PMID- 34083421 OWN - NLM STAT- MEDLINE DCOM- 20211220 LR - 20220716 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 6 DP - 2021 Jun TI - Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial. LID - 10.1136/jitc-2021-002568 [doi] LID - e002568 AB - BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting. METHODS: The phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria. RESULTS: From November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III-IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3-4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR. CONCLUSIONS: Neoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759. CI - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Ferris, Robert L AU - Ferris RL AUID- ORCID: 0000-0001-6605-2071 AD - UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA ferrisrl@upmc.edu. FAU - Spanos, William C AU - Spanos WC AD - Sanford Cancer Center, Sanford Health, Sioux Falls, South Dakota, USA. FAU - Leidner, Rom AU - Leidner R AUID- ORCID: 0000-0003-0788-7938 AD - Providence Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. FAU - Goncalves, Anthony AU - Goncalves A AD - Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France. FAU - Martens, Uwe M AU - Martens UM AD - SLK-Clinics, MOLIT Institute, Heilbronn, Germany. FAU - Kyi, Chrisann AU - Kyi C AD - Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Sharfman, William AU - Sharfman W AD - Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA. FAU - Chung, Christine H AU - Chung CH AD - Department of Head and Neck-Endocrine Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. FAU - Devriese, Lot A AU - Devriese LA AD - Department of Medical Oncology, University Medical Center Utrecht, Cancer Center, Utrecht, The Netherlands. FAU - Gauthier, Helene AU - Gauthier H AD - Department of Medical Oncology, Universite de Paris, Saint Louis Hospital, Paris, France. FAU - Chiosea, Simon I AU - Chiosea SI AD - UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA. FAU - Vujanovic, Lazar AU - Vujanovic L AD - UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA. FAU - Taube, Janis M AU - Taube JM AD - Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA. FAU - Stein, Julie E AU - Stein JE AD - Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA. FAU - Li, Jun AU - Li J AD - Bristol Myers Squibb, Princeton, New Jersey, USA. FAU - Li, Bin AU - Li B AD - Bristol Myers Squibb, Princeton, New Jersey, USA. FAU - Chen, Tian AU - Chen T AD - Bristol Myers Squibb, Princeton, New Jersey, USA. FAU - Barrows, Adam AU - Barrows A AD - Bristol Myers Squibb, Princeton, New Jersey, USA. FAU - Topalian, Suzanne L AU - Topalian SL AD - Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA. LA - eng SI - ClinicalTrials.gov/NCT02488759 GR - R01 CA206517/CA/NCI NIH HHS/United States GR - T32 CA193145/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - R01 DE029524/DE/NIDCR NIH HHS/United States GR - P50 CA097190/CA/NCI NIH HHS/United States GR - R01 DE026125/DE/NIDCR NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Immune Checkpoint Inhibitors) RN - 31YO63LBSN (Nivolumab) SB - IM EIN - J Immunother Cancer. 2021 Aug;9(8):. PMID: 34376555 MH - Administration, Intravenous MH - Adult MH - Aged MH - Aged, 80 and over MH - Female MH - Head and Neck Neoplasms/*drug therapy/virology MH - Humans MH - Immune Checkpoint Inhibitors/*administration & dosage/adverse effects MH - Male MH - Middle Aged MH - Neoadjuvant Therapy MH - Nivolumab/*administration & dosage/adverse effects MH - Papillomavirus Infections/complications/*drug therapy MH - Squamous Cell Carcinoma of Head and Neck/*drug therapy/virology MH - Treatment Outcome MH - Whole Genome Sequencing PMC - PMC8183204 OTO - NOTNLM OT - clinical trials as topic OT - head and neck neoplasms OT - immunotherapy COIS- Competing interests: RLF reports consulting or advisory from Bristol Myers Squibb (BMS), MedImmune, Merck, Lilly, Pfizer, Amgen, EMD Serono, PPD, Bain Capital Life Sciences, GlaxoSmithKline, Iovance Biotherapeutics, Numab Therapeutics AG, Oncorus, Ono Pharmaceutical, Regeneron, Novasenta, Aduro Biotech, MacroGenics, Nanobiotix, Torque Therapeutics, Lifescience Dynamics, Sanofi, and Zymeworks, Inc; and research funding from BMS, MedImmune, Merck, Tesaro, Novasenta, VentiRx, and AstraZeneca/MedImmune. WCS reports consulting from BMS and Regeneron. RL reports personal and institutional research funding from BMS. AG has nothing to disclose. UMM reports consulting and advisory from MSD Oncology, Roche, BMS, and Celgene; and travel accommodations from BMS, Celgene, Amgen, and Pierre Fabre. CK has nothing to disclose. WS reports honoraria from BMS and Array BioPharma; consulting or advisory from BMS, Novartis, Regeneron, ION Pharma, and Merck; research funding from Novartis, Merck, and Genentech; and institutional research funding from BMS. CHC reports consulting or advisory fees from BMS, CUE Biopharma, Ignyta, Mirati Therapeutics, and Sanofi; research funding from BMS, Ignyta, Lilly, Regeneron, IRX Therapeutics, and Lion Biotechnologies; and travel accommodation expenses from Mirati Therapeutics. LAD reports institutional expert input forum payments from MSD BV Netherlands; and institutional speaker fee payment from BMS. HG has nothing to disclose. SIC has nothing to disclose. LV has nothing to disclose. JMT reports consulting and advisory from BMS, MedImmune, Merck, Compugen, and Akoya Biosciences, and stock options from Akoya Biosciences. JES has nothing to disclose. JL reports employment and stock ownership from BMS. BL reports employment and stock ownership from BMS. TC reports employment and stock ownership from BMS. AB reports employment and stock ownership from BMS. SLT reports consulting or advisory from Five Prime Therapeutics, Immunocore, and Merck; travel accommodations from Five Prime Therapeutics, Merck, and BMS; research funding from BMS; stock ownership by her spouse in Tizona Therapeutics, DNAtrix, RAPT, WindMIL, Dragonfly Therapeutics, Ervaxx, Trieza Therapeutics, and Dracen Pharmaceuticals; consulting or advisory by her spouse in DNAtrix, RAPT, WindMIL, Dragonfly Therapeutics, Ervaxx, Amgen, AstraZeneca, Immunomic Therapeutics, Janssen Oncology, and Dynavax Technologies; royalties by her spouse in WindMIL, Immunomic Therapeutics, Arbor Pharmaceuticals, BMS, and NexImmune; and research funding by her spouse from Compugen. EDAT- 2021/06/05 06:00 MHDA- 2021/12/21 06:00 PMCR- 2021/06/02 CRDT- 2021/06/04 06:07 PHST- 2021/03/27 00:00 [accepted] PHST- 2021/06/04 06:07 [entrez] PHST- 2021/06/05 06:00 [pubmed] PHST- 2021/12/21 06:00 [medline] PHST- 2021/06/02 00:00 [pmc-release] AID - jitc-2021-002568 [pii] AID - 10.1136/jitc-2021-002568 [doi] PST - ppublish SO - J Immunother Cancer. 2021 Jun;9(6):e002568. doi: 10.1136/jitc-2021-002568.