Scott J.
AU - Hagemann, Ian S.
AU - Kallogjeri, Dorina
AU - Piccirillo, Jay F.
AU - Chernock, Rebecca D.
AU - Griffith, Malachi
AU - Griffith, Obi L.
AU - Adkins, Douglas R.
N1 - Funding Information:
We thank all patients and their families for their participation in this study. We recognize the support of the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, the Clinical Trials Core, the Biostatistics Shared Resource, and the Center for Biomedical Informatics. The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant #P30 CA91842. M. Griffith is funded by the National Human Genome Research Institute (NIH NHGRI R00HG007940), O.L. Griffith by the National Cancer Institute (NIH/NCI K22CA188163, NIH/NCI U01CA209936, and NIH/NCI U24CA237719), and a Cancer Research Foundation Young Investigator Award. R. Uppaluri is funded by the National Institute for Dental and Craniofacial Research (NIH/NIDCR R01DE024403, R01DE027736) and a V Foundation Translational Research Award. Clinical trial support was through a Merck Investigator Studies Program award to R. Uppaluri/D.R. Adkins.
Funding Information:
R. Uppaluri reports grants and personal fees from Merck Inc. K.M. Campbell reports being a shareholder in Geneoscopy LLC. P. Oppelt reports personal fees from Merck, Bristol Myers Squibb, and Eisai outside the submitted work. G.P. Dunn reports other from Immunovalent (Co-founder) outside the submitted work. E.K. Barnell reports other from Geneoscopy (stock, equity, and board member) outside the submitted work, and is listed as a co-inventor on a provisional patent application on methods for isolating eukaryotic RNA from stool that is owned by Geneoscopy Inc. T.J. Pugh is listed as a co-inventor on a provisional patent application on immune repertoire capture and sequencing that is owned by University Health Network. G.J. Hanna reports personal fees and non-financial support from BMS, Exicure, Kite Pharma, Regeneron, and Sanofi Genzyme, grants from ASCO/CCF and Gateway for Cancer Research, and personal fees from Merck and Bicara outside the submitted work. R. Haddad reports personal fees from BMS, MERCK, AZ, GSK, PFIZER, GENENTECH, IO BIOTECH, KURA, and EISAI during the conduct of the study; other from BMS, Merck, Pfizer, Kura, AstraZeneca, Genentech, and GSK (Research Support) outside the submitted work. J.D. Schoenfeld reports other from Merck (paid to the institution) during the conduct of the study; grants from Regeneron and Merck, personal fees from Debiopharm Group, ACI, Immunitas (SAB, equity), pKline & Spector PC, Heidell, Pittoni, Murphy and Bach, Catenion, LEK, TILOS, AstraZeneca, and Nanobiotix, and grants and personal fees from BMS outside the submitted work. A. Lako reports other from Bristol Myers Squibb (Employment) outside the submitted work. S.J. Rodig reports grants from Bristol Myers Squibb (Research support unrelated to this project), Merck (Research support unrelated to this project), Affimed (Research support unrelated to this project), and gKITE/Gilead (Research support unrelated to this project) outside the submitted work; is on a scientific advisory board for Immunitas, and received limited stock in the company, and is on a scientific advisory board for Rarecyte which is unrelated to this project. I.S. Hagemann reports personal fees from Change Healthcare outside the submitted work. D. Kallogjeri is a statistics editor for JAMA Otolaryngology Head and neck surgery, owns stock and served as consultant for PotentiaMetrics. R.D. Chernock reports personal fees from Roche (Advisory Board Member) and Merck (Consultant) during the conduct of the study. O.L. Griffith reports grants from V Foundation, NIH, and Cancer Research Foundation during the conduct of the study. D.R. Adkins reports grants and personal fees from Merck (research funding and advisory board) during the conduct of the study; Pfizer (research funding and advisory board), Eli Lilly (research funding and advisory board), Celgene - now BMS (research funding and advisory board), Cue Biopharma (research funding and advisory board), personal fees from Loxo Oncology (advisory board), grants from Novartis (research funding), Roche (research funding), Aduro (research funding), Atara (research funding), Matrix (research funding), Blueprint Medicine (research funding), Celldex (research funding), Enzychem (research funding), Exilixis (research funding), Shanghai De Novo (research funding), Kura (research funding), Astrazeneca (research funding), Medimmune (research funding), and Innate (research funding) outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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 IFNg 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.
AB - 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 IFNg 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.
UR - http://www.scopus.com/inward/record.url?scp=85097627415&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-1695
DO - 10.1158/1078-0432.CCR-20-1695
M3 - Article
C2 - 32665297
AN - SCOPUS:85097627415
SN - 1078-0432
VL - 26
SP - 5140
EP - 5152
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -