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. doi: 10.1016/S1470-2045(13)70334-6, 64. A clinical trial studying the side effects of chemotherapy for patients with locally recurrent head and neck squamous cell carcinoma. 2018. For larynx cancer, this approach was initially focused on reducing metastases, and preserving laryngeal function including speech and swallowing. Spotlight on landmark oncology trials: the latest evidence and novel There were excellent clinical outcomes and only one patient required adjuvant chemoradiation. Intriguingly, TMB was significantly higher among HPV-/EBV- responders and correlated with OS, but not high in HPV+/EBV+ responders who didnt show any correlation between TMB and OS (52). J Clin Oncol. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. doi: 10.1093/annonc/mdy227, 58. Lancet. The VA Larynx study, RTOG 91-11, a study by Bonner et al. High Tumor Mutation Burden Fails to Predict Immune Checkpoint Blockade Response Across All Cancer Types. JAMA Oncol (2016) 2(1):4654. Neoadjuvant Checkpoint Blockade for Cancer Immunotherapy. doi: 10.1200/JCO.2021.39.15_suppl.6006, 75. Programmed Death-1/Programmed Death-Ligand 1-Axis Blockade in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Stratified by Human Papillomavirus Status: A Systematic Review and Meta-Analysis. Mehanna H, et al. A. Lancet Oncol. In: Landmark Trials in Oncology. N Engl J Med. Notably, the treatments were safe and 16/26 patients (61.5%) had pathologic responses (>20%) and 8/26 (31%) of patients experienced complete response (72). Article Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. The data and subsequent meta-analysis showed the superiority of CCRT to preserve the larynx in advanced laryngeal cancer patients (8, 23). 20 studies in Head and Neck Cancer Center (open studies only). McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. BMC Medicine Hitt R, Grau JJ, Lpez-Pousa A, Berrocal A, Garca-Girn C, Irigoyen A, et al. 2015;373(1):2334. doi: 10.1200/JCO.2011.38.8595, 60. In: Proceedings from the American Association for Cancer Research Annual Meeting, April 25, 2017, Washington DC. BMC Med. doi: 10.1056/NEJMoa1305133, 30. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. In addition, adaptive designs for phase I combinations are being developed [40]. This trial included both definitive and salvage surgery patients. These included oral mucositis and one patient with autoimmune diabetes (68) and there were no surgical delays. BMC Med. J Clin Oncol. 2016;387(10030):183746. Forastiere A, et al. A meta-analysis which examined the results of clinical trials including Checkmate 141, KEYNOTE-012, KEYNOTE-055 showed that HPV infection status was associated with the response rate to anti-PD-1 treatment independently of PD-L1 expression and TMB in HNSCC (45). doi: 10.1200/EDBK_280687, Keywords: head and neck squamous cell carcinoma, neoadjuvant immunotherapy, clinical trial, biomarker, pathological tumor response, Citation: Shibata H, Saito S and Uppaluri R (2021) Immunotherapy for Head and Neck Cancer: A Paradigm Shift From Induction Chemotherapy to Neoadjuvant Immunotherapy. A new cancer treatment can wipe out tumours in terminally ill head and neck cancer patients, scientists have discovered. Clin Cancer Res (2017) 23(12):315867. 1. Immunological Effects of Nivolumab Immunotherapy in Patients With Oral Cavity Squamous Cell Carcinoma. Clin Cancer Res (2020) 26(3):67989. N Engl J Med. Therefore, in absence of data from this and similar trials, either therapeutic choice is adequate in the day-to-day practice. Although a total of 21 patients experienced AEs, including grade 3/4 AEs in 2 (N) and 5 (N+I) patients, there were no surgical delays. 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. The team lead by Professor Jean-Charles Soria discussed the successes and failures of immunotherapy in the first-line treatment of NSCLC [2]. Our own group is developing a novel Bayesian, adaptive randomised methodology [47]. N Engl J Med. Frontiers | Immunotherapy for Head and Neck Cancer: A Paradigm Shift Landmark Trials in Selected Head and Neck Cancers evaluated the role of measuring plasma EBV DNA and is included. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. It has become clear that neoadjuvant immunotherapy, especially checkpoint inhibitors, are safe and have shown signals of clinical efficacy in HNSCC. The first articles in the special article collection focus on landmark clinical trials in selected advanced solid tumours, with special attention on the most studied tumours with regards to immunotherapy development, namely melanoma [3, 4], NSCLC [], and head and neck cancer [].Recent developments and approvals in immunotherapy have significantly changed the landscape of melanoma and NSCLC . In a landmark trial, a cocktail of immunotherapy medications harnessed patients' immune systems to kill their own cancer cells and prompted "a positive trend in survival . 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). These results underscore that TPF IC is not recommended for survival benefit. In a spontaneous mouse metastatic breast cancer model, neoadjuvant checkpoint inhibitors showed an enhanced survival compared to the adjuvant setting by suppressing metastatic lesions (37). Lancet Oncol. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. We also highlight selected and recent practice-changing trials in chronic lymphocytic leu-kaemia as well as breast and gynaecological cancers, and review the advances offered by the development of novel clinical trial designs. In conclusion, the RESONATE-2 trial demonstrates that ibrutinib is a new important player in the treatment of elderly unfit patients and in those with high-risk disease. Int J Radiat Oncol Biol Phys. Another topic featured in this article collection is systemic therapy in STS [5], which is a heterogeneous group of rare solid tumours. Cottrell TR, Thompson ED, Forde PM, Stein JE, Duffield AS, Anagnostou V, et al. doi: 10.1016/S1470-2045(10)70017-6, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. 2016;34(Suppl; abstr 9504). Gillison ML, et al. 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. Blood. B Cell Signatures and Tertiary Lymphoid Structures Contribute to Outcome in Head and Neck Squamous Cell Carcinoma. HE has provided clinical advice at Advisory Board meetings for Roche, Pfizer and Astra Zeneca. Filter this list of studies by location, status and more. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott CL, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Dougherty B, Orr M, Hodgson D, Barrett JC, Matulonis U. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Importantly, phase III clinical trials which examined the clinical efficacy of IC treatment prior to surgery also failed to show suppression of loco-regional relapse and distant metastasis or extend OS (2628). The significant impact of checkpoint inhibitor therapy for R/M HNSCC has proven the existence of anti-cancer immunity in HNSCC (1214). Wang J, Sun H, Zeng Q, Guo XJ, Wang H, Liu HH, et al. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P, EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. Histological Assessment. Additionally, R/M HNSCC patients treated with pembrolizumab plus chemotherapy had significantly prolonged OS compared to the cetuximab with chemotherapy group. 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. 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. In Checkmate-141 phase III trial, there wasno correlation of survival extension and PD-L1 expression on tumors (PD-L1+ >1%, 5% and 10%) (12). 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. 2015;373(25):242537. However, although IC may help with surgical management, Phase III trial results showed no improvements in survival. Adjuvant Chemotherapy for Resectable Squamous Cell Carcinomas of the Head and Neck: Report on Intergroup Study 0034. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Signatures of Mutational Processes in Human Cancer. 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. J Clin Oncol. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. 2011;12(2):1539. Using a primary radiation based approach, several ongoing clinical trials aim to de-intensify the treatment impact by adding immunotherapy (77). Tumors with both PD-L1 and PD-L2 expression responded better than tumors with only PD-L1 expression, indicating that combinatorial scoring may be an attractive approach. IC resulted in larynx preservation but did not contribute to improved survival. 2014;370(12):110110. There are several questions about how this approach would integrate with current SOC including whether this treatment intensification is necessary especially in good prognosis HPV+ disease and the role of nivolumab as SBRT alone conferred a high rate of pathologic responses. 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. Combenefit: an interactive platform for the analysis and visualization of drug combinations. Molica S. Targeted therapy in the treatment of chronic lymphocytic leukemia: facts, shortcomings and hopes for the future. In another phase II neoadjuvant pembrolizumab clinical trial, we reported no severe grade 3/4 AEs and no surgical delays in a total of 36 treated HNSCC patients (54). Ann Oncol (2021) 32(5):66172. 2006;64(1):4756. Pathologic treatment effect (PTE) is another similar scale, which is evaluated by the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area (65). Herbst RS, Baas P, Kim DW, Felip E, Prez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro Jr G, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Head Neck. [39] published an interesting software to provide information in terms of synergy and/or antagonism between two compounds. Ferris RL, Spanos WC, Leidner R, Gonalves A, Martens UM, Kyi C, et al. 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. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Twenty-nine HNSCC patients with locoregionally recurrent disease who were surgically resectable were treated with neoadjuvant nivolumab and lirilumab, an anti-KIR blocking antibody focused on NK cell checkpoint inhibition. doi: 10.1136/jitc-2021-002568corr1, 68. 2011;1(1):4453. Although neither baseline CD8+ T cell infiltration status nor PD-L1 expression level correlated with overall response, there was a trend in which greater CD8+ T cells infiltrated patients tended to show MPR. No new safety signals were observed and there were no surgical delays. Eur J Cancer. doi: 10.1001/jamaoncol.2015.3638, 42. doi: 10.1200/JCO.2013.54.6309, 21. N Engl J Med. The Landmark Series - Society of Surgical Oncology The head and neck region is anatomically complex and serves essential functions such as eating, speaking, and breathing. HS: writing original draft, tables, and figure. New Treatment for Head/Neck Tumours | Tissuepathology.com 2014;371(3):21323. PubMedGoogle Scholar. doi: 10.1158/1078-0432.CCR-20-1695, 55. Loganathan SK, Schleicher K, Malik A, Quevedo R, Langille E, Teng K, et al. A pooled analysis of data from these two postoperative trials is included, which was designed to analyze the selection criteria, clinical and pathologic risk factors, and outcomes and to establish precisely which patients benefit from the addition of cisplatin to postoperative radiation therapy. They used pathological response (PR) criteria which was defined tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris (74). Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non-Small-Cell Lung Cancer. 2013;10(5):27788. Clin Pharmacol Ther. The Neoadjuvant Immuno-RadioTherapy (NIRT) phase Ib trial tested neoadjuvant stereotactic body radiation therapy (SBRT) with nivolumab (240 mg, q2 weeks x 3) prior to surgery in HNSCC patients (NCT03247712) (66). 2016;388(10043):48897. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A, POPLAR Study Group. JAMA Oncol (2020) 6(10):156370. She has been an expert advisor for NHS NICE Health Technology Assessments. We and others have focused on the definitive surgical setting with integration of neoadjuvant immunotherapy and in this review focus on historical and current approaches. N Engl J Med (2020) 383(13):121830. He works very closely with national patient advocacy groups for GIST and sarcoma and is Chairman of the Melanoma Academy in Poland. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. Lancet. doi: 10.1126/science.aar3593, 52. 2012;13(1):2532. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Given that CPIs are still expensive drugs and sometimes induce severe immune-related toxicities, it is important to establish the appropriate markers which can predict efficacy of CPIs (39, 40). Bertrand Baujat et al. He is the current Head of the Department of Soft Tissue/Bone Sarcoma and Melanoma, the Plenipotentiary Director of Institute for Clinical Trials at the Maria Sklodowska-Curie Memorial Cancer Center as well as the President of the Scientific Council of Maria Sklodowska-Curie Memorial Cancer Center. Overall, only 15-20% of patients ultimately benefit from anti-PD-1 in these studies highlighting the need for improving efficacy of CPIs for HNSCC treatment. chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. 2009;92:414. doi: 10.1093/annonc/mdt555, 29. 2016;375(19):184555. National Cancer Center Hospital East, Japan, University General Hospital Attikon, Greece. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. 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. Association of Pathological Response to Neoadjuvant Pembrolizumab With Tumor PD-L1 Expression and High Disease-Free Survival (DFS) in Patients With Resectable, Local-Regionally Advanced, Head and Neck Squamous Cell Carcinoma (HNSCC). N Engl J Med (1991) 324(24):168590. The primary endpoint of this trial was comparison between arms of a change in the CD8+ tumor infiltrating lymphocyte (TIL) density. Pathologic complete response means the ablation of all cancer cells in resected tumor after the treatment. In conclusion, neoadjuvant approaches provide a potential exciting new treatment paradigm for HNSCC patients.
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