Induction Chemotherapy Followed by Concurrent Chemoradiotherapy (Sequential Chemoradiotherapy) Versus Concurrent Chemoradiotherapy Alone in Locally Advanced Head and Neck Cancer (PARADIGM): A Randomised Phase 3 Trial. Therapeutically, HPV-positive HNSCC demonstrates sensitivity to chemoradiotherapy, and offers a better prognosis (2). 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. The goal of cytotoxic chemotherapy in this setting is to directly attack tumor cells to reduce tumor burden. doi: 10.1093/annonc/mdt555, 29. A Study to Evaluate Fractionated Radiation Therapy Utilizing GRID Therapy for Locally-advanced Bulky Tumors. Radiother Oncol. Hodi FS, Ballinger M, Lyons B, Soria JC, Nishino M, Tabernero J, et al. doi: 10.1038/nature13988, 16. doi: 10.1016/S0140-6736(18)31999-8, 14. Proc Natl Acad Sci USA (2010) 107(9):427580. A summary of recent pivotal trials for systemic therapy in advanced STS is presented in Table2 [19,20,21,22]. N Engl J Med. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. doi: 10.1200/JCO.2017.76.2591, 26. examined neoadjuvant 1) nivolumab (N) or 2) nivolumab plus ipilimumab (N+I) in untreated 29 oral cavity cancer patients in a phase II trial (eligible for T2 or node positive) (NCT02919683) (68). Xu Y, Zhu G, Maroun CA, Wu IXY, Huang D, Seiwert TY, et al. N Engl J Med (2003) 349(22):20918. quantification of plasma epstein-barr virus DNA in patients with advanced nasopharyngeal carcinoma. Front. 2017;15:55. In this article series, worldwide renowned experts in their fields provided an extensive overview on the state of the art in immunotherapy and discussed the possible future paths in these, still difficult, types of malignancies. Cite this article. 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. Hanna GJ, Lizotte P, Cavanaugh M, Kuo FC, Shivdasani P, Frieden A, et al. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebb C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. N Engl J Med. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. N Engl J Med. Lancet. N Engl J Med. Management of toxicities in this setting remains a challenge. Completed and ongoing trials have focused on a diverse group of HNSCC patients including early and advanced stage and HPV-positive and negative patients. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. Kaplan R, Maughan T, Crook A, Fisher D, Wilson R, Brown L, Parmar M. Evaluating many treatments and biomarkers in oncology: a new design. Part of Mol Cancer Ther (2017) 16(11):2598608. Lancet Oncol. 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). I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Liu J, ODonnell JS, Yan J, Madore J, Allen S, Smyth MJ, et al. Spotlight on landmark oncology trials: the latest evidence and novel trial designs, https://doi.org/10.1186/s12916-017-0884-7, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/. 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]). A literature review using Medline, Scopus, Google Scholar, the Cochrane Database of Systematic Reviews and the Cochrane cen N Engl J Med (2020) 383(13):121830. Clin Cancer Res (2020) 26(13):32119. Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck. In addition, in the KEYNOTE-040 phase III study, the correlation of clinical outcome and PD-L1 expression on tumor (PD-L1 tumor proportion score 50%) was evident (13). doi: 10.1002/cncr.33471, 22. How to accurately evaluate the effect of neoadjuvant immunotherapy is an evolving area. Price KAR, Nichols AC, Shen CJ, Rammal A, Lang P, Palma DA, et al. Laramore GE, Scott CB, al-Sarraf M, Haselow RE, Ervin TJ, Wheeler R, et al. doi: 10.1200/JCO.2019.37.15_suppl.TPS6090, 77. 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. Lancet Oncol (2013) 14(3):25764. They used pathological response (PR) criteria which was defined tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris (74). A total of 28 patients were eligible, and 24 (86%) of patients were HPV positive. Pathologic complete response means the ablation of all cancer cells in resected tumor after the treatment. The indications for IC are limited to those with significantly advanced disease and may result in a high frequency of severe adverse events. Neoadjuvant Immunoradiotherapy Results in High Rate of Complete Pathological Response and Clinical to Pathological Downstaging in Locally Advanced Head and Neck Squamous Cell Carcinoma. doi: 10.1126/science.aar3593, 52. Google Scholar. Mehanna H, et al. CAS doi: 10.1200/JCO.2016.70.1524, 45. Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non-Small-Cell Lung Cancer. JCI Insight (2018) 3(4):113. The pTR scores were evaluated by two independent pathologists and graded using the following scale: pTR-0 < 10%, pTR-1; 10-49%, pTR-2 50%. Finally, considering the ease of biopsies in the head and neck region, compared to adjuvant immunotherapy, neoadjuvant immunotherapy has the benefit to enable translational efforts such as TCR analysis, gene-expression profiling, and cytokine evaluation in the primary tumor which is not affected by other treatments including chemotherapeutics or radiation. In Cambridge, she is the cancer lead in the collaborative work stream for novel adaptive trial designs. Positive results from this study established the application of anti-PD-1 for R/M HNSCC treatment, and proved the existence of actionable, efficient anti-cancer immunity in HNSCC tumors. Bossi P, Lo Vullo S, Guzzo M, Mariani L, Granata R, Orlandi E, et al. 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 . HNCA recommends researching head and neck cancer clinical trials either by going to www.ClinicalTrials.gov a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world - or using our Clinical Trial Finder which is designed to be user-friendly for patients. doi: 10.1200/JCO.2019.37.15_suppl.2575, 73. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. Figure1 Representative figure of pathological tumor response (pTR). Postoperative Irradiation With or Without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer. doi: 10.1172/jci.insight.98811, 53. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A. KEYNOTE-006 investigators. Int J Radiat Oncol Biol Phys. By using this website, you agree to our Cohen EE, Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, et al. CAS Al-Saraff M, et al. 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. Harrington JA, Wheeler GM, Sweeting MJ, Mander AP, Jodrell DI. He works very closely with national patient advocacy groups for GIST and sarcoma and is Chairman of the Melanoma Academy in Poland. doi: 10.1038/nature14129, 11. The FOCUS 4 trial in metastatic colorectal cancer uses group-sequential multi-arm, multi-stage methodology [46] to achieve similar matching of novel therapy and biomarker groups. These findings highlight the clinical importance to establish standard pathological criteria to accurately evaluate the therapeutic effect of neoadjuvant immunotherapy after definitive surgery. doi: 10.1200/JCO.2021.39.15_suppl.6008, 76. Recently we reported an extension of this study with an additional 29 HNSCC patients treated with two cycles of neoadjuvant pembrolizumab. 2015;372(8):72434. Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, ODwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ, RESONATE-2 Investigators. The Annals of Surgical Oncology (ASO) is pleased to announce, The Landmark Series. J Natl Compr Canc Netw. In this review, we present a brief overview of the history of neoadjuvant (induction) chemotherapy in the definitive surgical management of HNSCC. 2016;375(1):1122. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. This was followed by BATTLE-2 [42], testing combination treatments in the same disease. Haddad R, ONeill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. The current mainstay of advanced head and neck squamous cell carcinoma (HNSCC) treatment remains surgery and radiotherapy with/without conventional chemotherapy. RU is funded by NIH/NIDCR R01DE024403, R01DE027736, and NIH/NCI/NIDCR U01DE029188. doi: 10.1158/1078-0432.CCR-16-1761, 43. 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. This trial aims to enroll 600 patients. N Engl J Med. J Radiat Oncol Biol Phys. Science (2020) 367(6483):12649. N Engl J Med. doi: 10.1016/S1470-2045(13)70011-1, 20. There were no treatment related delays thus achieving the primary safety endpoint. https://doi.org/10.1007/978-3-030-14405-0_7, Tax calculation will be finalised during checkout. However, while pCR and MPR are considered the gold standard, they do not take into account lesser degrees of immunological reaction in the tumor that may still impact clinical outcomes. The expression level of PD-L1 in the tumor does not necessarily correlate withthe response to CPIs. doi: 10.1136/jitc-2021-002568corr1, 68. In: Proceedings from the American Association for Cancer Research Annual Meeting, April 25, 2017, Washington DC. Pembrolizumab Versus Methotrexate, Docetaxel, or Cetuximab for Recurrent or Metastatic Head-and-Neck Squamous Cell Carcinoma (KEYNOTE-040): A Randomised, Open-Label, Phase 3 Study. 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). 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. Weissferdt A, Pataer A, Vaporciyan AA, Correa AM, Sepesi B, Moran CA, et al. Oliva M, Spreafico A, Taberna M, Alemany L, Coburn B, Mesia R, et al. N Engl J Med. HPV-Positive Status Associated With Inflamed Immune Microenvironment and Improved Response to Anti-PD-1 Therapy in Head and Neck Squamous Cell Carcinoma. 2016;387(10030):183746. In this trial, primary endpoints are rate of major pathological response (10% tumor cells in resected primary and lymph nodes on central review) and event-free survival (EFS). In addition, the dynamic expression change of PD-L1 with tumor heterogeneity also makes it difficult to evaluate the expression of PD-L1 (41). Liu J, Blake SJ, Yong MC, Harjunp H, Ngiow SF, Takeda K, et al. 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. In a landmark trial, a . PubMedGoogle Scholar. doi: 10.1038/s41591-020-01188-3, 65. N Engl J Med. Clinical outcomes were better than historical with 70% 1-year disease free survival and 85% 1-year overall survival. 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. BMC Med 15, 111 (2017). Google Scholar. Three trials are discussed that studied various forms of treatment de-intensification in patients with HPV-positive oropharyngeal carcinoma, including a phase 2 study by ECOG, RTOG 1016, and the De-ESCALaTE trial. Terms and Conditions, 2016;375(19):184555. Any pTR was seen in 44% and pTR-2 was seen in 22% of patients. Despite this multi-modality treatment, advanced human papillomavirus (HPV)-negative HNSCC shows poor prognosis. J Immunother Cancer (2021) 9(6):111. doi: 10.1038/nature12634, 50. 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. 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. The primary cancer (oral cavity) invades in various directions, which are color-coded vectors (arrows) representing stage of progression: Tis, yellow; T1, green; T2, blue; T3, purple; T4A, red; and T4B, black. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Nature (2013) 500(7463):41521. 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. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. 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: 10.1056/NEJMoa2002788, 31. Compared to our initial cohort with one dose, we found that 50% of patients had any pTR and 44% of patients exhibited pTR2. Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-nave patients with advanced melanoma (CheckMate 067). PD-L1 expression in tumor cells and immune cells remains the most widely used biomarker in HNSCC and other cancers (40, 41). Lancet Oncol. It remains the fifth leading cause of cancer in the United States and constitutes 10% or more of all cancers worldwide. Ang KK, et al. Both trials did not show a significant extension of OS and DFS, consistent with the subsequent studies (24, 25). Int J Radiat Oncol Biol Phys (1996) 36(5):9991004. volume15, Articlenumber:111 (2017) 1991;324:168590. J Clin Oncol (2021) 39(15_suppl):60088. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The checkmate 141 phase III trial evaluated the effect of anti-PD-1 (nivolumab) for R/M HNSCC patients (12). 2015;373(1):2334. The BATTLE-2 Study: a biomarker-integrated targeted therapy study in previously treated patients with advanced nonsmall-cell lung cancer. More effective and cost-efficient phase II trial designs would rapidly lead to landmark trials and practice-changing results. BMC Med. Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemotherapy. Preoperative Chemotherapy in Advanced Resectable OCSCC: Long-Term Results of a Randomized Phase III Trial. that compared radiation therapy plus or minus cetuximab, and RTOG 0522 are included as landmark trials in the development of an organ preservation approach for the management of locoregionally advanced disease. Sholl LM. Piotr Rutkowski. The combinatorial therapy group did not significantly increase the CD8+ TILs. doi: 10.1016/S1470-2045(10)70017-6, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. cancer [2], melanoma [3, 4], STS [5], head and neck cancer [6]). This material is provided for educational purposes only and with the goal of encouraging further study about the landmark trials that have impacted oncology. Ann Oncol (2018) 29(8):185360. HPV-related oropharyngeal HNSCC shows better survival related to HPV-negative oropharyngeal HNSCCs. As described by ASO Editor-in-Chief, Kelly M. McMasters, MD, PhD, "The Landmark Series is designed to trace the origins of current multidisciplinary therapy for each type of solid tumor, and demonstrate the logical progression of clinical trials and other key evidence. Redman JM, Gibney GT, Atkins MB. 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. 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). Nat Commun (2021) 12(1):3349. doi: 10.1038/s41467-021-23355-x, 56. 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. An important consideration in neoadjuvant immunotherapy approaches is appropriate patient selection. 2016;35:4907. 2012;13(1):2532. In addition to this design, immunotherapy is being integrated in several neoadjuvant combinations with radiation or chemotherapy prior to surgery. We also highlight selected and recent practice-changing trials in chronic lymphocytic leukaemia as well as breast and gynaecological cancers, and review the advances offered by the development of novel clinical trial designs. The premise of neoadjuvant immunotherapy is to use the existing tumor mass as an in-situ source of tumor-specific antigens to enhance systemic immunity via dendritic cell antigen presentation to rejuvenate T cells and priming especially for cytotoxic T cells (34). 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. These early studies led to two randomized Phase III trials, which provided Level 1 evidence supporting the use of concurrent chemoradiotherapy in high-risk HNSCC patients (57). These included oral mucositis and one patient with autoimmune diabetes (68) and there were no surgical delays. The Checkmate 358 phase I/II study examined clinical safety and efficacy of two doses of neoadjuvant nivolumab in HPV positive or negative HNSCC (NCT02488759) (67). To be eligible, patients had to have N2 or N3 adenopathy. In addition to the adjuvant chemotherapy, platinum-based neoadjuvant chemotherapy (induction chemotherapy; IC) has also been examined to augment subsequent (chemo)radiotherapy or surgery. Furthermore, although distinct tumor-suppressor mutations including TP53, CDKN2A, NOTCH have been reported in HNSCC, cancer-promoting driver oncogenic mutations have not been detected (911), which makes it challenging to apply molecular targeted therapies. 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. 2009;86(1):97100. Lancet Oncol. N Engl J Med. In the KEYNOTE-048 phase III trial, significant survival benefit of pembrolizumab for patients was seen with PD-L1 expression 1% and 20% by CPS (14). Saad ED, Paoletti X, Burzykowski T, Buyse M. Precision medicine needs randomized clinical trials. Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. Several landmark trials established the clinical benefit of using cisplatin-based chemoradiotherapy after surgery for locally advanced, . 2011;12(2):1539. Abstract. Ferris RL, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. We classified pTR into pTR-0 (10%), pTR-1 (10-49%), and pTR-2 (50%) (54). Both trials demonstrated significant benefit for maintenance PARP inhibitors in all subgroups of platinum-sensitive relapsed high-grade serous ovarian cancer. This was nearly double what we saw with one dose of pembrolizumab. BMC Medicine Per standard of care, postoperative RT or CCRT were performed, and adjuvant pembrolizumab treatment was used in high-risk patients with positive surgical margins or extra-nodal extension. A. Understanding Patterns of Pathologic Response Following Neoadjuvant Immunotherapy for Solid Tumors. 2013;31(36):45628. 11:727433. doi: 10.3389/fonc.2021.727433. 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). Following this, the phase III KEYNOTE-048 trial established a new paradigm for first-line R/M HNSCC patients (14). doi: 10.1038/s41591-020-0805-8, 36. These data together support further investigation in Phase III trials such as KEYNOTE-689 to define evidence for survival benefit and identify high-risk patients who may benefit from this approach. doi: 10.1158/1078-0432.CCR-20-1695, 55. Ther Adv Med Oncol (2021) 13:1758835920984061. doi: 10.1177/1758835920984061, 40. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. We reported a phase II trial, in which neoadjuvant/adjuvant pembrolizumab was tested in locally advanced, resectable HPV-negative HNSCC patients (NCT02296684) (54). Below are current clinical trials. This trial included both definitive and salvage surgery patients. Safety and Tumor Responses With Lambrolizumab (Anti-PD-1) in Melanoma. Front Oncol (2020) 10:566315. doi: 10.3389/fonc.2020.566315, 66. 14 Articles, This article is part of the Research Topic, Rationale of Neoadjuvant Immunotherapy for HNSCC, Patient Selection for Neoadjuvant Immunotherapy, Biomarker Candidates for Neoadjuvant Immunotherapy, Pathologic Response Criteria for Neoadjuvant Immunotherapy, Clinical Studies of Neoadjuvant Immunotherapy for HNSCC, Immune Related Adverse Events in Neoadjuvant Immunotherapy Treated Patients, Creative Commons Attribution License (CC BY). Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance Among Tumor Antigen-Specific T Cells. Recent landmark immunotherapy trials - melanoma, Mandal R, enbabaolu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, et al. On the other hand, MPR represents 10% of residual viable tumor (63). In support of this, neoadjuvant anti-PD-1 treatment in a mouse HNSCC model resulted in conversion of functional immune-dominance and induced robust anti-cancer responses, supporting the application of neoadjuvant immunotherapy for HNSCC (38). J Clin Oncol (2015) 33(8):83645. doi: 10.1126/science.aax0182, 35. Int J Radiat Oncol Biol Phys (1992) 23(4):70513. Pathological complete response (pCR) and major pathologic response (MPR) are widely used as surrogate clinical endpoints for long-term survival (5962). Ann Oncol (2019) 30(1):4456. 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. These data highlight the difficulty of interpreting peripheral lymphocyte populations with clinical responses in HNSCC patients treated with neoadjuvant immunotherapy. Clin Lung Cancer (2020) 21(4):3418. Lancet Oncol. Thus, targeting immune suppression pathways with checkpoint inhibitors has been broadened to the exploration of therapeutic options in all HNSCC treatment settings. Indeed, ibrutinib demonstrated a survival advantage over chlorambucil despite the studys crossover design. 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.