Analysis of the data gathered from these large trials continues to contribute valuable understanding about related issues, including . Cancer Discov. Turner NC, Ro J, Andr F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M, PALOMA3 Study Group. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Rochester, Minn., Jacksonville, Fla. Readers are encouraged to refer to the full manuscript of these trials for a greater understanding. Nat Commun (2021) 12(1):3349. doi: 10.1038/s41467-021-23355-x, 56. Clin Cancer Res (2020) 26(3):67989. Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. BMC Med. Byrd JC, Brown JR, OBrien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P, RESONATE Investigators. 2011;1(1):4453. National Cancer Center Hospital East, Japan, University General Hospital Attikon, Greece. Abstract. The indications for IC are limited to those with significantly advanced disease and may result in a high frequency of severe adverse events. Updated results of a phase II neoadjuvant pembrolizumab trial prior to surgery followed by adjuvant concurrent pembrolizumab and radiation along with cisplatin for clinically high-risk (T3/4 stage and/or 2+ LNs) HPV-negative HNSCC patients (NCT02641093) were recently presented (74). Di Veroli et al. Lancet Oncol. Oncol. doi: 10.1073/pnas.0915174107, 72. BMC Cancer (2020) 20(1):229. doi: 10.1186/s12885-020-06726-3, 70. Combinations of chlorambucil with an anti-CD2O monoclonal antibody, such as rituximab, ofatumumab or obinutuzumab, are now the standard of care in patients unsuited to receive fludarabine, cyclophosphamide and rituximab [34,35,36]. This overview examines the treatment history of neoadjuvant approaches for HNSCC, and especially focuses on the recent topics of neoadjuvant immunotherapy for HNSCC. Nivolumab (3 mg/kg) was administered on weeks 1 and 3, while ipilimumab (1 mg/kg) was given on week 1 only. Bonner J, et al. 2016;387(10028):162937. Cancer (2021) 127(12):198492. A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course [37]. 2012;379:187986. Blood. To be eligible, patients had to have N2 or N3 adenopathy. Radiation Oncology Consultants (ROC), Chicago, IL, USA, You can also search for this author in The RTOG 90-03 trial . Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus-Related Oropharyngeal Carcinomas. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Pignon J-P, et al. First published on Mon 11 Oct 2021 07.19 EDT. Zuur CL, Elbers JBW, Vos JL, Avd L, Qiao X, Karakullukcu B, et al. HNSCC patients with high CD8+ T cells infiltration showed better anti-PD-1 response in the adjuvant setting (52, 54). Marur S, et al. Part of Springer Nature. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. 2005;27:84350. Atezolizumab versus docetaxel for patients with previously treated nonsmall-cell lung cancer (POPLAR): a multicentre, open label, phase 2 randomised controlled trial. Kiong KL, Yao C, Lin FY, Bell D, Ferrarotto R, Weber RS, et al. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. 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. Postoperative Irradiation With or Without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer. doi: 10.1016/0360-3016(92)90027-F, 19. PubMed Central HS received funding from the Uehara Foundation (201941070). 2023 BioMed Central Ltd unless otherwise stated. https://doi.org/10.1007/978-3-030-14405-0_7, DOI: https://doi.org/10.1007/978-3-030-14405-0_7. How to accurately evaluate the effect of neoadjuvant immunotherapy is an evolving area. She has been an expert advisor for NHS NICE Health Technology Assessments. HPV-Positive Status Associated With Inflamed Immune Microenvironment and Improved Response to Anti-PD-1 Therapy in Head and Neck Squamous Cell Carcinoma. J Clin Oncol (2021) 39(15_suppl):60088. The primary endpoint of this trial was comparison between arms of a change in the CD8+ tumor infiltrating lymphocyte (TIL) density. The effects of checkpoint inhibitors are mainly derived from reinvigoration and activation of tumor-oriented antigen-specific T cells (15). 2006;64(1):4756. Lancet. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. 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). Moreover, recent trials of immune checkpoint inhibitors in melanoma, non-small cell lung carcinoma, and head and neck cancers have significantly influenced the therapeutic landscape by providing promising evidence for immunotherapy efficacy in the adjuvant setting in high-risk locoregional disease. doi: 10.1158/1078-0432.CCR-19-3977, 71. Nature (2014) 515(7528):57781. However, PD-L1 negative tumors sometimes respond to CPI treatment, suggestingthe existence of other mechanisms. 2017;15(4):50435. 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. 2016;14(4):45073. Science (2018) 362(6411):110. Oncoimmunology (2019) 8(5):e1581530. doi: 10.1136/jitc-2021-002568corr1, 68. Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. The BATTLE-2 Study: a biomarker-integrated targeted therapy study in previously treated patients with advanced nonsmall-cell lung cancer. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebb C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. As trials mature, patient selection for neoadjuvant immunotherapy will need to be defined further. 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). statement and 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. Bertrand Baujat et al. Google Scholar. NIRT did impact healing of wounds that all ultimately resolved. Wise-Draper TM, Takiar V, Mierzwa ML, Casper K, Palackdharry S, Worden FP, et al. cancer [2], melanoma [3, 4], STS [5], head and neck cancer [6]). 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. Chen Q, Jain N, Ayer T, Wierda WG, Flowers CR, OBrien SM, Keating MJ, Kantarjian HM, Chhatwal J. Clinical Trial Endpoint Development for Locally Advanced Head and Neck IC resulted in larynx preservation but did not contribute to improved survival. 2006;64(1):7782. J Clin Oncol (2018) 36(9):8508. Our doctors are running clinical trials testing: new drug therapies for head and neck cancer, including immunotherapies and targeted therapies, that can boost the effectiveness of your care. 2014;14:31723. radiotherapy for early glottic carcinoma (T1N0M): results of prospective randomized study of radiation fraction size and overall treatment time. Remon J, Besse B, Soria JC. Pathologic responses were evaluated in 34 patients (17 HPV+ and 17 HPV-negative). Liu J, ODonnell JS, Yan J, Madore J, Allen S, Smyth MJ, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. 2017. doi:10.1186/s12916-017-0872-y. Goodman AM, Kato S, Bazhenova L, Patel SP, Frampton GM, Miller V, et al. 2016;128(24):27703. 2015;373(25):242537. Article J Natl Compr Canc Netw. University of Cambridge Department of Oncology, NIHR Cambridge Biomedical Research Centre, and Hon Consultant in Medical Oncology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK, Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, 88100, Catanzaro, Italy, Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute - Oncology Center, Roentgena 5, 02-781, Warsaw, Poland, You can also search for this author in Notably, the timing of immune checkpoint inhibitors may influence the outcome of cancer treatment (33). N Engl J Med (1991) 324(24):168590. Landmark Trials. Sholl LM. HPV infection results in production of virus-related proteins, which may induce de novo T cell response and more CD8+ T cell infiltration in tumor (43). 2004;350:246170. 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. N Engl J Med (2013) 369(2):13444. 2015;373:162739. It has become clear that neoadjuvant immunotherapy, especially checkpoint inhibitors, are safe and have shown signals of clinical efficacy in HNSCC. Both trials did not show a significant extension of OS and DFS, consistent with the subsequent studies (24, 25). N Engl J Med. Google Scholar. 2016;53:12534. Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer. Lancet Oncol (2014) 15(1):e4250. A more recent niraparib study had similar results [30], where patients in the niraparib group had a significantly longer PFS than the placebo group in all cohorts tested (21.0 vs. 5.5months in the gBRCA cohort; 12.9 vs. 3.8months in the non-gBRCA cohort for patients who had tumours with homologous recombination deficiency; and 9.3 vs. 3.9months in the overall non-gBRCA cohort; P<0.001). PDF Spotlight on landmark oncology trials: the latest evidence and novel Ann Oncol (2014) 25(2):4626. A literature review using Medline, Scopus, Google Scholar, the Cochrane Database of Systematic Reviews and the Cochrane cen J Clin Oncol (2021) 39(15_suppl):60066. 2016;34(30):363847. Cookies policy. The combinatorial therapy group did not significantly increase the CD8+ TILs. Copyright 2021 Shibata, Saito and Uppaluri. The landmark phase III trials in high-grade serous ovarian cancer are testing PARP inhibitors as maintenance therapy after response to platinum-based therapy in relapsed disease. doi: 10.1158/1078-0432.CCR-16-1761, 43. Hanna GJ, Lizotte P, Cavanaugh M, Kuo FC, Shivdasani P, Frieden A, et al. Article Recently we reported an extension of this study with an additional 29 HNSCC patients treated with two cycles of neoadjuvant pembrolizumab. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. 2014;32:273543. Xiong Y, Neskey DM, Horton JD, Paulos CM, Knochelmann HM, Armeson KE, et al. In the neoadjuvant setting, the NeoSphere trial demonstrated significantly improved pathological complete response rates [23] and a trend favouring improved PFS and OS at 5years [24]. This trial highlighted the effectiveness of combination immunotherapy and chemotherapy for subsets of HNSCC patients. 2016;387:154050. Oliva M, Spreafico A, Taberna M, Alemany L, Coburn B, Mesia R, et al. 2017. doi:10.1186/s12916-017-0879-4. J Clin Oncol. Platinum-Based Chemotherapy Plus Cetuximab in Head and Neck 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). Int J Radiat Oncol Biol Phys (1996) 36(5):9991004. strategies for preserving the quality of life during and after treatment. Patients received two cycles of drug therapy. doi: 10.1056/NEJMoa032646, 6. doi: 10.1038/nature14129, 11. Matlung SE, Wilhelmina van Kempen PM, Bovenschen N, van Baarle D, Willems SM. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Tumour Regression in Non-Small-Cell Lung Cancer Following Neoadjuvant Therapy. In this editorial, we discuss the special article collection entitled Spotlight on landmark oncology trials recently published in BMC Medicine, which focuses on the core clinical trials of selected solid tumours (lung cancer [2], melanoma [3, 4], STS [5], head and neck cancer [6]). Ann Oncol (2019) 30(1):4456. Histological Assessment. 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. J Clin Oncol (2015) 33(8):83645. Enhanced Pathologic Tumor Response With Two Cycles of Neoadjuvant Pembrolizumab in Surgically Resectable, Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma (HNSCC). Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomized trial, and relation between cetuximab-induced rash and survival. Recent landmark immunotherapy trials - melanoma, 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. Topalian SL, Taube JM, Pardoll DM. Future Sci OA (2016) 2(1):Fso88. This is a preview of subscription content, access via your institution. Key pathological findings after neoadjuvant immunotherapy include 1) keratinous debris, 2) giant cells, histiocytic reaction and 3) tumor necrosis. An important consideration in neoadjuvant immunotherapy approaches is appropriate patient selection. Another topic featured in this article collection is systemic therapy in STS [5], which is a heterogeneous group of rare solid tumours. Bossi P, Lo Vullo S, Guzzo M, Mariani L, Granata R, Orlandi E, et al. There were no treatment related delays thus achieving the primary safety endpoint. Google Scholar. Ther Adv Med Oncol (2021) 13:1758835920984061. doi: 10.1177/1758835920984061, 40. Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazz D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Finally, we recently reported a second cohort of our neoadjuvant pembrolizumab trial where instead of one dose, patients received two doses of drug similar to the neoadjuvant phase of the KEYNOTE-689 Phase II trial (75). Google Scholar. Table1 Completed neoadjuvant immunotherapy clinical trials. 2017;35(2):16674. N Engl J Med (2003) 349(22):20918. For larynx cancer, this approach was initially focused on reducing metastases, and preserving laryngeal function including speech and swallowing. N Engl J Med. 2012;13(1):2532. 2016;34(8):78693. The TAX 324 trial compared two different induction chemotherapy regimens in patients undergoing chemoradiotherapy, and the PARADIGM and DECIDE trials studied the role of induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone. 11:727433. doi: 10.3389/fonc.2021.727433. RU: editing and supervising the manuscript, tables and figure. Considering the high-frequency of severe adverse events and lack of significant effect OS prolongation with induction chemotherapy, neoadjuvant immunotherapy thus represents an attractive option for advanced HNSCC treatment. There are hundreds of trials to choose from, and therefore, no claim toward completeness can be made in the current format. BMC Med. They used pathological response (PR) criteria which was defined tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris (74). Lancet. Bernier J, et al. doi: 10.1200/JCO.2021.39.15_suppl.6053, 74. PubMed Central doi: 10.1158/1078-0432.CCR-20-1695, 55. CAS Ferris RL, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Timing of Neoadjuvant Immunotherapy in Relation to Surgery Is Crucial for Outcome. Recent landmark trials in HER2-positive breast cancer include those using dual HER2-targeted therapy pertuzumab and trastuzumab with docetaxel. 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 . Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Head And Neck Cancer - SlideShare Molica S. Targeted therapy in the treatment of chronic lymphocytic leukemia: facts, shortcomings and hopes for the future. Licitra L, Grandi C, Guzzo M, Mariani L, Lo Vullo S, Valvo F, et al. J Clin Oncol. She is co-lead for the Breast Cancer Programme at the Cancer Research UK Cambridge Cancer Centre and significantly contributes to the translational endeavour in precision medicine and the development of personalised treatment pathways in breast cancer. His current research is focused on investigating the impact of novel laboratory parameters for assessing prognosis of CLL. Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr., Sun J, et al. doi: 10.1200/JCO.2019.37.15_suppl.TPS6090, 77. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. These trials relate to the multidisciplinary management of head and neck cancer from the perspective of a radiation oncologist. 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).