The checkmate 141 phase III trial evaluated the effect of anti-PD-1 (nivolumab) for R/M HNSCC patients (12). safer and more-effective approaches to head and neck radiation therapy. Gutirrez Caldern V, Cantero Gonzlez A, Glvez Carvajal L, Aguilar Lizarralde Y, Rueda Domnguez A. Neoadjuvant Immunotherapy in Resectable Head and Neck Cancer: Oral Cavity Carcinoma as a Potential Research Model. 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. This chapter contains a summary of some key findings from a selection of 18 trials related to oral cavity, nasopharynx, oropharynx, larynx, and hypopharynx cancer. Lancet Oncol. In addition to radiation and immunotherapy combinations, other trials are testing chemotherapy/immunotherapy combinations. Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F, COMPLEMENT 1 Study Investigators. Finally, biomarker and minimal residual disease assessment may ultimately be useful to guide the targeted agent or regimen of choice and the duration of treatment [38]. The goals of induction chemotherapy are to achieve rapid tumor responses in particular with large volume disease and to chemo-select patients prior for definitive (chemo)radiotherapy or surgery. Lancet. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. Completed and ongoing trials have focused on a diverse group of HNSCC patients including early and advanced stage and HPV-positive and negative patients. Ann Oncol (2021) 32(5):66172. However, IC remains an attractive approach for specific cases of advanced disease with a high risk for local or distant failure or to debulk rapidly growing tumors (19). These trials led to US Food and Drug Administration (FDA) approval of the use of anti-PD-1 (nivolumab and pembrolizumab) for second-line for recurrent and metastatic HNSCC patients who had already experienced platinum-based therapies (31). Google Scholar. defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). 2009;92:414. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. J Clin Oncol. A summary of recent pivotal trials for systemic therapy in advanced STS is presented in Table2 [19,20,21,22]. Pathological Complete Response and Long-Term Clinical Benefit in Breast Cancer: The CTNeoBC Pooled Analysis. doi: 10.1126/science.aax0902, 10. Molica S. Targeted therapy in the treatment of chronic lymphocytic leukemia: facts, shortcomings and hopes for the future. Wason JMS, Abraham JE, Baird RD, Gounaris I, Vallier A-V, Brenton JD, Earl HM, Mander AP. Bertrand Baujat et al. Figure1 Representative figure of pathological tumor response (pTR). Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, Oscier DG, Dearden CE, Kennedy DB, Pettitt AR, Nathwani A, Varghese A, Cohen D, Rawstron A, Oertel S, Pocock CF. A clinical trial studying the side effects of chemotherapy for patients with locally recurrent head and neck squamous cell carcinoma. PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. In fact, meta-analysis of melanoma neoadjuvant immunotherapy trials has shown that any degree of pathologic response and not just MPR/pCR, was correlated with better clinical outcomes (64). Below are current clinical trials. Adjuvant Chemotherapy for Resectable Squamous Cell Carcinomas of the Head and Neck: Report on Intergroup Study 0034. 2014;89(1):1320. Mehanna H, et al. Immune Biomarkers of Response to Immune-Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma. N Engl J Med. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, DAmico TA, DeCamp MM, Dilling TJ, Dobelbower M, Doebele RC, Govindan R, Gubens MA, Hennon M, Horn L, Komaki R, Lackner RP, Lanuti M, Leal TA, Leisch LJ, Lilenbaum R, Lin J, Loo Jr BW, Martins R, Otterson GA, Reckamp K, Riely GJ, Schild SE, Shapiro TA, Stevenson J, Swanson SJ, Tauer K, Yang SC, Gregory K, Hughes M. Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. 2023 Springer Nature Switzerland AG. In fact, a study evaluating 20 resected non-small cell lung cancer (NSCLC) tumors after neoadjuvant anti-PD-1 treatment showed a discrepancy between radiological and pathological evaluation (58). We and others have focused on HPV-negative, locally advanced disease patients with high-risk pathologic features (positive surgical margins or extra-nodal extension). These data highlight the difficulty of interpreting peripheral lymphocyte populations with clinical responses in HNSCC patients treated with neoadjuvant immunotherapy. He is also Coordinator of the Polish Clinical GIST Registry, and a reviewer for several international scientific journals, as well as a member of the Editorial Board of Annals of Surgical Oncology, BMC Medicine and European Journal of Surgical Oncology. Frameshift Events Predict Anti-PD-1/L1 Response in Head and Neck Cancer. Compared to our initial cohort with one dose, we found that 50% of patients had any pTR and 44% of patients exhibited pTR2. Oncol. J Radiat Oncol Biol Phys. doi: 10.1200/JCO.2017.75.1644, 57. Hanna GJ, Lizotte P, Cavanaugh M, Kuo FC, Shivdasani P, Frieden A, et al. Bernier J, et al. In neoadjuvant breast cancer, the I-SPY 1 and 2 trials have successfully matched treatment and biomarkers, using adaptive randomised designs [43, 44]. Novel trial designs could potentially lead to a different type of landmark trial that would accelerate the process and allow cancer patients to access new treatments faster. doi: 10.1016/j.radonc.2009.04.014, 9. Induction Chemotherapy Plus Radiation Compared With Surgery Plus Radiation in Patients With Advanced Laryngeal Cancer. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus-Related Oropharyngeal Carcinomas. doi: 10.1200/JCO.2021.39.15_suppl.6006, 75. 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). Notably, patients with PR (partial plus major) showed significantly improved 1-year DFS compared to patients with no PR (100% versus 68%, p = 0.01; HR = 0.23). The RTOG 90-03 trial . Haddad R, ONeill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. No new safety signals were observed and there were no surgical delays. 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. 1991;324:168590. These trials represent the end of the long process of translating scientific innovation and drug discovery, through first-in-man studies, followed by phase II trials and finally by randomised phase III trials as required for licensing of new treatments. For example, a phase II/III trial in patients with early-stage HPV-positive HNSCC is testing whether RT plus chemotherapy (cisplatin) or immunotherapy (nivolumab or durvalumab) can be used for de-intensification (NCT03952585, NCT03410615). Google Scholar. doi: 10.1056/NEJMoa1801946, 48. PubMed Central Three HPV-positive tumors and one HPV-negative tumor had partial pathologic responses. quantification of plasma epstein-barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med (2004) 350(19):193744. J Clin Oncol. Based on this study and depending on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) either pembrolizumab alone or with chemotherapy represents the first choice for these patients (14). Saad ED, Paoletti X, Burzykowski T, Buyse M. Precision medicine needs randomized clinical trials. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. J Clin Oncol (2019) 37(15_suppl):25755. 2017;15:55. Expert Rev Hematol. A trial done by Tata Memorial Centre is included that randomized patients with mostly oral tongue carcinoma to elective neck dissection at the time of primary cancer surgery or watchful waiting with therapeutic neck dissection for nodal relapse. evaluated the role of measuring plasma EBV DNA and is included. Defining Risk Levels in Locally Advanced Head and Neck Cancers: AComparative Analysis of Concurrent Postoperative Radiation Plus Chemotherapy Trials of the EORTC (#22931) and RTOG (# 9501). doi: 10.1016/j.annonc.2021.02.006, 54. Then, we focus on the rationale and clinical trials of neoadjuvant immunotherapy and its potential impact on HNSCC treatment. 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). Landmark results include those in triple negative breast cancer for the combination of velaparib and carboplatin [44] and neratinib in HER2-positive breast cancer [45]. Article They used pathological response (PR) criteria which was defined tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris (74). Further clinical trials are under way to determine how best to integrate combination immunotherapy and other treatment modalities as well as to establish the correct sequence of therapy with targeted treatment in BRAF-mutated cases. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. There were no treatment related delays thus achieving the primary safety endpoint. Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck. In this trial, only one patient showed a grade III AE (rash) while no patients had grade IV AE, consistent with the safety and tolerability of neoadjuvant immunotherapy (75). N Engl J Med. 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. Of eighty evaluated patients, 32 patients (40%) showed a PR [26 partial PR ( 20% and <90%) and 6 with major PR (>90%)]. She is an Editorial Board Member for BMC Medicine. 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.