J Clin Oncol (2019) 37(15_suppl):25755. 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. Kiong KL, Yao C, Lin FY, Bell D, Ferrarotto R, Weber RS, et al. CrossRef 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. J Clin Oncol. Article 2014;32(12):123641. 2004;350:246170. Table1 Completed neoadjuvant immunotherapy clinical trials. Ferrarotto R, Bell D, Rubin ML, Hutcheson KA, Johnson JM, Goepfert RP, et al. Safety and Tumor Responses With Lambrolizumab (Anti-PD-1) in Melanoma. SS: editing the manuscript. 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). doi: 10.1093/annonc/mdy507, 41. Oncoimmunology (2019) 8(5):e1581530. Neoadjuvant Checkpoint Blockade for Cancer Immunotherapy. Results from the CLEOPATRA trial in the metastatic setting of the same treatment have produced remarkable results [25]; the same combination produced a 56.5-month median OS compared with 40.8months achieved with trastuzumab and docetaxel alone, showing an increase of 15.7months to OS in the pertuzumab group. Liu J, Blake SJ, Yong MC, Harjunp H, Ngiow SF, Takeda K, et al. Patients also received 6 months of adjuvant nivolumab and lirilumab. The Head and Neck Cancer Immune Landscape and Its Immunotherapeutic Implications. 2015;113(5):699705. PD-1 and CTLA-4 Combination Blockade Expands Infiltrating T Cells and Reduces Regulatory T and Myeloid Cells Within B16 Melanoma Tumors. 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). Exclusive: combination of drugs causes tumours to vanish in some terminally ill patients, study finds A new cancer treatment can wipe out tumours in terminally ill head and neck cancer patients, scientists have discovered. Lancet. 2016;34(30):363847. 2015;373:162739. Recent clinical trials of neoadjuvant immunotherapy show promising results and this methodology has the potential to change the treatment algorithm of HNSCC. 2014;15(8):85261. Based on KEYNOTE-048, the FDA approved use of pembrolizumab monotherapy in the first-line for R/M HNSCC with CPS 1 and pembrolizumab plus platinum-based chemotherapy for those with CPS<1 R/M HNSCC (31). Phase 2, Open-Label, Single Arm Study, With BST-236 in Adults With R/R AML or Higher-Risk MDS. 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). Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. doi: 10.1016/S1470-2045(10)70017-6, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. PubMed Central 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). doi:10.1080/17474086.2017.1313108. First, neoadjuvant immunotherapies will enhance systemic T cell responses for tumor-specific antigens before surgery (34). BMC Med. E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynxECOG-ACRIN Cancer Research Group. 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. doi: 10.1093/annonc/mdy227, 58. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. J Clin Oncol. 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. Although only 15-20% of patients benefit, immunotherapies have been approved and widely used for recurrent and metastatic HNSCC. He has participated in several investigator-driven trials in melanoma and sarcoma. Ann Oncol (2018) 29(8):185360. doi: 10.1056/NEJMoa2002788, 31. 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. These data suggest that virus infection status impacts TMB as a biomarker. 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. 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. doi: 10.1056/NEJMoa031317, 24. N Engl J Med (2020) 383(13):121830. 2015;385(9980):187383. 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. 2016;17(6):791800. Lancet Oncol (2010) 11(8):7819. doi: 10.1158/1078-0432.CCR-19-2209, 39. In addition to the adjuvant chemotherapy, platinum-based neoadjuvant chemotherapy (induction chemotherapy; IC) has also been examined to augment subsequent (chemo)radiotherapy or surgery. 2006;64(1):4756. 2016;17(4):42539. PubMed Thus, targeting immune suppression pathways with checkpoint inhibitors has been broadened to the exploration of therapeutic options in all HNSCC treatment settings. The primary endpoint of this trial was comparison between arms of a change in the CD8+ tumor infiltrating lymphocyte (TIL) density. The EORTC 22931 and RTOG 9501 trials were published in 2004 and demonstrated that the addition of concurrent cisplatin chemotherapy to radiation therapy in the postoperative setting improved outcomes for selected (based on pathologic features) patients with squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx. doi: 10.1200/JCO.2019.37.15_suppl.2575, 73. Licitra L, Grandi C, Guzzo M, Mariani L, Lo Vullo S, Valvo F, et al. N Engl J Med. BMC Medicine Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. SM does not have any conflict of interest to disclose. In addition, adaptive designs for phase I combinations are being developed [40]. PubMed Central 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. 2016;375(19):184555. Notably, any pTR after neoadjuvant pembrolizumab correlated with baseline tumor PD-L1, immune infiltration, and IFN- activity, but not TMB. This is a preview of subscription content, access via your institution. Comprehensive Genomic Characterization of Head and Neck Squamous Cell Carcinomas. 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. JCI Insight (2016) 1(17):e89829. doi: 10.1016/S0360-3016(96)00430-0, 5. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. TMB is a potential predictive biomarker that also needs further exploration. Price KAR, Nichols AC, Shen CJ, Rammal A, Lang P, Palma DA, et al. These findings highlight the clinical importance to establish standard pathological criteria to accurately evaluate the therapeutic effect of neoadjuvant immunotherapy after definitive surgery. Ann Oncol (2014) 25(2):4626. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, 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. Lancet Oncol. The IMCISION study (NCT03003637) presented at ESMO 2020 is examining neoadjuvant nivolumab and ipilimumab for stage II-IVa HNSCC patients. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. Nature (2015) 517(7536):57682. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. The studies listed below represent the first major clinical trials to evaluate risk reduction for people at high risk of breast, prostate, lung, colorectal, ovarian, cervical, and lung cancer. NEngl J Med (2016) 375(19):185667. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. Nat Rev Clin Oncol. By using this website, you agree to our Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. A phase II trial was reported by Xiong etal. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Springer, Cham. Lancet (2019) 394(10212):191528. 2016;14(4):45073. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria Jr R, Conti I, Cosaert J, Schwartz GK. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus-Related Oropharyngeal Carcinomas. 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 [2], and head and neck cancer [6]. These results underscore that TPF IC is not recommended for survival benefit. 2016;34(8):78693. 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. (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). Secondary endpoints are OS, complete pathological response, and assessment of safety and tolerability. Article N Engl J Med. Rochester, Minn., Jacksonville, Fla. Indeed, ibrutinib demonstrated a survival advantage over chlorambucil despite the studys crossover design. PD-L1 expression in tumor cells and immune cells remains the most widely used biomarker in HNSCC and other cancers (40, 41). Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefbvre JL, Greiner RH, et al. Three trials dealing with nasopharynx cancer are discussed including the Intergroup 0099 trial and the MAC-NPC Collaborative Group meta-analysis which studied the role of chemotherapy. 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. Lancet (2014) 384(9938):16472. J Clin Oncol. Ann Oncol (2021) 32(5):66172. Cohen E, et al. In addition to radiation and immunotherapy combinations, other trials are testing chemotherapy/immunotherapy combinations. The Society for Immunotherapy of Cancer Consensus Statement on Immunotherapy for the Treatment of Squamous Cell Carcinoma of the Head and Neck (HNSCC). Nevertheless, the selection of systemic therapy must be strictly individualised and based upon several factors, including the histology and biological behaviour of the disease. BMC Cancer (2020) 20(1):229. doi: 10.1186/s12885-020-06726-3, 70. Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer. As mentioned above, to date neoadjuvant immunotherapy has been shown to be safe and has not resulted in surgical delays. Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance Among Tumor Antigen-Specific T Cells. Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, et al. Am Soc Clin Oncol Educ Book (2020) 40:113. All authors read and approved the final manuscript. doi: 10.1093/annonc/mdy218, 59. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. 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. Part of Springer Nature. Earl, H., Molica, S. & Rutkowski, P. Spotlight on landmark oncology trials: the latest evidence and novel trial designs. This was nearly double what we saw with one dose of pembrolizumab. Bayesian adaptive designs for biomarker trials with biomarker discovery. 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. No new safety signals were observed and there were no surgical delays. The BATTLE-2 Study: a biomarker-integrated targeted therapy study in previously treated patients with advanced nonsmall-cell lung cancer. The November 3, 2021 "Clinical Trial Endpoint Development" (12pm - 5:00 pm ET) will address Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. Despite this multi-modality treatment, advanced human papillomavirus (HPV)-negative HNSCC shows poor prognosis. Correspondence to Nat Med (2021) 27(2):3019. Furthermore, the one-year relapse rate in high-risk patients was 16.7%, which was lower than historical data. 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). He was/is member of the editorial board of Leukemia and Lymphoma, BMC Medicine, ISRN Hematology and International Journal of Hematologic Oncology. There were no treatment related delays thus achieving the primary safety endpoint. BMC Med 15, 111 (2017). There are several distinct mechanisms of how radiation and/or chemotherapy can work with immunotherapy and other have covered these topics. This was followed by BATTLE-2 [42], testing combination treatments in the same disease. Pignon JP, le Matre A, Maillard E, Bourhis J. Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC): An Update on 93 Randomised Trials and 17,346 Patients. Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemotherapy. However, although IC may help with surgical management, Phase III trial results showed no improvements in survival. PubMed Frezza AM, Stacchiotti S, Gronchi A. 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. 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. Ang KK, et al. 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). Science (2018) 362(6411):110. Head and neck cancer was the seventh most common cancer worldwide in 2018 (890,000 new cases and 450,000 deaths), 1 accounting for 3% of all cancers (51,540 new cases) and just over . Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial. Delay to Surgery After Neoadjuvant Chemotherapy in Head and Neck Squamous Cell Carcinoma Affects Oncologic Outcomes. Landmark Trials. These data suggest clinical tolerability and effectiveness of neoadjuvant immunotherapy. 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/. CAS A Randomized Phase III Trial Comparing Induction Chemotherapy Followed by Chemoradiotherapy Versus Chemoradiotherapy Alone as Treatment of Unresectable Head and Neck Cancer. Filter this list of studies by location, status and more. doi: 10.1038/nature12477, 51. Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer? These patients have the worst prognosis despite multimodality approaches and may benefit from neoadjuvant/adjuvant immunotherapy. Mehanna H, 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. Piotr Rutkowski. The landmark oncology trials highlighted in the BMC Medicine series Spotlight on landmark oncology trials and this editorial are recent trials that have produced practice-changing results for patients. A. However, a potential setback is represented by the control arm since chlorambucil is no longer regarded an adequate therapy in CLL [26]. Enhanced Pathologic Tumor Response With Two Cycles of Neoadjuvant Pembrolizumab in Surgically Resectable, Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma (HNSCC). Induction Chemotherapy Plus Radiation Compared With Surgery Plus Radiation in Patients With Advanced Laryngeal Cancer. 2014;89(1):1320. 2006;64(1):7782. Notably, the timing of immune checkpoint inhibitors may influence the outcome of cancer treatment (33). Tumour Regression in Non-Small-Cell Lung Cancer Following Neoadjuvant Therapy. Gillison ML, et al. 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. 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. An important consideration in neoadjuvant immunotherapy approaches is appropriate patient selection. 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). Ann Oncol (2014) 25(1):21625. Pan-Tumor Genomic Biomarkers for PD-1 Checkpoint Blockade-Based Immunotherapy. doi: 10.1200/JCO.2021.39.15_suppl.6053, 74. Furthermore, tertiary lymphoid structures (TLS) in the tumor bed are suggested tocontribute favorable outcome (55). He works very closely with national patient advocacy groups for GIST and sarcoma and is Chairman of the Melanoma Academy in Poland. doi: 10.1158/2159-8290.CD-16-0577, 38. For example, radiological tumor examination is widely used in Response Evaluation Criteria In Solid Tumors (RECIST) after organ preservation therapy including radiotherapy and chemotherapy. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new. We classified pTR into pTR-0 (10%), pTR-1 (10-49%), and pTR-2 (50%) (54). Atezolizumab versus docetaxel for patients with previously treated nonsmall-cell lung cancer (POPLAR): a multicentre, open label, phase 2 randomised controlled trial. Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. doi: 10.1038/s41591-020-01188-3, 65. A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course [37]. Cancer Discov (2016) 6(12):138299. Cohen EEW, Soulires D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. doi: 10.1200/JCO.2017.75.1644, 57. Ann Oncol (2019) 30(1):4456. PubMedGoogle Scholar, Yajnik, S. (2019). Therefore, in absence of data from this and similar trials, either therapeutic choice is adequate in the day-to-day practice. 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). The head and neck region is anatomically complex and serves essential functions such as eating, speaking, and breathing.