2015;373(3):20919. Neoadjuvant Immunotherapy Leads to Pathological Responses in MMR-Proficient and MMR-Deficient Early-Stage Colon Cancers. Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr., Sun J, et al. PR reports personal fees (honoraria for lectures and Advisory Board Member) from Novartis, BMS, Roche, MSD, GSK, Pfizer, and Amgen outside the submitted work. Clin Cancer Res (2017) 23(12):315867. Park JW, Liu MC, Yee D, Yau C, van t Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA, I-SPY 2 Investigators. To determine the survival benefit of IC using docetaxel plus cisplatin and fluorouracil (TPF) regimen followed by CCRT, two-phase III randomized trials were completed: the PARADIGM trial reported in 2013 (19) and DeCIDE trial reported in 2014 (20). A Randomized Phase III Trial Comparing Induction Chemotherapy Followed by Chemoradiotherapy Versus Chemoradiotherapy Alone as Treatment of Unresectable Head and Neck Cancer. The establishment of the best pathological method to evaluate the response of neoadjuvant immunotherapy is still evolving as the ultimate clinical impact of histologic changes is understood. PubMed HNSCC shows a relatively high tumor-mutational burden (TMB) (16) and immune infiltration (17), consistent with a potential to achieve therapeutic efficacy from cancer immunotherapy. Oncoimmunology (2019) 8(5):e1581530. The landmark phase III CheckMate 141 trial resulted in the approval of nivolumab in the R/M second-line HNSCC setting (12). doi: 10.1200/JCO.2017.76.2591, 26. Treatment intensification with neoadjuvant (induction) chemotherapies with platinum drugs are insufficient to significantly prolong overall survival. CAS Immunotherapy in head and neck cancer: aiming at EXTREME precision. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Landmark Trials in Selected Head and Neck Cancers. Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson 3rd WE, Daniels GA, DiMaio D, Ernstoff M, Fields RC, Fleming MD, Gonzalez R, Guild V, Halpern AC, Hodi Jr FS, Joseph RW, Lange JR, Martini MC, Materin MA, Olszanski AJ, Ross MI, Salama AK, Skitzki J, Sosman J, Swetter SM, Tanabe KK, Torres-Roca JF, Trisal V, Urist MM, McMillian N, Melanoma EA. Intriguingly, in preclinical mouse models, a specific interval between neoadjuvant immunotherapy and subsequent surgery was important to establish potent systemic T cell response (33), suggesting that it will be important to establish the optimal duration in the clinical setting. 1991;324:168590. Considering the treatment nave situation and the absence of treatment-resistant cells compared with the R/M setting, neoadjuvant immunotherapy is hypothetically likely able to result in a strong and durable therapeutic effect. Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. KEYNOTE-689: Phase 3 Study of Adjuvant and Neoadjuvant Pembrolizumab Combined With Standard of Care (SOC) in Patients With Resectable, Locally Advanced Head and Neck Squamous Cell Carcinoma. The phase II Checkpoint Inhibitors Assessment in Oropharynx cancer (CIAO) trial (NCT03144778) tested a combination of durvalumab (1500 mg) and tremelimumab (75 mg) in the neoadjuvant setting, preceding SOC (surgery with or without radiation therapy) (70). doi: 10.1056/NEJMoa032646, 6. By using this website, you agree to our Hodi FS, Ballinger M, Lyons B, Soria JC, Nishino M, Tabernero J, et al. J Clin Oncol (2003) 21(2):32733. The CD8+ T cell data was correlated with preclinical models, where anti-PD-1 and anti-CTLA4 combinatorial therapy increased tumor-infiltrating CD8+ T cells (71). doi: 10.1158/1078-0432.CCR-20-1695, 55. Notably, other work has contradicted the above studies on TMB and concluded that that high TMB failed to predict the effect of ICI (53). Lawrence MS, Sougnez C, Lichtenstein L, Cibulskis K, Lander E, Gabriel SB, et al. doi: 10.1056/NEJMoa1716078, 37. Int J Radiat Oncol Biol Phys (1996) 36(5):9991004. doi: 10.1200/JCO.2003.06.146, 27. She is an Editorial Board Member for BMC Medicine. Redman JM, Gibney GT, Atkins MB. CrossRef Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Terms and Conditions, is discussed which was the first prospective randomized trial to study hypofractionation versus standard fractionation in early-stage larynx cancer. Science (2011) 333(6046):115760. These data suggest the reactivity of neoadjuvant immunotherapy is related to immunogenic phenotype before treatment and highlights the future possibility to select patients for neoadjuvant immunotherapy before surgery. Ann Oncol (2014) 25(2):4626. The published and ongoing trials described above focused on single agent checkpoint blockade immunotherapy prior to surgery. Piotr Rutkowski. Phase 2, Open-Label, Single Arm Study, With BST-236 in Adults With R/R AML or Higher-Risk MDS. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Immune checkpoint blockade therapies, especially anti-PD-1 and anti-CTLA4, were first approved in advanced melanoma patients (29) and then applied for various cancers (30), which has dramatically impacted the cancer treatment algorithm. Head Neck. Bayesian adaptive designs for biomarker trials with biomarker discovery. The RTOG 90-03 trial . Intriguing findings from this study reported discordant responses between primary tumor and regional metastatic lymph nodes (NCT03238365) (65). Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. BMC Med. With the advent of novel oral agents that are well tolerated and highly efficacious, the therapeutic landscape of CLL underwent radical changes [31]. doi: 10.1126/science.aax0182, 35. Cohen EEW, Soulires D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. Given that the genomic analyses of HNSCC has not identified widely shared oncogenic driver mutations but shows relatively high TMB (49, 50), the relationship between TMB and response to CPIs is promising. Palbociclib in hormone-receptor-positive advanced breast cancer. Rare Driver Mutations in Head and Neck Squamous Cell Carcinomas Converge on NOTCH Signaling. Median PFS was 9.5months in the fulvestrant plus palbociclib group and 4.6months in the fulvestrant plus placebo group with a hazard ratio of 0.46, which was highly statistically significant. J Clin Oncol. Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. J Clin Oncol (2015) 33(8):83645. https://doi.org/10.1007/978-3-030-14405-0_7, DOI: https://doi.org/10.1007/978-3-030-14405-0_7. HS: writing original draft, tables, and figure. As opposed to the CIAO and IMCISION trials where some patients enrolled were undergoing salvage surgery, a third trial recently presented at ASCO 2021 focused exclusively on challenging recurrent, surgically resectable HNSCC patients (NCT03341936) (73). 2017;35(2):16674. Subsequently the Keynote-048 study, a randomized multi-center phase III study from 37 countries, examined pembrolizumab alone or with chemotherapy (platinum plus fluorouracil) versus cetuximab with chemotherapy (the EXTREME regimen (32)) for first-line treatment of R/M HNSCC (14). How to accurately evaluate the effect of neoadjuvant immunotherapy is an evolving area. J Clin Oncol (2021) 39(15_suppl):60533. (NCT03021993), in which a total of 10 locally advanced OSCC patients were treated with neoadjuvant nivolumab (3 mg/kg on days 1, 14 and 28) (69). A total of 36 patients (T3/T4; 80%, stage IV; 92%) were enrolled and received one time dose of neoadjuvant pembrolizumab (200 mg) followed by surgery two or three weeks after the immunotherapy. Although these Level 1 data established a new postoperative standard of care to treat high-risk HNSCC patients, the five-year survival rate in for these patients remains suboptimal. doi: 10.1016/S1470-2045(13)70011-1, 20. He is also an active member of the EORTC Melanoma Group and the Global Melanoma Task Force. J Clin Oncol (2012) 30(15):1796804. Enhanced Pathologic Tumor Response With Two Cycles of Neoadjuvant Pembrolizumab in Surgically Resectable, Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma (HNSCC). J Clin Oncol. She has been an expert advisor for NHS NICE Health Technology Assessments. Feasibility and Toxicity of Neoadjuvant Nivolumab With or Without Ipilimumab Prior to Extensive (Salvage) Surgery in Patients With Advanced Head and Neck Cancer (the IMCISION Trial, NCT03003637). RU serves on an advisory board for Merck, Inc. Therapeutically, HPV-positive HNSCC demonstrates sensitivity to chemoradiotherapy, and offers a better prognosis (2). Ther Adv Med Oncol (2021) 13:1758835920984061. doi: 10.1177/1758835920984061, 40. Lancet. However, as immunotherapy has associated toxicities (see section on this below) and is expensive, careful patient selection to determine who may benefit from these approaches is critical. Pathologic responses were evaluated in 34 patients (17 HPV+ and 17 HPV-negative). Similarly, the Keynote-040 randomized phase III trial compared the efficacy of pembrolizumab (anti-PD-1) versus SOC (methotrexate, docetaxel, or cetuximab) (13) for R/M HNSCC patients after platinum-containing treatment. SM currently serves as referee for several haematology and oncology journals such as Journal Clinical Oncology, Blood, Haematologica, Leukemia Research, Leukemia, Leukemia & Lymphoma, European Journal Haematology, Cancer, British Journal of Haematology, and Lancet Haematology. doi: 10.1038/nature13988, 16. California Privacy Statement, 2016;14:20. Key pathological findings after neoadjuvant immunotherapy include 1) keratinous debris, 2) giant cells, histiocytic reaction and 3) tumor necrosis. Beitler J, et al. doi: 10.1200/JCO.2021.39.15_suppl.6008, 76. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course [37]. Haddad R, et al. In addition, CD8+ T cells with lymphocyte-activation gene 3 (LAG-3) or T cell immunoglobulin domain and mucin domain-3 (TIM-3) co-expression with PD-1 was higher among non-responders (52). 2023 BioMed Central Ltd unless otherwise stated. doi: 10.1200/JCO.2021.39.15_suppl.6053, 74. Menzies AM, Amaria RN, Rozeman EA, Huang AC, Tetzlaff MT, van de Wiel BA, et al. Cancer Discov (2016) 6(12):138299. Then, we focus on the rationale and clinical trials of neoadjuvant immunotherapy and its potential impact on HNSCC treatment. 2005;27:84350. PubMed Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, et al. doi: 10.1016/0360-3016(92)90642-U, 4. Hanna GJ, ONeill AM, Jo VY, Wong K, Lizotte PH, Annino DJ, et al. N Engl J Med. Ann Oncol (2018) 29(8):16302. Head Neck (2005) 27(10):84350. N Engl J Med. I. Nivolumab Plus Ipilimumab in Lung Cancer With a High Tumor Mutational Burden. There was an 86% MPR rate and a 67% pCR rate. Immune Biomarkers of Response to Immune-Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma. 2010;11:218. Neoadjuvant immunotherapy has the potential to enhance clinical outcomes by increasing anti-tumor immune responses in the presence of abundant tumor-derived antigen in an immune microenvironment that has not been exposed to previous therapy. The era of precision oncology is marked with prominent successes in the therapy of advanced soft tissue sarcomas, breast cancer, ovarian cancer and haematological neoplasms, among others. NIRT did impact healing of wounds that all ultimately resolved. JAMA Oncol (2020) 6(10):156370. These encouraging findings have led to numerous ongoing studies testing combinations to improve CPI response rates and also testing these agents in other settings. Preoperative Chemotherapy in Advanced Resectable OCSCC: Long-Term Results of a Randomized Phase III Trial. 2016;375(22):215464. Burtness B, Harrington KJ, Greil R, Soulires D, Tahara M, de Castro G Jr, et al. J Clin Oncol. These findings highlight the clinical importance to establish standard pathological criteria to accurately evaluate the therapeutic effect of neoadjuvant immunotherapy after definitive surgery. Clin Cancer Res (2020) 26(3):67989. Gillison ML, et al. A literature review using Medline, Scopus, Google Scholar, the Cochrane Database of Systematic Reviews and the Cochrane cen An important consideration in neoadjuvant immunotherapy approaches is clinical safety as the possibility of lifelong autoimmune complications in the definitive surgical setting needs to be weighed carefully. As mentioned above, to date neoadjuvant immunotherapy has been shown to be safe and has not resulted in surgical delays. The RTOG 90-03 trial compared four radiation therapy fractionation schemes for locoregionally advanced patients undergoing radiation therapy alone and is discussed.